This is nothing that anyone doesn't already know, but every side effect is always described as being rare (http://scholar.google.com/scholar?q=%22is+a+rare%22+%22side+effect%22+OR+complication&hl=en&lr=). Is each of those 77,000+ side effects or complications always rare? This is just in relation to the last posting and the things I saw in it. I'm sorry to have to put this up on the blog, and it's deeply disturbing to me. But I'm going to put it up. This article is called "Finding Haystacks Full of Needles: From Opus to Osler" [Levine, 2005: (http://www.chestjournal.org/cgi/content/full/127/5/1488)(http://www.ncbi.nlm.nih.gov/pubmed/15888818)]. I'm not trying to make any kind of statement by posting this, and I know there's a daily need to use various forms of heparin. That's especially true in view of the absence of any substitute for it or source of more-reliably-nonimmunogenic heparan-based or heparin-like polymers. But the author discusses research estimating or finding evidence to indicate that there are 600,000 cases of thrombocytopenia associated with some forms of heparin (I'll call it "heparin-associated thrombocytopenia") each year. The condition is a form of autoimmunity and is driven by antibodies to different platelet proteins, etc. The research also estimates that 90,000 of those people die each year from it and that 300,000 of them experience thrombotic complications. The condition can go on for months and is very difficult to treat.
The author also notes that the condition is described as being "rare" in almost every instance in which it's discussed. It's fine to state that something is rare, if it is, in fact, rare or if one legitimately thinks it's rare (because of clinical experience, etc.). But one point of that article is that there's frequently a delay to the appearance of the devastating phase of the thrombogenicity, so that people may leave the hospital and may have been forced to discontinue the form of heparin (or may have not had any ill effects at all) and may then develop thromboses a month later. They may then go into the emergency room and be treated with heparin and deteriorate in a dramatic way, as one would expect. So some or many of the cases are probably never recognized. In any case, it's just one of those things. One could say that the researchers made inaccurate estimates of the deaths or complication rates, but I'll bet there's more research that's similar. I don't much feel like seeking it out, the way I wound up doing in the last posting.
Tuesday, June 30, 2009
Adenine Nucleotide Translocase and Mitochondrial Creatine Kinase Activities in the "Maintenance" of mtDNA Integrity; Relevance to Cytotoxic Therapies
This article [Palmieri et al., 2005: (http://hmg.oxfordjournals.org/cgi/content/full/14/20/3079)(http://www.ncbi.nlm.nih.gov/pubmed/16155110?dopt=Abstract)] is really interesting, and the authors described a patient who had no functional activity of the ANT1 isoform of the adenosine/adenine nucleotide translocase protein, which transports ADP into mitochondria and ATP out of the mitochondrial matrix, and had mitochondrial DNA (mtDNA) deletions in the skeletal muscles (and probably also the heart). The ANT1 isoform is the predominant isoform expressed in cardiac and skeletal muscles, and the authors describe the way the person had exercise intolerance and very gradual deterioration in fitness but did not demonstrate decompensated heart failure (Palmieri et al., 2005). The ANT1 isoform is also expressed in the brain, the authors say, but the authors say that the expression of the other isoforms is thought to be significant enough to compensate for the loss of functional ANT1 in different cell types in the brain (Palmieri et al., 2005).
That research may help explain the capacity of creatine supplementation to treat people who have mitochondrial disorders, and the mechanisms by which creatine can sometimes be beneficial in those conditions are not well-understood (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=creatine+monohydrate+mitochondrial). Not all of those studies have shown benefits, however. But creatine has sometimes been shown to decrease or abolish paracrystalline inclusions and other types of structural abnormalities in skeletal muscle mitochondria (or in the myocytes, more broadly). Even though creatine is clearly not a magic bullet, in any way, in the treatment of mitochondrial disorders, in my opinion, I do think there could be some potential, at low dosages, for creatine to prevent the accumulation of mtDNA deletions by its capacity to increase ADP recycling, via the functional coupling of mitochondrial creatine kinase activity (which is in the intermembrane space and intercristae space, outside the mitochondrial matrix) [Dolder et al., 2003: (http://www.jbc.org/cgi/content/full/M208705200)(http://www.ncbi.nlm.nih.gov/pubmed/12621025)] (it's actually thought to form complexes with ANT proteins) to adenine nucleotide translocase activity [Barbour et al., 1984: (http://www.jbc.org/cgi/reprint/259/13/8246)(http://www.ncbi.nlm.nih.gov/pubmed/6330105?dopt=Abstract); (http://scholar.google.com/scholar?q=%22nucleotide+translocase%22+%22creatine+kinase%22&hl=en&lr=)]. Essentially, ANT exports ATP from the mitochondrial matrix, and the activity of mitochondrial creatine kinase ensures, in the presence of an adequate pool of creatine, that ADP is recycled (it's the kinetics of the coupling reactions and spatial proximity, I think, that allow this to occur and to limit the loss of ADP, by diffusion, from the intermembrane space to the cytosol) back into the mitochondrial matrix. That's an oversimplification, but it conveys the concept. The intramitochondrial ADP pool has repeatedly been shown to be maintained, in a creatine-sensitive manner, somewhat or even largely independently of the cytosolic ADP pool, and the effect of creatine can be especially significant during ischemia, etc. This occurs despite the fact that there is no meaningful physical barrier (nothing like the inner mitochondrial membrane) to the diffusion of ADP from the intermembrane space to the cytosol proper. I guess the diffusion can be restricted to some extent, by the outer mitochondrial membrane, but I think the effect of the membrane is not all that significant.
It's important to note, though, that I think the therapeutic dosage range of creatine is fairly small (maybe 1-3 grams/day), but that's just my opinion. I think it has the potential, at higher dosages (or, conceivably, at any dosage in someone with liver disease, for example) to interfere with the transport of other guanidino compounds, including urea cycle intermediates, but that's just my opinion. I've discussed those issues in past postings.
There's actually more research showing that some bisphosphonates can induce apoptosis by forming either xenobiotic-and nucleotide-containing polyphosphates or can inhibit mevalonate-pathway enzymes and increase the formation of endogenous dinucleotide triphosphates, such as inosine triphosphoadenosine (IpppA), and those dinucleotides or dinucleotide-mimetics can inhibit adenine nucleotide translocase activity and thereby contribute to the pro-apoptotic effects of some bisphosphonates in cultured cells, etc. [Monkkonen et al., 2006: (http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1616989)(http://www.ncbi.nlm.nih.gov/pubmed/16402039)]. This is not always "bad," providing one can effectively target the cells one wants to target. In any case, I have to say that that mechanism doesn't sound very good to me, for many reasons, but that's just my opinion. And a person would obviously want to weigh the risks vs. the benefits in all of these cases and discuss all of those issues with one's doctor before doing anything. There are some case studies included in this search result list that are disturbing to me, and I really shouldn't get into some of these obscure topics sometimes (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=bisphosphonate+mitochondrial+translocase). I end up just finding more and more things I'd almost rather not know about, but I'm probably too idealistic.
That research may help explain the capacity of creatine supplementation to treat people who have mitochondrial disorders, and the mechanisms by which creatine can sometimes be beneficial in those conditions are not well-understood (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=creatine+monohydrate+mitochondrial). Not all of those studies have shown benefits, however. But creatine has sometimes been shown to decrease or abolish paracrystalline inclusions and other types of structural abnormalities in skeletal muscle mitochondria (or in the myocytes, more broadly). Even though creatine is clearly not a magic bullet, in any way, in the treatment of mitochondrial disorders, in my opinion, I do think there could be some potential, at low dosages, for creatine to prevent the accumulation of mtDNA deletions by its capacity to increase ADP recycling, via the functional coupling of mitochondrial creatine kinase activity (which is in the intermembrane space and intercristae space, outside the mitochondrial matrix) [Dolder et al., 2003: (http://www.jbc.org/cgi/content/full/M208705200)(http://www.ncbi.nlm.nih.gov/pubmed/12621025)] (it's actually thought to form complexes with ANT proteins) to adenine nucleotide translocase activity [Barbour et al., 1984: (http://www.jbc.org/cgi/reprint/259/13/8246)(http://www.ncbi.nlm.nih.gov/pubmed/6330105?dopt=Abstract); (http://scholar.google.com/scholar?q=%22nucleotide+translocase%22+%22creatine+kinase%22&hl=en&lr=)]. Essentially, ANT exports ATP from the mitochondrial matrix, and the activity of mitochondrial creatine kinase ensures, in the presence of an adequate pool of creatine, that ADP is recycled (it's the kinetics of the coupling reactions and spatial proximity, I think, that allow this to occur and to limit the loss of ADP, by diffusion, from the intermembrane space to the cytosol) back into the mitochondrial matrix. That's an oversimplification, but it conveys the concept. The intramitochondrial ADP pool has repeatedly been shown to be maintained, in a creatine-sensitive manner, somewhat or even largely independently of the cytosolic ADP pool, and the effect of creatine can be especially significant during ischemia, etc. This occurs despite the fact that there is no meaningful physical barrier (nothing like the inner mitochondrial membrane) to the diffusion of ADP from the intermembrane space to the cytosol proper. I guess the diffusion can be restricted to some extent, by the outer mitochondrial membrane, but I think the effect of the membrane is not all that significant.
It's important to note, though, that I think the therapeutic dosage range of creatine is fairly small (maybe 1-3 grams/day), but that's just my opinion. I think it has the potential, at higher dosages (or, conceivably, at any dosage in someone with liver disease, for example) to interfere with the transport of other guanidino compounds, including urea cycle intermediates, but that's just my opinion. I've discussed those issues in past postings.
There's actually more research showing that some bisphosphonates can induce apoptosis by forming either xenobiotic-and nucleotide-containing polyphosphates or can inhibit mevalonate-pathway enzymes and increase the formation of endogenous dinucleotide triphosphates, such as inosine triphosphoadenosine (IpppA), and those dinucleotides or dinucleotide-mimetics can inhibit adenine nucleotide translocase activity and thereby contribute to the pro-apoptotic effects of some bisphosphonates in cultured cells, etc. [Monkkonen et al., 2006: (http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1616989)(http://www.ncbi.nlm.nih.gov/pubmed/16402039)]. This is not always "bad," providing one can effectively target the cells one wants to target. In any case, I have to say that that mechanism doesn't sound very good to me, for many reasons, but that's just my opinion. And a person would obviously want to weigh the risks vs. the benefits in all of these cases and discuss all of those issues with one's doctor before doing anything. There are some case studies included in this search result list that are disturbing to me, and I really shouldn't get into some of these obscure topics sometimes (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=bisphosphonate+mitochondrial+translocase). I end up just finding more and more things I'd almost rather not know about, but I'm probably too idealistic.
Monday, June 29, 2009
Endogenous Formation of Dinucleotide Polyphosphates: Crude Discussion of Interactions with the Mevalonate Pathway, Nucleotide Metabolism, and aa-tRNAs
This is an interesting article [Jankowski et al., 2009: (http://www.brjpharmacol.org/view/0/earlyView.html)], and the authors discuss the fact that dinucleotide polyphosphates (DNPP) are made endogenously and stored in platelets, adrenal chromaffin cells, and also neurons in the brain. The general formula for a DNPP is N-p(x)-N, where N = adenosine, guanosine, uridine, etc., and x = 2 to 7 phosphates linking two 5'-carbons of the ribose moieties of the nucleotides. Some common examples are diadenosine tetraphosphate (Ap4A) and Ap5A, Up4A (U = uridine), etc. That article doesn't discuss that much about their biosynthesis, but it turns out they're formed by aminoacyl-tRNA synthetases, just as the isoprenoid-based nucleotide polyphosphates are (see recent posting). They can also be formed by Ap4A phosphorylases, luciferase enzymes, and guanylyltransferases [Schluter et al., 1998: (http://www.pubmedcentral.nih.gov/picrender.fcgi?doi=10.1172/JCI119882&blobtype=pdf)(http://www.ncbi.nlm.nih.gov/pubmed/9449703)]. The different DNPP's have agonist and antagonist effects, at low concentrations, on purinergic receptors, and the article by Jankowski et al. (2009) catalogues a lot of those effects on platelet aggregation, etc. They're apparently degraded fairly slowly by various hydrolase enzymes.
So I guess to understand the interactions of cholesterol and nucleotide metabolism, one should read about the regulation of aminoacyl-tRNA synthetases. That's bizarre, but it seems interesting. It looks like the DNPP's have both "good" and "bad" effects, as one might expect, and it sounds like the concentrations can be fairly high, in the millimolar range, in vesicles in neurons or in platelet secretory granules. They basically are thought to act locally, the way purines and other nucleotides act on purinergic receptors. The plasma concentrations of different diadenosine oligophosphates/polyphosphates are 0.18 to 0.89 uM, but Jankowski et al. (2009) think that they may act locally on platelets and influence platelet aggregation under some circumstances. It sounds like one effect might be on phosphate homeostasis, as the authors of that article on isopentenyl-ATP derivatives were implying and suggesting. It seems like there may be a tendency to focus a lot on the effects of DNPP's on purinergic receptors, but it sounds like the intracellular effects might be more important. I haven't read much of anything on this topic yet, and there's probably some research about that type of thing. Maybe they regulate cholesterol metabolism or interfere with nucleotide transport. Some genetic mutations that affect nucleotide transport can cause mtDNA depletion, and then there are the more short-term effects (of DNPP's), such as on respiration, that could potentially occur via the inhibition of the adenine nucleotide translocase transporter. I wonder if there's anything on mRNA stability or something like that or on transcription. Presumably there are all sorts of potential pathological effects, but I actually don't know anything about the mechanisms governing the intracellular transport of DNPP's. I also don't know what factors regulate their formation by the aminoacyl-tRNA synthetases or by other enzymes. Schluter et al. (1998) say that the half lives of various DNPP's range from 49 to 69 minutes, and those are much longer than the half-lives of purines. The half-life of plasma adenosine is about 0.5 to 1.5 seconds.
It's interesting that Schluter et al. (1998) say that the aminoacyl-tRNA synthetases transfer the AMP of an aminoacyl-AMP to a nucleotide diphosphate or triphosphate and form the DNPP and also release an amino acid. I wonder if there's some kind of specificity to the aminoacyl-tRNAs that form specific DNPP's. If there were (I have no idea if there is), then that could explain some of these strange effects of different amino acids. That could explain some of the puzzling effects of glutamine, such as its antiapoptotic effects. For example, glutaminyl-tRNA synthetase [Ko et al., 2001: (http://www.jbc.org/cgi/content/full/276/8/6030)(http://www.ncbi.nlm.nih.gov/pubmed/11096076?dopt=Abstract)] produces antiapoptotic effects, in a glutamine-dependent manner, by obscure mechanisms. Ko et al. (2001) discuss some of the mechanisms by which glutaminyl-tRNA synthetase may contribute to the supposed antiapoptotic effects of glutamine. Maybe there's some intermediary influence of glutaminyl-tRNA-derived DNPP's in the antiapoptotic effects of glutamine, under some circumstances. I mean, maybe the DNPP formation is facilitated in some way by protein-protein interactions of glutaminyl-tRNA synthetase and some other protein [even the apoptosis signal-regulating kinase 1, discussed by Ko et al. (2001), that interacts with glutaminyl-tRNA synthetase, etc.]. Those are crude ideas, but it's interesting. The article by Ko et al. (2001) discusses the effects of glutamine on various mitogen-activated protein kinase pathways.
So I guess to understand the interactions of cholesterol and nucleotide metabolism, one should read about the regulation of aminoacyl-tRNA synthetases. That's bizarre, but it seems interesting. It looks like the DNPP's have both "good" and "bad" effects, as one might expect, and it sounds like the concentrations can be fairly high, in the millimolar range, in vesicles in neurons or in platelet secretory granules. They basically are thought to act locally, the way purines and other nucleotides act on purinergic receptors. The plasma concentrations of different diadenosine oligophosphates/polyphosphates are 0.18 to 0.89 uM, but Jankowski et al. (2009) think that they may act locally on platelets and influence platelet aggregation under some circumstances. It sounds like one effect might be on phosphate homeostasis, as the authors of that article on isopentenyl-ATP derivatives were implying and suggesting. It seems like there may be a tendency to focus a lot on the effects of DNPP's on purinergic receptors, but it sounds like the intracellular effects might be more important. I haven't read much of anything on this topic yet, and there's probably some research about that type of thing. Maybe they regulate cholesterol metabolism or interfere with nucleotide transport. Some genetic mutations that affect nucleotide transport can cause mtDNA depletion, and then there are the more short-term effects (of DNPP's), such as on respiration, that could potentially occur via the inhibition of the adenine nucleotide translocase transporter. I wonder if there's anything on mRNA stability or something like that or on transcription. Presumably there are all sorts of potential pathological effects, but I actually don't know anything about the mechanisms governing the intracellular transport of DNPP's. I also don't know what factors regulate their formation by the aminoacyl-tRNA synthetases or by other enzymes. Schluter et al. (1998) say that the half lives of various DNPP's range from 49 to 69 minutes, and those are much longer than the half-lives of purines. The half-life of plasma adenosine is about 0.5 to 1.5 seconds.
It's interesting that Schluter et al. (1998) say that the aminoacyl-tRNA synthetases transfer the AMP of an aminoacyl-AMP to a nucleotide diphosphate or triphosphate and form the DNPP and also release an amino acid. I wonder if there's some kind of specificity to the aminoacyl-tRNAs that form specific DNPP's. If there were (I have no idea if there is), then that could explain some of these strange effects of different amino acids. That could explain some of the puzzling effects of glutamine, such as its antiapoptotic effects. For example, glutaminyl-tRNA synthetase [Ko et al., 2001: (http://www.jbc.org/cgi/content/full/276/8/6030)(http://www.ncbi.nlm.nih.gov/pubmed/11096076?dopt=Abstract)] produces antiapoptotic effects, in a glutamine-dependent manner, by obscure mechanisms. Ko et al. (2001) discuss some of the mechanisms by which glutaminyl-tRNA synthetase may contribute to the supposed antiapoptotic effects of glutamine. Maybe there's some intermediary influence of glutaminyl-tRNA-derived DNPP's in the antiapoptotic effects of glutamine, under some circumstances. I mean, maybe the DNPP formation is facilitated in some way by protein-protein interactions of glutaminyl-tRNA synthetase and some other protein [even the apoptosis signal-regulating kinase 1, discussed by Ko et al. (2001), that interacts with glutaminyl-tRNA synthetase, etc.]. Those are crude ideas, but it's interesting. The article by Ko et al. (2001) discusses the effects of glutamine on various mitogen-activated protein kinase pathways.
Correction on Past Posting
In reference to this price difference I alluded to in a recent posting (http://hardcorephysiologyfun.blogspot.com/2009/06/note-on-triacetyluridine.html), I was going to mention that I remembered it incorrectly. I didn't check it when I did that posting, but it looks like it's about a 9-fold difference in price. That's still a fairly big difference. I've actually never seen such a large difference for that type of thing.
Sunday, June 28, 2009
A Glimmer of Clarity and Understanding About the Significance of Serum Alkaline Phosphatase, in Relation to Vitamin B6 and Vitamin D
This is a complex and difficult-to-understand area of research, for various reasons, but some of these articles have helped me to sort of understand the alkaline phosphatase issue. The authors of this article [Lomashvili et al., 2004: (http://jasn.asnjournals.org/cgi/content/full/15/6/1392)(http://www.ncbi.nlm.nih.gov/pubmed/15153550?dopt=Abstract)] discuss evidence that elevated alkaline phosphatase activity, either on the plasma membranes of smooth muscle cells or in soluble form, apparently, in the plasma, hydrolyzes pyrophosphate (P03-O-PO3)(4-) (PPi) and thereby prevents the inhibition of vascular calcification that PPi is thought to confer, even in the presence of elevated levels of free calcium Ca2+ and inorganic PO4(3-) (PO4). Vitamin B6 repletion/supplementation and vitamin D3 repletion generally decrease serum alkaline phosphatase (ALP) and may reduce calcification, in part, by those mechanisms (to the extent that reductions in free ALP activity reflect some changes at the sites of calcification). Matias et al. (2009) [Matias et al., 2009: (http://www.ncbi.nlm.nih.gov/pubmed/18775809?dopt=Abstract)], for example, found that 25-hydroxyvitamin D concentrations correlated inversely with the extents of vascular calcification among patients with renal failure. The PPI is thought to bind to sites of existing calcification and block PO4 from binding and forming more hydroxyapatite crystals. I cited some of the articles showing the vitamin B6 associations and mechanisms, in relation to ALP, in some past postings [(http://hardcorephysiologyfun.blogspot.com/2009/01/another-article-mentioning-plp-in.html); (http://hardcorephysiologyfun.blogspot.com/2009/01/pyridoxine-calcium-channels-and.html)].
This is a really confusing area of research, and it's still not clear to me what the origin of serum ALP is. Supposedly serum ALP decreases as bone turnover decreases, and Regidor et al. (2008) [Regidor et al., 2008: (http://www.asn-online.org/press/pdf/2008-Media/Kalantar-Zadeh-Bone%20Disease%20Study.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/18667733)] discussed the fact that extreme and pathological decreases in bone turnover (such as might result from some of the osteoclast-and-monocyte-macrophage-lineage-cell-cytotoxic approaches to treating bone demineralization) can decrease serum ALP to pathologically low levels. I don't think those kinds of decreases would occur in response to reasonable dosages of supplemental vitamin D, but the increases in serum calcium that tend to result from either excessive vitamin D or calcium supplementation could, in my opinion, promote thrombogenic effects (hypercoagulability, etc.) (http://hardcorephysiologyfun.blogspot.com/2009/01/calcium-magnesium-serum-calcium-vitamin.html). The article by Seelig (1990) is especially good, and here are two articles that discuss those issues and that are cited in that old posting [Ruttmann et al., 2007:(http://www.anesthesiaanalgesia.org/cgi/content/full/104/6/1475) (http://www.ncbi.nlm.nih.gov/pubmed/17513645); Seelig, 1990: (http://www.ncbi.nlm.nih.gov/pubmed/2132751)]. Supposedly the actual serum ALP activity is partially a result of ALP, which acts extracellularly, on the plasma membranes of neutrophils, etc. I just read through an editorial and a couple of articles on ALP and calcification, and the researchers talk about the way no one really understands research on ALP. They don't say that, but they discuss the fact that it's not entirely clear if it's active on neutrophils or other cell types and then cleaved into a soluble form or what is even going on. It sounds like serum ALP is sort of like serum soluble transferrin receptor (sTfR), in the sense that serum ALP is normally produced, released upon cleavage of the membrane-anchored form during apoptosis (?), at some rate that correlates with the rate of turnover of osteoclasts and osteoblasts. But it can be elevated in cholestatic liver disease also (see 2nd old posting on vitamin B6 and ALP), etc. I guess this one article that I don't have time to cite right now says that serum ALP is enzymatically active but doesn't contribute to PPi cleavage. The authors also say that serum ALP don't correlate with serum PPi and that it's mainly the ALP expressed by smooth muscle cells that hydrolyzes PPi locally and is thought to thereby contribute to calcification (by forming PO4 locally, from PPi). The authors say no one knows why vascular calcification nonetheless seems to correlate with changes in bone turnover. I'm not sure what the correlation is that they're referring to, but presumably they're saying that increases in calcification accompany extremely low levels of bone turnover (presumably as a result of localized decreases in extracellular PPi at sites of vascular calcification, if one accepts the validity of these associations and mechanisms). They're saying they don't know how the expression and activity of smooth-muscle-cell ALP could be changed in association with changes in osteoblast apoptosis (and with the associated changes in serum ALP that do not contribute significantly to the localized cleavage of PPi, on the plasma membranes of the smooth muscle cells).
The research on vitamin B6 and ALP is just really confusing to everyone who reads it, seemingly, and to me. I can understand the basics--that plasma-membrane ALP cleaves albumin-bound pyridoxal-5'-phosphate (PLP) into pyridoxal, which then enters cells and is rephosphorylated, to PLP, by pyridoxal kinase. Humans and animals that have genetic mutations that decrease the activities of one or more of their alkaline phosphatase isoforms apparently have elevated serum PLP levels but have functional B6 deficiency, because ALP is required for the uptake of pyridoxal into cells (as discussed above). But it's not at all clear to me what the mechanism is by which an increase in B6 intake would decrease serum ALP. It's not an especially enjoyable topic to read about. I also think that excesses of B6 could produce neuropathy, in part, by decreasing ALP excessively, but that's just my opinion. And excesses of vitamin D intake could promote vascular calcification by elevating serum calcium, given that the traditional focus on the [Ca] x [PO4] product, as a factor whose elevation is associated with an increase in the extent calcification, shouldn't just be completely discounted or ignored. Everyone still seems to think taking a lot of calcium supplementation, beyond the RDA or whatever, is a good idea. I don't think it is, and I think people don't realize the manifold factors that can prevent the absorption or retention of dietary magnesium. I've discussed some of them in past postings and have discussed some of the dosage ranges that have been applied to extreme states, such as liver disease, in which magnesium absorption can become compromised. The dosage range for magnesium is fairly large, and I don't know what the right dosage is. That's the type of thing one would want to discuss with one's doctor.
This is a really confusing area of research, and it's still not clear to me what the origin of serum ALP is. Supposedly serum ALP decreases as bone turnover decreases, and Regidor et al. (2008) [Regidor et al., 2008: (http://www.asn-online.org/press/pdf/2008-Media/Kalantar-Zadeh-Bone%20Disease%20Study.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/18667733)] discussed the fact that extreme and pathological decreases in bone turnover (such as might result from some of the osteoclast-and-monocyte-macrophage-lineage-cell-cytotoxic approaches to treating bone demineralization) can decrease serum ALP to pathologically low levels. I don't think those kinds of decreases would occur in response to reasonable dosages of supplemental vitamin D, but the increases in serum calcium that tend to result from either excessive vitamin D or calcium supplementation could, in my opinion, promote thrombogenic effects (hypercoagulability, etc.) (http://hardcorephysiologyfun.blogspot.com/2009/01/calcium-magnesium-serum-calcium-vitamin.html). The article by Seelig (1990) is especially good, and here are two articles that discuss those issues and that are cited in that old posting [Ruttmann et al., 2007:(http://www.anesthesiaanalgesia.org/cgi/content/full/104/6/1475) (http://www.ncbi.nlm.nih.gov/pubmed/17513645); Seelig, 1990: (http://www.ncbi.nlm.nih.gov/pubmed/2132751)]. Supposedly the actual serum ALP activity is partially a result of ALP, which acts extracellularly, on the plasma membranes of neutrophils, etc. I just read through an editorial and a couple of articles on ALP and calcification, and the researchers talk about the way no one really understands research on ALP. They don't say that, but they discuss the fact that it's not entirely clear if it's active on neutrophils or other cell types and then cleaved into a soluble form or what is even going on. It sounds like serum ALP is sort of like serum soluble transferrin receptor (sTfR), in the sense that serum ALP is normally produced, released upon cleavage of the membrane-anchored form during apoptosis (?), at some rate that correlates with the rate of turnover of osteoclasts and osteoblasts. But it can be elevated in cholestatic liver disease also (see 2nd old posting on vitamin B6 and ALP), etc. I guess this one article that I don't have time to cite right now says that serum ALP is enzymatically active but doesn't contribute to PPi cleavage. The authors also say that serum ALP don't correlate with serum PPi and that it's mainly the ALP expressed by smooth muscle cells that hydrolyzes PPi locally and is thought to thereby contribute to calcification (by forming PO4 locally, from PPi). The authors say no one knows why vascular calcification nonetheless seems to correlate with changes in bone turnover. I'm not sure what the correlation is that they're referring to, but presumably they're saying that increases in calcification accompany extremely low levels of bone turnover (presumably as a result of localized decreases in extracellular PPi at sites of vascular calcification, if one accepts the validity of these associations and mechanisms). They're saying they don't know how the expression and activity of smooth-muscle-cell ALP could be changed in association with changes in osteoblast apoptosis (and with the associated changes in serum ALP that do not contribute significantly to the localized cleavage of PPi, on the plasma membranes of the smooth muscle cells).
The research on vitamin B6 and ALP is just really confusing to everyone who reads it, seemingly, and to me. I can understand the basics--that plasma-membrane ALP cleaves albumin-bound pyridoxal-5'-phosphate (PLP) into pyridoxal, which then enters cells and is rephosphorylated, to PLP, by pyridoxal kinase. Humans and animals that have genetic mutations that decrease the activities of one or more of their alkaline phosphatase isoforms apparently have elevated serum PLP levels but have functional B6 deficiency, because ALP is required for the uptake of pyridoxal into cells (as discussed above). But it's not at all clear to me what the mechanism is by which an increase in B6 intake would decrease serum ALP. It's not an especially enjoyable topic to read about. I also think that excesses of B6 could produce neuropathy, in part, by decreasing ALP excessively, but that's just my opinion. And excesses of vitamin D intake could promote vascular calcification by elevating serum calcium, given that the traditional focus on the [Ca] x [PO4] product, as a factor whose elevation is associated with an increase in the extent calcification, shouldn't just be completely discounted or ignored. Everyone still seems to think taking a lot of calcium supplementation, beyond the RDA or whatever, is a good idea. I don't think it is, and I think people don't realize the manifold factors that can prevent the absorption or retention of dietary magnesium. I've discussed some of them in past postings and have discussed some of the dosage ranges that have been applied to extreme states, such as liver disease, in which magnesium absorption can become compromised. The dosage range for magnesium is fairly large, and I don't know what the right dosage is. That's the type of thing one would want to discuss with one's doctor.
Formation of ATP Derivatives of Intermediates in Cholesterol Biosynthesis: Potential Relevance to Energy Metabolism in the Brain, etc.
This article [Sillero et al., 2009: (http://www.ncbi.nlm.nih.gov/pubmed/19414000)] discuss the capacity of some bisphosphonates to inhibit farnesyl pyrophosphate synthetase, thereby inhibiting cholesterol biosynthesis and also the posttranslational prenylation of GTPases and other proteins. The authors also found that a variety of ligase enzymes, such as DNA ligases, apparently, cleave ATP and, as part of their catalytic mechanisms, attach the AMP derived from that cleavage to the ligase enzyme or to a cosubstrate, X (it's not clear what the cosubstrates are, and I don't feel like looking them up). This forms an E-X-AMP or E-AMP complex of AMP with the enzyme. Some of the ligase enzymes can then transfer the AMP to isopentenyl pyrophosphate (Iso-pp) or to a bisphosphonate and form Iso-pppAdenosine or "ATP derivatives" of bisphosphonates that may contribute to the induction of apoptosis in osteoclasts or monocyte-macrophage lineage cells, including osteoclast progenitor cells. One mechanism by which these ATP derivatives are thought to cause apoptosis is through the inhibition of the mitochondrial adenine nucleotide translocase transporter. Faust et al. (1980) [Faust et al., 1980: (http://www.jbc.org/cgi/reprint/255/14/6546.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/7391033)] found that aminoacyl-tRNA synthetases could form delta2-isopentenyl-tRNA, and those tRNAs are similar to the ATP derivatives, discussed above, in the sense that the isopentenyl group is transfered to the N6 nitrogen atom of an adenosine that is part of the tRNA. Faust et al. (1980) claim that, when cholesterol levels are low in some cells, more mevalonate is diverted into cholesterol formation than into ubiquinone and isopentenyl derivatives (isopentenyladenosine is one commonly-discussed derivative, and I'm actually forgetting if that's the same thing as Iso-pppAdenosine or is different from that). I don't know that that's true, because supposedly the ubiquinone pathway, at least, is maintained very efficiently under almost all circumstances, as I recall. It's only when HMG-CoA reductase activity has become greatly decreased that ubiquinone formation decreases, as I remember. But Faust et al. (1980) nonetheless show that inhibiting HMG-CoA reductase can decrease mevalonate levels, as is well-known, and thereby reduce the formation of some of these endogenous isopentenyl-adenosine derivatives (either free Iso- derived species or tRNA-bound derivatives, etc.).
This could be relevant to the roles that decreases in the neuronal or astrocytic cholesterol contents may play in the etiologies of neurodegenerative or psychiatric conditions, in my view. If the cellular cholesterol concentration that is capable of influencing HMG-CoA reductase activity in a cell in the brain were to be too low to maintain low levels of these nucleotide derivatives of isoprenoids, it's conceivable that that could, in some way, influence energy metabolism. The isopentenyl adenosine derivatives might interfere with nucleotide transport or contribute to DNA damage, etc. I haven't thought about the details of this, but Sillero et al. (2009) discuss the very large capacity of the mevalonate-derived isoprenoids and other cholesterol-biosynthetic intermediates to sequester pyrophosphate, and that could compromise adenosine nucleotide salvage. Fructose, for example, can cause ATP depletion in the liver by sequestering phosphate in one of the fructose bisphosphates (I forget which one), etc. These are fairly crude suggestions, but it's an interesting area of research.
This could be relevant to the roles that decreases in the neuronal or astrocytic cholesterol contents may play in the etiologies of neurodegenerative or psychiatric conditions, in my view. If the cellular cholesterol concentration that is capable of influencing HMG-CoA reductase activity in a cell in the brain were to be too low to maintain low levels of these nucleotide derivatives of isoprenoids, it's conceivable that that could, in some way, influence energy metabolism. The isopentenyl adenosine derivatives might interfere with nucleotide transport or contribute to DNA damage, etc. I haven't thought about the details of this, but Sillero et al. (2009) discuss the very large capacity of the mevalonate-derived isoprenoids and other cholesterol-biosynthetic intermediates to sequester pyrophosphate, and that could compromise adenosine nucleotide salvage. Fructose, for example, can cause ATP depletion in the liver by sequestering phosphate in one of the fructose bisphosphates (I forget which one), etc. These are fairly crude suggestions, but it's an interesting area of research.
Saturday, June 27, 2009
Note on Triacetyluridine and Uridine Prodrugs
I was going to mention that triacetyluridine, as discussed in a couple of recent postings, is not only being sold on that obscure website. If one searches on "google shopping," for example, one sees it for sale there. Some of the preparations, however, are sold at either 100 or 200 times the price that triacetyluridine is sold for on that obscure website that I linked to in a posting last winter. I forget the precise difference, but I did a quick calculation on it, when I did the posting in the winter. The company that anyone can look up the name of and that had been researching triacetyluridine has apparently moved on to the testing of RG2417, another uridine prodrug. I'm almost certain that it's just some other acyluridine, but the company is literally not revealing the identity of the compound. I can't find it online. The authors of this article [Tochigi et al., 2008: (http://www.ncbi.nlm.nih.gov/pubmed/18068248)] said, in 2008, that "A large-scale clinical trial of uridine (RG2417) for bipolar depression is underway" (Tochigi et al., 2008, p. 189). It's a uridine prodrug and is probably one of those more lipophilic acyluridines. That would be my guess. The description of it as an "intracellular mood stabilizer" (http://www.marketresearch.com/map/prod/1344386.html) implies that it may be more lipophilic than uridine or triacetyluridine and that it enters cells more readily (i.e. because it's more lipophilic, presumably to enhance entry into the brain). That's just my guess, though, my opinion. I'm not sure what an "extracellular mood stabilizer" would be--I guess one that doesn't actually enter cells. Triacetyluridine is or was designated RG2133 and was also named PN401, because a different company had previously owned the patents or been researching it. Maybe the secrecy is because of all of the controversy that occurred when PN401 (triacetyluridine) was first being researched in mitochondrial disorders. The people who had mitochondrial disorders really wanted PN401 and wanted it to be researched more, and there was just a mess with it. I think the people who wanted it knew, on some level, that it was so close to being identical to uridine itself that....well, I shouldn't talk about all of these issues anymore.
Adenosine vs. Ribose vs. AICAriboside for the Restoration of Adenosine Nucleotides in the Heart Following Ischemia
In this article [Mauser et al., 1985: (http://circres.ahajournals.org/cgi/reprint/56/2/220.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/3918804)], Mauser et al. (1985) show that the intraarterial infusion of adenosine produced a 90-fold increase in the rate of adenosine nucleotide resynthesis (mostly by purine salvage pathways), following cardiac ischemia in dogs, and infusions of equimolar dosages of ribose or AICAriboside produced only between 5-fold and 9-fold increases in the rate of adenosine nucleotide formation, by either the salvage or de novo pathways. Only adenosine significantly restored ATP levels, following ischemia. All of the compounds were infused intraarterially, into the left coronary arteries of the dogs.
This article shows, in my opinion, that adenosine is far superior to ribose as an approach to restoring adenosine nucleotide levels following their depletion, and the research casts doubt on the idea, as suggested by the authors of some articles, that the entries of the carbons of ribose, derived from exogenous purine nucleotides, into the nonoxidative pentose cycle and into glycolytic pathways make a substantial contribution to the purine-mediated protection of cultured cells, such as astrocytes, against death due to glucose deprivation or other conditions. In most of those articles, the only evidence that ribose mediates the protective effects is that purine nucleoside phosphorylase (PNP) inhibitors sometimes block the protective effects of exogenous purines. But, as discussed by other authors, that doesn't mean that the use of ribose as a glycolytic substrate mediates the protective effects of purines or that ribose can substitute for the preformed nucleotides. It may just mean that ribose-1-phosphate has to be derived from nucleoside phosphorolysis to maintain purine salvage and that, paradoxically, more purine nucleobases are lost when ribose is "locked" in nucleosides and nucleotides than are lost when some turnover of nucleoside-derived ribose is allowed to occur, via the PNP-mediated formation of ribose-1-phosphate and purine bases. Also, the inhibition of nucleoside phosphorolysis prevents the formation of uric acid from the exogenous purines, and some authors have suggested that uric acid-induced peroxynitrite scavenging may partially mediate the protective effects of purines on cultured cells. There's a lot of research showing that uric acid can maintain mitochondrial functioning, in cells in the liver or in other cells, by preventing the inactivation of respiratory-chain enzymes by peroxynitrite, etc. Additionally, adenosine is normally kept at a very low concentration intracellularly, and massive amounts of adenosine have to be supplied, normally, to produce adenosine-mediated toxic effects and S-adenosylhomocysteine accumulation, etc., in cells [usually 1 mM (1000 uM) or higher of extracellular adenosine is required, a concentration that is supraphysiological] [Adair, 2005: (http://ajpregu.physiology.org/cgi/content/full/289/2/R283)(http://www.ncbi.nlm.nih.gov/pubmed/16014444)]. If adenosine were to accumulate as a result of PNP inhibition, that accumulation could produce toxic effects. But adenosine is normally metabolized extremely rapidly.
The rate of de novo purine biosynthesis is extremely slow, and this is one reason, as Mauser et al. (1985) discussed, that AICAr did not produce very significant restorative effects on adenosine nucleotide levels. Ribose did not even appear to contribute much to purine salvage, in my opinion, in comparison to the effects of adenosine. Even if the effects of ribose depended on its metabolism into glycolytic intermediates, the presence of the preformed purine nucleotides, such as can be derived from exogenous adenosine, appear to be crucial and to be a limiting factor in the rate of ATP resynthesis and nucleotide replenishment following ischemia. There are other articles that provide similar data.
In the case of pyrimidines, the research showing that uridine phosphorylase (UP) inhibition can abolish the cytoprotective effects of exogenous uridine, as in astrocytes, tends to not take into account the role that UP is thought to play in the salvage of uracil in rodents and cultured astrocytes, etc. The traditional view is that pyrimidine bases are not salvaged and that pyrimidine salvage occurs only at the level of the whole nucleoside, meaning that the main salvage pathway for uridine, for example, is its phosphorylation to UMP by uridine kinase. Some of these articles discuss the fact that, in the brains of rodents, UP appears to play an "anabolic," rather than catabolic, role and to be required for pyrimidine salvage [Mascia et al., 1999, etc.: (http://scholar.google.com/scholar?q=%22uridine+phosphorylase%22+salvage&hl=en&lr=)]. Also, inhibition UP may indirectly inhibit purine salvage, given that UP inhibition would prevent uridine from serving as a source of ribose-1-phosphate. This could decrease the formation of PRPP from uridine-derived ribose-1-phosphate, thereby increasing the loss of purines and compromising both ATP formation and the ATP-dependent salvage of uridine, etc. The depletion of purines has been shown to lead to secondary depletion of pyrimidines, even in the context of the fructose-induced depletion of ATP from the liver. Fructose has been shown to transiently elevate plasma uridine levels, and that's very much a pathological effect, in my opinion. Some people seem to think that the fructose-induced elevation of plasma uric acid levels is "good" or desirable, given that uric acid scavenges peroxynitrite. But the elevations in uric acid levels, following fructose ingestion or infusion, are mainly the result of pronounced ATP depletion in the liver, in my opinion (and as shown by countless articles). That's not desirable. In any case, the articles in these areas are interesting.
This article shows, in my opinion, that adenosine is far superior to ribose as an approach to restoring adenosine nucleotide levels following their depletion, and the research casts doubt on the idea, as suggested by the authors of some articles, that the entries of the carbons of ribose, derived from exogenous purine nucleotides, into the nonoxidative pentose cycle and into glycolytic pathways make a substantial contribution to the purine-mediated protection of cultured cells, such as astrocytes, against death due to glucose deprivation or other conditions. In most of those articles, the only evidence that ribose mediates the protective effects is that purine nucleoside phosphorylase (PNP) inhibitors sometimes block the protective effects of exogenous purines. But, as discussed by other authors, that doesn't mean that the use of ribose as a glycolytic substrate mediates the protective effects of purines or that ribose can substitute for the preformed nucleotides. It may just mean that ribose-1-phosphate has to be derived from nucleoside phosphorolysis to maintain purine salvage and that, paradoxically, more purine nucleobases are lost when ribose is "locked" in nucleosides and nucleotides than are lost when some turnover of nucleoside-derived ribose is allowed to occur, via the PNP-mediated formation of ribose-1-phosphate and purine bases. Also, the inhibition of nucleoside phosphorolysis prevents the formation of uric acid from the exogenous purines, and some authors have suggested that uric acid-induced peroxynitrite scavenging may partially mediate the protective effects of purines on cultured cells. There's a lot of research showing that uric acid can maintain mitochondrial functioning, in cells in the liver or in other cells, by preventing the inactivation of respiratory-chain enzymes by peroxynitrite, etc. Additionally, adenosine is normally kept at a very low concentration intracellularly, and massive amounts of adenosine have to be supplied, normally, to produce adenosine-mediated toxic effects and S-adenosylhomocysteine accumulation, etc., in cells [usually 1 mM (1000 uM) or higher of extracellular adenosine is required, a concentration that is supraphysiological] [Adair, 2005: (http://ajpregu.physiology.org/cgi/content/full/289/2/R283)(http://www.ncbi.nlm.nih.gov/pubmed/16014444)]. If adenosine were to accumulate as a result of PNP inhibition, that accumulation could produce toxic effects. But adenosine is normally metabolized extremely rapidly.
The rate of de novo purine biosynthesis is extremely slow, and this is one reason, as Mauser et al. (1985) discussed, that AICAr did not produce very significant restorative effects on adenosine nucleotide levels. Ribose did not even appear to contribute much to purine salvage, in my opinion, in comparison to the effects of adenosine. Even if the effects of ribose depended on its metabolism into glycolytic intermediates, the presence of the preformed purine nucleotides, such as can be derived from exogenous adenosine, appear to be crucial and to be a limiting factor in the rate of ATP resynthesis and nucleotide replenishment following ischemia. There are other articles that provide similar data.
In the case of pyrimidines, the research showing that uridine phosphorylase (UP) inhibition can abolish the cytoprotective effects of exogenous uridine, as in astrocytes, tends to not take into account the role that UP is thought to play in the salvage of uracil in rodents and cultured astrocytes, etc. The traditional view is that pyrimidine bases are not salvaged and that pyrimidine salvage occurs only at the level of the whole nucleoside, meaning that the main salvage pathway for uridine, for example, is its phosphorylation to UMP by uridine kinase. Some of these articles discuss the fact that, in the brains of rodents, UP appears to play an "anabolic," rather than catabolic, role and to be required for pyrimidine salvage [Mascia et al., 1999, etc.: (http://scholar.google.com/scholar?q=%22uridine+phosphorylase%22+salvage&hl=en&lr=)]. Also, inhibition UP may indirectly inhibit purine salvage, given that UP inhibition would prevent uridine from serving as a source of ribose-1-phosphate. This could decrease the formation of PRPP from uridine-derived ribose-1-phosphate, thereby increasing the loss of purines and compromising both ATP formation and the ATP-dependent salvage of uridine, etc. The depletion of purines has been shown to lead to secondary depletion of pyrimidines, even in the context of the fructose-induced depletion of ATP from the liver. Fructose has been shown to transiently elevate plasma uridine levels, and that's very much a pathological effect, in my opinion. Some people seem to think that the fructose-induced elevation of plasma uric acid levels is "good" or desirable, given that uric acid scavenges peroxynitrite. But the elevations in uric acid levels, following fructose ingestion or infusion, are mainly the result of pronounced ATP depletion in the liver, in my opinion (and as shown by countless articles). That's not desirable. In any case, the articles in these areas are interesting.
Tuesday, June 23, 2009
Serum Uric Acid, Energy Metabolism, Sympathetic Activation, and Goal-Oriented Behavior or "Grant-Money-Getting" Behavior
This article [Hunter et al., 1990: (http://www.ncbi.nlm.nih.gov/pubmed/2345757)] is one that I cited in a previous posting (http://hardcorephysiologyfun.blogspot.com/2009/03/interactions-of-caffeine-with-purine.html), but I didn't have time to discuss some interesting research that Hunter et al. (1990) discuss and cite. There's old research showing positive associations of serum uric acid (UA) levels with goal-oriented behavior and, essentially, activity level in general, and there's also some more recent research looking at UA per se as being a supposedly-reliable mediator of hyperactivity or mania or whatever other conditions. What interests me is the reasons why UA might be associated with goal-oriented behavior. I remember that a professor I took a class from once mentioned research showing that higher serum UA levels were associated with more success in getting grant money (in successfully getting grants awarded, etc.). He was referring to old research, from the 1950's or 1960's, but I wonder if it doesn't have to do with brain activity in some generalized sense. There's a vast amount of research showing that electrical stimulation or glutamatergic stimulation or noradrenergic activity increases extracellular-fluid (ECF) adenosine and UA levels in the brain. It's a generalized response that may just have to do with an increase in the metabolic demands of neurons. I tend to think that the cerebral metabolic activity or noradrenergic activity might just be making people slightly more aggressive or driven and might be accompanied by increases in sympathetic outflow from the central nervous system, and that could account for the serum UA elevations. That type of process, however, would not mean that low serum UA levels could not also be associated with excessively-prolonged increases in noradrenergic activity and sympathetic activation. There could be a pathological activation that would eventually compromise beta-adrenergic sensitivity, such as in people with multiple sclerosis (in whom the serum UA levels tend to be very low). Astrocytic beta2-adrenoreceptor density and sensitivity has been reported to be very low in people with MS, and there's research associating prescriptions for asthma (specifically beta2-adrenoreceptor agonists) with lower incidences of MS. Obviously, taking beta-agonists would be potentially dangerous for people with MS, and one would want to discuss that type of thing with one's doctor. The association only was found when researchers looked at medical records across many years, also, although beta2-adrenoreceptor activation does tend to be anti-inflammatory and immunosuppressive. One could make the argument that robust increases and equally-robust decreases in noradrenergic activity in the brain, accompanied by augmentations in sympathetic outflow, would produce elevations in UA that would account for the associations of high serum UA with goal-oriented behavior. Poorly-regulated noradrenergic activity could conceivably lead to gradual, "functional sympathectomy-like" changes (reduced beta-adrenoreceptor sensitivity) that could produce decreases in serum UA, etc. This is very general and imprecise, but it's interesting to think about. Low serum UA is a generalized feature of a variety of intracranial disease states and is thought to be partially a result of poor osmoregulation in the brain, such that the sympathetic innervation of the kidneys changes. The decreases in functional, sympathetic innervation of the kidneys is thought to play more of a role in the etiology of cerebral salt wasting (CSW) than in the etiology of syndrome of inappropriate antidiuretic hormone secretion (SIADH). But there must be some more precise neurobiological changes that could account for the UA depletion that occurs in SIADH and CSW, and I'm not convinced that it only has to do with osmoregulatory failures per se or with changes in renal UA reabsorption. I think it might have to do with derangements in energy metabolism. Here's an interesting article that shows that the intramitochondrial UA levels are higher in rats with diabetes [Kristal et al., 1999: (http://www.ncbi.nlm.nih.gov/pubmed/10496973)]. But as the disease process and poor glycemic control in the rats' diabetes became more pronounced, the UA production normalized or decreased again. That's potentially really important for understanding why UA is low in people with MS, and it also casts serious doubt on the use of all of these association studies showing UA to be some kind of "independent" risk factor for (or variable independently-associated with) cardiovascular disease. One could claim to be able to control for insulin sensitivity in some association study, but that's unlikely to be possible. Energy metabolism, as related to insulin sensitivity, is far too complex to control for in an association study that looks at some blood tests from 20,000 people.
Perspectives on Reductionism, etc.
This is an obscure but interesting article [Haught, 2006: (http://www.metanexus.net/conference2007/pdf/Haught_What)], and the author discusses the ways in which factors outside of a given system or problem can be important for understanding the system or problem in question. The author discusses some of the writings of Pierre Teilhard de Chardin, etc. This is an interesting perspective from Teilhard on creativity:
"Love has always been carefully eliminated from realist and positivist concepts of the world; but sooner or later we shall have to acknowledge that it is the fundamental impulse of Life...with love omitted there is truly nothing ahead of us except the forbidding prospect of standardisation and enslavement—the doom of ants and termites...Love is the free and imaginative outpouring of the spirit over all unexplored paths" [Teilhard, 1959, cited in King, 2004: (http://cat.inist.fr/?aModele=afficheN&cpsidt=15629733)].
"Love has always been carefully eliminated from realist and positivist concepts of the world; but sooner or later we shall have to acknowledge that it is the fundamental impulse of Life...with love omitted there is truly nothing ahead of us except the forbidding prospect of standardisation and enslavement—the doom of ants and termites...Love is the free and imaginative outpouring of the spirit over all unexplored paths" [Teilhard, 1959, cited in King, 2004: (http://cat.inist.fr/?aModele=afficheN&cpsidt=15629733)].
Sunday, June 21, 2009
Pyridoxal 5'-Phosphate and P2 Purinergic Receptor Antagonism
This article [Alexander et al., 2008: (http://www.ncbi.nlm.nih.gov/pubmed/18381567)] discusses the results of a trial using 250 mg/day of oral pyridoxal 5'-phosphate (PLP, the coenzymated form of vitamin B6) to improve postsurgical outcomes following coronary bypass surgeries. There's a whole series of articles in which different authors argue that PLP acts as a pan-P2-purinergic receptor antagonist (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=P2+pyridoxal+purinergic+OR+purinoceptor) and blocks calcium influx into cells by that mechanism. It may be that that does occur, but there are many, many other effects of PLP. It's a cofactor for a large number of enzymes. I forget the number, but it's over 100. It looks like PLP can be more potent than pyridoxine (B6), the usual form of vitamin B6 that's used [Mason and Emerson, 1973: (http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1588335&blobtype=pdf)(http://www.ncbi.nlm.nih.gov/pubmed/4691061)]. That's similar to this article [Lee et al., 1966: (http://www.ncbi.nlm.nih.gov/pubmed/5931587)], which shows pronounced hematological effects of B6 in a person in a disease state [Natuzzi et al., 1999: (http://www.ncbi.nlm.nih.gov/pubmed/10682911)] [see discussion here: ((http://hardcorephysiologyfun.blogspot.com/2009/01/note-on-pyridoxine.html)]. The inhibition of calcium influx by P2 receptor antagonism could conceivably reduce platelet aggregation and account for some of the supposed protective effects [and for the decrease in the risk of deep vein thrombosis among people with higher serum PLP concentrations (http://hardcorephysiologyfun.blogspot.com/2009/01/note-on-pyridoxine.html)], but I would wonder if that type of effect wouldn't become maximal after a certain point. The effect of additional PLP on glutamate-oxaloacetate transaminase (aspartate aminotransferase) could also enhance mitochondrial functioning in the short term and account for some of the effects. Also, there's research showing that PLP can inhibit mitochondrial dicarboxylic acid transporters, such as for 2-oxoglutarate, etc. (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=pyridoxal+phosphate+%22oxoglutarate+carrier%22+OR+%22dicarboxylate+carrier%22+OR+%22dicarboxylate+transport%22). The article by Alexander et al. (2008) cited some articles showing protective effects of PLP, when given to people, after surgeries, for short periods of time.
I just am not sure why they're assuming that it's acting as a P2 antagonist in vivo. What are the EC50 (i.e. for inhibition of some effect that is reliably elicited by P2 receptor activation in vivo) or Ki values for the inhibition of P2 receptors by PLP, and what are the serum PLP values following oral PLP? For some cofactors and physiological substrates, it can be difficult to draw facile conclusions about EC50 values, based on known Ki values. It's often possible to predict meaningful inhibition in vivo, if one knows that the concentration of the ligand is likely to be near, in vivo and in the vicinity of the receptor in question, the Ki for receptor inhibition by that ligand. The Kd/EC50 (the coupling efficiency index, which is a way of looking at receptor-effector coupling) (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=%22Kd%2FEC50%22+coupling+efficiency) values tend to be somewhat predictable for drug agonists, and people sometimes assume that the EC50 is about the same as the Ki or Kd for a ligand (even for physiological ligands, such as GABA). The IC50 usually refers to some specific effect in an isolated system, such as the inhibition of ligand binding to a receptor. The EC50 refers to the concentration at which 50 percent of either an inhibitory or agonistic effect occurs in some system at large, such as in a cell or in vivo. Some people use the terms more loosely, but, for the purposes of some analyses, they're not the same thing. Some researchers look at selectivity indices, such as the IC50 (for cytotoxicity)/EC50(for antiviral effects in vitro or in vivo), etc. In any case, the Kd/EC50 values and Kd values themselves can be very strange for physiological ligands, particularly for something like PLP (which is metabolized and bound almost *everywhere* in the body). This article describes some of the pitfalls in drawing hasty conclusions about druglike effects of physiological ligands/substrates, such as GABA [Edgar et al., 1992: (http://www.ncbi.nlm.nih.gov/pubmed/1319548)]. It's not that one can't draw crude conclusions, but one has to be careful in drawing those conclusions. Vitamin B6 just has really big effects on lots of different functions and enzymes.
In my opinion, the main problem would be using PLP in the long term at such high dosages. Even though these trials look to be fairly short in duration, I've come to think that, in the long term, the therapeutic dosage range for B6 [note in the article by Mason and Emerson (1973) that PLP can be four or more times as potent as B6] is lower than most people might think. I don't know what the right dosage is, but, in my opinion, a long-term dosage range might be 25-75 mg/day. In past postings, I've discussed vitamin B6 in relation to glutamate-oxaloacetate transaminase (GOT) and glutamate/glutamine/2-oxoglutarate metabolism, and my current thinking is that that enzyme and maybe glutamate decarboxylase and glycogen phosphorylase (also PLP-dependent enzymes) contribute in important ways to a lot of the so-called therapeutic effects of B6 and PLP and also to their toxic effects. The effects of B6 or PLP supplementation on alkaline phosphatase activity are also likely to be important for some of the toxic effects at higher dosages (effects that would primarily emerge in the long term, in my opinion, but who's to say what the long term is). These are just my opinions, and they're not very specific statements. For example, increases in GOT activity could, in my opinion, accelerate the turnover and oxidation of tricarboxylic acid cycle substrates and cause problems. It's hard to think outside the box, when it comes to something like B6. I used to think that the absence of reports of peripheral neuropathy at doses below 100 mg/day (and the extreme rarity of reports at doses between 125 and 200 mg/day or so) meant that 100 mg/day would be a safe long-term dosage. I'm not sure I think that anymore. It doesn't make a lot of sense to think that, in part because I don't see any reason to think that toxic metabolites of B6 accumulate at those dosages. I think it produces a lot of different effects that change as one increases the dosage (and the effects of increasing PLP levels on some enzymes are larger than on others, etc.), but I don't think it's possible to clearly define what's a therapeutic effect and what isn't. For example, B6 supplementation tends to increase glycogenolysis (http://scholar.google.com/scholar?q=pyridoxine+glycogenolysis+OR+glycogenolytic&hl=en&lr=), and that could be beneficial, under some conditions, and also could become pathological, in conjunction with other effects of B6. The glycogenolytic effects are unlikely to be solely due to increases in catecholamine biosynthesis and release (i.e. by the PLP-dependent enzyme dopa decarboxylase), in my opinion, and I say that partly because fairly low dosages of B6 are used to treat McArdle's disease, a genetic disorder that impairs glycogenolysis (PLP is a cofactor for glycogen phosphorylase) (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=pyridoxine+McArdle%27s). (Myophosphorylase is the muscle-specific isoform of glycogen phosphorylase) When they say there's low muscle B6 or PLP in McArdle's disease, it's not because the disorder specifically affects B6 metabolism. It's almost certainly because there's an acceleration of B6 turnover, due to all the rhabdomyolysis and other metabolic stresses that occur in people who have the disorder. People who have McArdle's disease have a variety of different mutations that cause loss of function in myophosphorylase. In any case, the point is that saturating all or some or most of the PLP-dependent enzymes is not necessarily going to be beneficial, in my opinion, in the long term. There are no biochemical rules that say that PLP-dependent enzymes "should" be saturated or nearly saturated with their PLP cofactors or that the enzymes' saturation will produce saturation of "health potential" or whatever. I guess no one refers to anything in those terms, but I just wanted to make that point.
I just am not sure why they're assuming that it's acting as a P2 antagonist in vivo. What are the EC50 (i.e. for inhibition of some effect that is reliably elicited by P2 receptor activation in vivo) or Ki values for the inhibition of P2 receptors by PLP, and what are the serum PLP values following oral PLP? For some cofactors and physiological substrates, it can be difficult to draw facile conclusions about EC50 values, based on known Ki values. It's often possible to predict meaningful inhibition in vivo, if one knows that the concentration of the ligand is likely to be near, in vivo and in the vicinity of the receptor in question, the Ki for receptor inhibition by that ligand. The Kd/EC50 (the coupling efficiency index, which is a way of looking at receptor-effector coupling) (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=%22Kd%2FEC50%22+coupling+efficiency) values tend to be somewhat predictable for drug agonists, and people sometimes assume that the EC50 is about the same as the Ki or Kd for a ligand (even for physiological ligands, such as GABA). The IC50 usually refers to some specific effect in an isolated system, such as the inhibition of ligand binding to a receptor. The EC50 refers to the concentration at which 50 percent of either an inhibitory or agonistic effect occurs in some system at large, such as in a cell or in vivo. Some people use the terms more loosely, but, for the purposes of some analyses, they're not the same thing. Some researchers look at selectivity indices, such as the IC50 (for cytotoxicity)/EC50(for antiviral effects in vitro or in vivo), etc. In any case, the Kd/EC50 values and Kd values themselves can be very strange for physiological ligands, particularly for something like PLP (which is metabolized and bound almost *everywhere* in the body). This article describes some of the pitfalls in drawing hasty conclusions about druglike effects of physiological ligands/substrates, such as GABA [Edgar et al., 1992: (http://www.ncbi.nlm.nih.gov/pubmed/1319548)]. It's not that one can't draw crude conclusions, but one has to be careful in drawing those conclusions. Vitamin B6 just has really big effects on lots of different functions and enzymes.
In my opinion, the main problem would be using PLP in the long term at such high dosages. Even though these trials look to be fairly short in duration, I've come to think that, in the long term, the therapeutic dosage range for B6 [note in the article by Mason and Emerson (1973) that PLP can be four or more times as potent as B6] is lower than most people might think. I don't know what the right dosage is, but, in my opinion, a long-term dosage range might be 25-75 mg/day. In past postings, I've discussed vitamin B6 in relation to glutamate-oxaloacetate transaminase (GOT) and glutamate/glutamine/2-oxoglutarate metabolism, and my current thinking is that that enzyme and maybe glutamate decarboxylase and glycogen phosphorylase (also PLP-dependent enzymes) contribute in important ways to a lot of the so-called therapeutic effects of B6 and PLP and also to their toxic effects. The effects of B6 or PLP supplementation on alkaline phosphatase activity are also likely to be important for some of the toxic effects at higher dosages (effects that would primarily emerge in the long term, in my opinion, but who's to say what the long term is). These are just my opinions, and they're not very specific statements. For example, increases in GOT activity could, in my opinion, accelerate the turnover and oxidation of tricarboxylic acid cycle substrates and cause problems. It's hard to think outside the box, when it comes to something like B6. I used to think that the absence of reports of peripheral neuropathy at doses below 100 mg/day (and the extreme rarity of reports at doses between 125 and 200 mg/day or so) meant that 100 mg/day would be a safe long-term dosage. I'm not sure I think that anymore. It doesn't make a lot of sense to think that, in part because I don't see any reason to think that toxic metabolites of B6 accumulate at those dosages. I think it produces a lot of different effects that change as one increases the dosage (and the effects of increasing PLP levels on some enzymes are larger than on others, etc.), but I don't think it's possible to clearly define what's a therapeutic effect and what isn't. For example, B6 supplementation tends to increase glycogenolysis (http://scholar.google.com/scholar?q=pyridoxine+glycogenolysis+OR+glycogenolytic&hl=en&lr=), and that could be beneficial, under some conditions, and also could become pathological, in conjunction with other effects of B6. The glycogenolytic effects are unlikely to be solely due to increases in catecholamine biosynthesis and release (i.e. by the PLP-dependent enzyme dopa decarboxylase), in my opinion, and I say that partly because fairly low dosages of B6 are used to treat McArdle's disease, a genetic disorder that impairs glycogenolysis (PLP is a cofactor for glycogen phosphorylase) (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=pyridoxine+McArdle%27s). (Myophosphorylase is the muscle-specific isoform of glycogen phosphorylase) When they say there's low muscle B6 or PLP in McArdle's disease, it's not because the disorder specifically affects B6 metabolism. It's almost certainly because there's an acceleration of B6 turnover, due to all the rhabdomyolysis and other metabolic stresses that occur in people who have the disorder. People who have McArdle's disease have a variety of different mutations that cause loss of function in myophosphorylase. In any case, the point is that saturating all or some or most of the PLP-dependent enzymes is not necessarily going to be beneficial, in my opinion, in the long term. There are no biochemical rules that say that PLP-dependent enzymes "should" be saturated or nearly saturated with their PLP cofactors or that the enzymes' saturation will produce saturation of "health potential" or whatever. I guess no one refers to anything in those terms, but I just wanted to make that point.
Friday, June 19, 2009
Cholesterol in Steroid Hormone Biosynthesis; Cholesterol (and Vitamin D) in Hedgehog Signalling in the Brain and Liver
This is a great article [Kanat et al., 2007: (http://www.ncbi.nlm.nih.gov/pubmed/17234355)] that I cited in a recent posting (http://hardcorephysiologyfun.blogspot.com/2009/06/provocative-articles-showing-effects-of.html), and the authors discuss evidence that some cholesterol-lowering treatments may reduce the serum concentrations of testosterone, cortisol, or other adrenal steroid hormones. I remember seeing case reports of decreases in testosterone from some cholesterol-lowering approaches, but it's easy to "forget" that type of thing. I was just reading about the effects of squalene, a supplement that, in my opinion, doesn't sound very useful, on testosterone levels in animals, but, for some reason, that didn't remind me of the related avenues of research. Kanat et al. (2007) also mentioned that researchers had generally not found any increases in serum luteinizing hormone (LH) or follicle-stimulating hormone (FSH) in response to the decreases in serum testosterone. That's not that surprising, and I think that some people who write physiology textbooks or whatever other traditional reference "manuals" have this idea that the endocrinological regulatory mechanisms really work efficiently and "strictly" or "tightly" regulate the concentrations and cellular responses of hormones. It's hard for me to understand that, given the thousands of case studies and articles showing that failures in regulatory mechanisms are commonplace. That's a separate issue, though.
That article by Kanat et al. (2007) is disturbing to see, and it goes without saying that those reductions in cortisol and testosterone could conceivably also occur in people who have very low cholesterol levels and are not taking cholesterol-lowering drugs, in my opinion. In a person taking no medications, one would not expect to see pronounced inhibition of de novo cholesterol formation, such as can be produced by some cholesterol by the statins, in extrahepatic cells. But I wouldn't be surprised to see some of those changes in adrenal or gonadal steroid hormones showing up in people who have pathologically-low cholesterol levels. But that doesn't mean that increasing serum cholesterol is likely to just neatly fix endocrinological abnormalities, especially in a person who has extremely low serum cholesterol levels and is suicidally depressed, etc. So someone would obviously want to talk with his or her doctor about these issues. There are countless other possible causes of endocrinological abnormalities that have little to do with cholesterol.
There's quite a bit of interesting research showing that dietary cholesterol can improve some forms of liver disease in animal models, and there's this researcher who suggested that cholesterol supplementation could be used to treat liver disease (http://www.dukehealth.org/HealthLibrary/News/10021):
"Li pointed out that the findings could have other theoretical implications as well. He said giving alcoholics supplemental cholesterol could help slow down or prevent the occurrence of alcoholic liver disease, even chronic alcoholic induced cirrhosis, characterized by replacement of liver tissue by scar tissue, leading to progressive loss of liver function."
It's important to note that a lot of research shows that very high dietary cholesterol intakes in animals worsens the fatty liver disease that results from the animals' consumption of large amounts of dietary fat, etc. But many of the articles showing apparently therapeutic effects of cholesterol use much lower dosages than researchers have used in many of the dime-a-dozen articles on the effects of dietary cholesterol. I looked up some of the research that Li has been involved in, and it's interesting. He and his colleagues are researching some of the cell groups and signalling pathways, such as in relation to hedgehog signalling (by proteins such as sonic hedgehog (SHH), indian hedgehog, and desert hedgehog), that influence liver regeneration or repair, even in adult mammals [(http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=Yin-Xiong+Li+cholesterol); (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=Yin-Xiong+Li+fetal+alcohol); (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=Yin-Xiong+Li+cholesterol+OR+hepatic+OR+hepatocyte+OR+hedgehog)]. SHH is important for brain development, and deletion of either megalin, an endocytic receptor that also transports vitamin D, bound to vitamin D receptor, and is also a receptor for SHH (among other ligands), or patched, the classical SHH receptor, produces holoprosencephaly (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=holoprosencephaly+megalin+OR+patched). In that type of profoundly disordered brain development, the brain doesn't develop two distinct hemispheres, etc.
A few years ago, I was thinking that vitamin D3 depletion during brain development could disturb hegehog signalling and contribute to developmental brain disorders that have been suggested to be associated with vitamin D depletion. It was basically like applying the findings of Bijlsma et al. (2008) [Bijlsma et al., 2008: (http://www.ncbi.nlm.nih.gov/pubmed/17870251)] to brain development, but I think it's probably difficult to tell what, if any, effects on hedgehog signalling would result from vitamin D depletion (or if the effect would be significant, etc.). It would be very complex. Those authors, though, have done research showing that 7-dehydrocholesterol inhibits SHH signalling by substituting for cholesterol in hedgehog processing. Vitamin D or 25-hydroxyvitamin D or hormonal vitamin D could conceivably also substitute for cholesterol, because vitamin D steroids exist as rotamers and convert back and forth between s-cis and s-trans rotamers hundreds of times per second [(http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=%22vitamin+D%22+%22s-cis%22+OR+%22s-trans%22); (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=%22vitamin+D%22+rotamer+%22s-cis%22+OR+%22s-trans%22); (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=%22vitamin+D%22+%22cholesterol-like%22+%22s-cis%22+OR+%22s-trans%22)]. So vitamin D and its metabolites can assume cholesterol-like conformations, etc. Maybe someone's already shown that vitamin D or its hydroxylated metabolites can't substitute for cholesterol in hedgehog processing, but anyway--it's just one of my wild, old ideas that sounds far-fetched to me now. I briefly looked at all of these byzantine interactions of VDR-ligand-mediated changes in gene expression with SHH signalling, etc., based partly on the fact that megalin is a receptor for both vitamin D receptor (vitamin-D-bound or drug-ligand-bound) and SHH. I don't even remember what effect I thought vitamin D repletion would have on SHH signalling. The mechanisms that Bijlsma et al. (2008) have researched look focused to me and look to be more plausible than the potential interactions with vitamin D metabolism and signalling appear to be. It looks like a nightmare (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=hedgehog+cholesterol+%22vitamin+D%22+OR+hydroxyvitamin+OR+dihydroxyvitamin), partly because VDR activation can influence the expression of SHH and other hedgehog proteins and can also influence the responsiveness to the cellular actions of SHH, etc. There might be some capacity for vitamin D or its metabolites to serve as substrates for enzymes that metabolize or otherwise utilize cholesterol or for proteins that bind cholesterol, etc. Some orally-administered vitamin D3 binds to lipoproteins [this article is probably not the best, as far as describing that, but it shows the effect: Teramoto et al., 1995: (http://www.ncbi.nlm.nih.gov/pubmed/7575591)], and that occurs more with oral vitamin D than with vitamin D from the skin (which circulates, almost exclusively, bound to VDR, supposedly). That type of binding is not necessarily indicative of cholesterol-mimesis, but it's interesting.
In any case, I don't completely understand the research by Li and colleagues yet, but the covalent binding of cholesterol to SHH is necessary for SHH to be completely functional [this is one paper that Li is a coauthor of: Sicklick et al., 2005: (http://www.nature.com/labinvest/journal/v85/n11/full/3700349a.html)(http://www.ncbi.nlm.nih.gov/pubmed/16170335)]. The authors suggest that some cholesterol-lowering drugs may reduce hepatic stellate cell activation (mitogenic activation, proliferation, etc.) and liver collagen accumulation by reducing SHH signalling (i.e. by reducing cholesterol availability for binding to SHH). That's an interesting hypothesis, but I can't find any mention of supplemental cholesterol in these articles I've looked at so far. In another article that Li is a coauthor of [Yang et al., 2008: (http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2196213)(http://www.ncbi.nlm.nih.gov/pubmed/18022723)], the authors basically say that SHH is upregulated in hepatic stellate cells, in response to their activation with platelet-derived growth factor (PDGF) and other mitogens, etc., and helps to promote the survival of those stellate cells. That's evidently viewed as being pathological. So how, in that type of context, would dietary cholesterol supplementation ameliorate liver disease? It sounds like the activation of hepatic stellate cells is kind of a mixed bag and may be able to produce either regeneration or an exacerbation of fibrosis, in my opinion. But I'm not all that sure about that.
I've never seen anyone suggest that, though, about increases in intracellular cholesterol levels in cells in the liver being able to augment cell proliferation or survival, potentially, by maintaining the functionality of SHH and other hedgehog proteins. It's completely new. That might be relevant to research on Alzheimer's disease or psychiatric conditions [(http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=cholesterol+hedgehog+Alzheimer%27s); (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=antidepressant+hedgehog)]. A lot of the research on cholesterol metabolism in relation to Alzheimer's disease is still focusing on isoprenoid signalling, and a lot of it doesn't seem to be going much of anywhere, in my opinion. If hedgehog signalling is involved in progenitor cell survival in the liver in adult mammals [Sicklick et al., 2006: (http://ajpgi.physiology.org/cgi/content/full/290/5/G859)(http://www.ncbi.nlm.nih.gov/pubmed/16322088)], then maybe it also could promote neuronal progenitor cell survival. I don't know if decreases in neuronal progenitor cell viability do, in fact, contribute to psychiatric or neurodegenerative diseases. There's a lot of research suggesting that they do, but it's always seemed sort of unclear, in my mind, what the real mechanism would be. Exercise and a grab bag of other factors increases neuronal progenitor cell proliferation in the subventricular zone, etc., but most of the cells don't survive. There's a patent on using a "hedgehog agonist to treat depression" and some articles on hedgehog signalling in neuronal progenitor cell proliferation (hippocampal neurogenesis) [(http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=antidepressant+hedgehog); (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=psychiatric+sonic+hedgehog+adult)]. When one takes a very crude look at things, cholesterol is like a weak hedgehog agonist, in my opinion, because it activates or maintains hedgehog functionality. This posting is deteriorating. A lot of those, in that last search, look to be related to the proliferation of progenitor cell populations, but hedgehog could also conceivably promote or regulate the cell-cycle re-entry of terminally-differentiated neurons (this is "bad" cell-cycle re-entry) (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=Alzheimer%27s+hedgehog+%22cell+cycle%22+reentry+OR+%22re-entry%22).
In any case, I was going to mention that there's obviously another side to liver-related issues and some cholesterol-lowering drugs, and this is one article that addresses some of those issues and concerns [Argo et al., 2008: (http://www.ncbi.nlm.nih.gov/pubmed/18666246)]. There are two sides to lots of those issues, and I'm not going to get into a discussion about all of that.
That article by Kanat et al. (2007) is disturbing to see, and it goes without saying that those reductions in cortisol and testosterone could conceivably also occur in people who have very low cholesterol levels and are not taking cholesterol-lowering drugs, in my opinion. In a person taking no medications, one would not expect to see pronounced inhibition of de novo cholesterol formation, such as can be produced by some cholesterol by the statins, in extrahepatic cells. But I wouldn't be surprised to see some of those changes in adrenal or gonadal steroid hormones showing up in people who have pathologically-low cholesterol levels. But that doesn't mean that increasing serum cholesterol is likely to just neatly fix endocrinological abnormalities, especially in a person who has extremely low serum cholesterol levels and is suicidally depressed, etc. So someone would obviously want to talk with his or her doctor about these issues. There are countless other possible causes of endocrinological abnormalities that have little to do with cholesterol.
There's quite a bit of interesting research showing that dietary cholesterol can improve some forms of liver disease in animal models, and there's this researcher who suggested that cholesterol supplementation could be used to treat liver disease (http://www.dukehealth.org/HealthLibrary/News/10021):
"Li pointed out that the findings could have other theoretical implications as well. He said giving alcoholics supplemental cholesterol could help slow down or prevent the occurrence of alcoholic liver disease, even chronic alcoholic induced cirrhosis, characterized by replacement of liver tissue by scar tissue, leading to progressive loss of liver function."
It's important to note that a lot of research shows that very high dietary cholesterol intakes in animals worsens the fatty liver disease that results from the animals' consumption of large amounts of dietary fat, etc. But many of the articles showing apparently therapeutic effects of cholesterol use much lower dosages than researchers have used in many of the dime-a-dozen articles on the effects of dietary cholesterol. I looked up some of the research that Li has been involved in, and it's interesting. He and his colleagues are researching some of the cell groups and signalling pathways, such as in relation to hedgehog signalling (by proteins such as sonic hedgehog (SHH), indian hedgehog, and desert hedgehog), that influence liver regeneration or repair, even in adult mammals [(http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=Yin-Xiong+Li+cholesterol); (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=Yin-Xiong+Li+fetal+alcohol); (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=Yin-Xiong+Li+cholesterol+OR+hepatic+OR+hepatocyte+OR+hedgehog)]. SHH is important for brain development, and deletion of either megalin, an endocytic receptor that also transports vitamin D, bound to vitamin D receptor, and is also a receptor for SHH (among other ligands), or patched, the classical SHH receptor, produces holoprosencephaly (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=holoprosencephaly+megalin+OR+patched). In that type of profoundly disordered brain development, the brain doesn't develop two distinct hemispheres, etc.
A few years ago, I was thinking that vitamin D3 depletion during brain development could disturb hegehog signalling and contribute to developmental brain disorders that have been suggested to be associated with vitamin D depletion. It was basically like applying the findings of Bijlsma et al. (2008) [Bijlsma et al., 2008: (http://www.ncbi.nlm.nih.gov/pubmed/17870251)] to brain development, but I think it's probably difficult to tell what, if any, effects on hedgehog signalling would result from vitamin D depletion (or if the effect would be significant, etc.). It would be very complex. Those authors, though, have done research showing that 7-dehydrocholesterol inhibits SHH signalling by substituting for cholesterol in hedgehog processing. Vitamin D or 25-hydroxyvitamin D or hormonal vitamin D could conceivably also substitute for cholesterol, because vitamin D steroids exist as rotamers and convert back and forth between s-cis and s-trans rotamers hundreds of times per second [(http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=%22vitamin+D%22+%22s-cis%22+OR+%22s-trans%22); (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=%22vitamin+D%22+rotamer+%22s-cis%22+OR+%22s-trans%22); (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=%22vitamin+D%22+%22cholesterol-like%22+%22s-cis%22+OR+%22s-trans%22)]. So vitamin D and its metabolites can assume cholesterol-like conformations, etc. Maybe someone's already shown that vitamin D or its hydroxylated metabolites can't substitute for cholesterol in hedgehog processing, but anyway--it's just one of my wild, old ideas that sounds far-fetched to me now. I briefly looked at all of these byzantine interactions of VDR-ligand-mediated changes in gene expression with SHH signalling, etc., based partly on the fact that megalin is a receptor for both vitamin D receptor (vitamin-D-bound or drug-ligand-bound) and SHH. I don't even remember what effect I thought vitamin D repletion would have on SHH signalling. The mechanisms that Bijlsma et al. (2008) have researched look focused to me and look to be more plausible than the potential interactions with vitamin D metabolism and signalling appear to be. It looks like a nightmare (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=hedgehog+cholesterol+%22vitamin+D%22+OR+hydroxyvitamin+OR+dihydroxyvitamin), partly because VDR activation can influence the expression of SHH and other hedgehog proteins and can also influence the responsiveness to the cellular actions of SHH, etc. There might be some capacity for vitamin D or its metabolites to serve as substrates for enzymes that metabolize or otherwise utilize cholesterol or for proteins that bind cholesterol, etc. Some orally-administered vitamin D3 binds to lipoproteins [this article is probably not the best, as far as describing that, but it shows the effect: Teramoto et al., 1995: (http://www.ncbi.nlm.nih.gov/pubmed/7575591)], and that occurs more with oral vitamin D than with vitamin D from the skin (which circulates, almost exclusively, bound to VDR, supposedly). That type of binding is not necessarily indicative of cholesterol-mimesis, but it's interesting.
In any case, I don't completely understand the research by Li and colleagues yet, but the covalent binding of cholesterol to SHH is necessary for SHH to be completely functional [this is one paper that Li is a coauthor of: Sicklick et al., 2005: (http://www.nature.com/labinvest/journal/v85/n11/full/3700349a.html)(http://www.ncbi.nlm.nih.gov/pubmed/16170335)]. The authors suggest that some cholesterol-lowering drugs may reduce hepatic stellate cell activation (mitogenic activation, proliferation, etc.) and liver collagen accumulation by reducing SHH signalling (i.e. by reducing cholesterol availability for binding to SHH). That's an interesting hypothesis, but I can't find any mention of supplemental cholesterol in these articles I've looked at so far. In another article that Li is a coauthor of [Yang et al., 2008: (http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2196213)(http://www.ncbi.nlm.nih.gov/pubmed/18022723)], the authors basically say that SHH is upregulated in hepatic stellate cells, in response to their activation with platelet-derived growth factor (PDGF) and other mitogens, etc., and helps to promote the survival of those stellate cells. That's evidently viewed as being pathological. So how, in that type of context, would dietary cholesterol supplementation ameliorate liver disease? It sounds like the activation of hepatic stellate cells is kind of a mixed bag and may be able to produce either regeneration or an exacerbation of fibrosis, in my opinion. But I'm not all that sure about that.
I've never seen anyone suggest that, though, about increases in intracellular cholesterol levels in cells in the liver being able to augment cell proliferation or survival, potentially, by maintaining the functionality of SHH and other hedgehog proteins. It's completely new. That might be relevant to research on Alzheimer's disease or psychiatric conditions [(http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=cholesterol+hedgehog+Alzheimer%27s); (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=antidepressant+hedgehog)]. A lot of the research on cholesterol metabolism in relation to Alzheimer's disease is still focusing on isoprenoid signalling, and a lot of it doesn't seem to be going much of anywhere, in my opinion. If hedgehog signalling is involved in progenitor cell survival in the liver in adult mammals [Sicklick et al., 2006: (http://ajpgi.physiology.org/cgi/content/full/290/5/G859)(http://www.ncbi.nlm.nih.gov/pubmed/16322088)], then maybe it also could promote neuronal progenitor cell survival. I don't know if decreases in neuronal progenitor cell viability do, in fact, contribute to psychiatric or neurodegenerative diseases. There's a lot of research suggesting that they do, but it's always seemed sort of unclear, in my mind, what the real mechanism would be. Exercise and a grab bag of other factors increases neuronal progenitor cell proliferation in the subventricular zone, etc., but most of the cells don't survive. There's a patent on using a "hedgehog agonist to treat depression" and some articles on hedgehog signalling in neuronal progenitor cell proliferation (hippocampal neurogenesis) [(http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=antidepressant+hedgehog); (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=psychiatric+sonic+hedgehog+adult)]. When one takes a very crude look at things, cholesterol is like a weak hedgehog agonist, in my opinion, because it activates or maintains hedgehog functionality. This posting is deteriorating. A lot of those, in that last search, look to be related to the proliferation of progenitor cell populations, but hedgehog could also conceivably promote or regulate the cell-cycle re-entry of terminally-differentiated neurons (this is "bad" cell-cycle re-entry) (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=Alzheimer%27s+hedgehog+%22cell+cycle%22+reentry+OR+%22re-entry%22).
In any case, I was going to mention that there's obviously another side to liver-related issues and some cholesterol-lowering drugs, and this is one article that addresses some of those issues and concerns [Argo et al., 2008: (http://www.ncbi.nlm.nih.gov/pubmed/18666246)]. There are two sides to lots of those issues, and I'm not going to get into a discussion about all of that.
Thursday, June 18, 2009
Interactions of the de novo Cholesterol and Fatty Acid Biosynthetic Pathways
This article [Gibbons, 2003: (http://www.ncbi.nlm.nih.gov/pubmed/14559068)] is good, and the author discusses some interactions, in terms of the HMG-CoA and acetyl-CoA availabilities, of the overall, de novo cholesterol and fatty acid biosynthetic pathways. The author provides an "equation" that is evidently meant to allow one to get a sense of the ways the overall cytosolic HMG-CoA concentration changes in response to changes in the cytosolic acetyl-CoA/(free)CoA ratio. This is it:
[HMG-CoA](cytosolic) = kapp [acetyl-CoA]^3/[CoA]^2
(or, rather, is proportional to) [Acetyl-CoA]^3/[CoA]^2
So the author says that a doubling of the cytosolic acetyl-CoA concentration, without any change in the free CoA concentration, would cause the cytosolic HMG-CoA concentration to increase by a factor of 8. I think there's probably something to that, but I don't know why it's necessary to have an equation. The author also cites research showing that the flux of cytosolic acetyl-CoA into de novo fatty acid formation is ten times the flux, in the liver, of acetyl-CoA into cholesterol formation.
The author also mentions some interesting research on the regulation of HMG-CoA reductase, the so-called rate-limiting enzyme in de novo cholesterol formation, by AMPK. Evidently, pharmacological AMPK activation tends to decrease the HMG-CoA reductase activity in cells, such as the liver, and also decreases de novo fatty acid formation from acetyl-CoA. I haven't read much of the research on the interactions of AMPK and cholesterol metabolism, and it's a lot more complex than that. But that's an important mechanism.
That's relevant to research showing cholesterol depletion from the brains of people who died by violent suicide (there's a whole series of articles showing that violent suicide but not nonviolent suicide is associated with reductions in cholesterol levels in various parts of the brain, at autopsy). That doesn't necessarily mean that the reduction in cholesterol per se was the problem, however, because mitochondrial dysfunction in astrocytes, for example, could reduce citrate export from the mitochondria and hence reduce both astrocytic ketogenesis and cholesterol biosynthesis, etc. I came across this whole series of articles discussing the fact that plasma free fatty acids essentially don't reach neurons, to a significant extent, because the astrocytes utilize them and are in close apposition to the basolateral membranes of cerebral blood vessels. I don't have time to link to them now, but that's an important distinction, for a number of reasons. There are countless articles stating that FFAs are important energy substrates or even the most important energy substrates for astrocytes, and then there are articles that just proclaim that beta-oxidation doesn't occur in the adult brain. It just doesn't even sound plausible, from the standpoint of "common sense" or a general sense of the brain and of cells in general, to think that no cells in the brain would be capable of oxidizing fatty acids. Given that FFAs cross the blood brain barrier by passive diffusion (Cullingford et al., 1999, cited below), what would happen to all the FFAs entering the brain? Do they just accumulate in cells or diffuse back out? How is it that they don't form micelles? It just doesn't make sense, in my opinion, because all cholesterol would then have to be formed from glucose or amino acids, most of which are poor lipogenic substrates, or lactate, which is evidently a good lipogenic substrate, or from the relatively low levels of plasma ketones.
Whenever I see an article with a title saying something "does not" occur or a statement expressing a "strict rule," having to do with just about anything, I tend to immediately suspect that the statement or article will have major flaws, on closer examination of the issue. Things just do not tend to work in a rigid, "tightly-regulated," yes-or-no manner. That's just my obnoxious statement for the day, but it tends to be the case. Another possibility is that the statement itself is sort of correct but misses the point. For example, some of the research showing no passage of deuterium-labeled cholesterol from the blood to the brain seems to have given people the impression that changes in plasma cholesterol have no influence on brain functioning. That's not the case, and there are many mechanisms by which changes in serum cholesterol could strongly influence the brain. I've also read articles, related to Alzheimer's disease, in which the authors discuss their suspicion that some cholesterol does enter the brain from the blood. Researchers tend to dismiss the research (on the basis of 40-year-old studies using acute dosages of deuterium-labeled cholesterol) showing LDL translocation across both the luminal and abluminal membranes of cerebral vascular endothelial cells. I still think most cholesterol is made de novo in the brain, but the small fraction that may not be made in the brain could nonetheless become significant under some conditions. Moreover, researchers have almost always generalized from research in healthy animals to animals or humans in disease states. It may well be that there is an increase in the uptake, into the brain, of plasma lipoprotein-bound cholesterol in response to a brain injury, etc.
Another thing that is noteworthy is that plasma FFAs consist of mostly palmitate and oleate and one other common fatty acid. I forget which one, but plasma FFAs tend to be either saturated or at least "not-highly-unsaturated." In contrast, the FFAs that are liberated in response to cerebral ischemia can be these highly reactive, polyunsaturated fatty acids and can produce much more severe damage than saturated fatty acids can. That's my sense of it, anyway. This is one of the articles [Cullingford et al., 1999: (http://www.ncbi.nlm.nih.gov/pubmed/10709651)] that discusses the fact that astrocytes probably use a lot of plasma FFAs because of the close proximity of the astrocytes to cerebral blood vessels. The perivascular endfeet of astrocytes maintain and, to some extent, constitute part of the blood-brain barrier. That article also discusses research showing that meningeal fibroblasts can produce ketones, and meningeal fibroblasts are also present in the adult brain.
There is, however, the fact that intermediates in cholesterol biosynthesis tend to cause problems, when they accumulate, and so the provision of a lot of ketones or FFAs might, under some circumstances, just cause a lot of intermediates in cholesterol biosynthesis to accumulate and cause problems.
Gibbons (2003) also mentioned that an increase in membrane cholesterol is thought to reduce the membrane "permeability" to sodium and reduce ATP consumption by that "mechanism," but I'm not sure how that's supposed to occur. I remember reading that, many years ago, but I'm not sure if there's any quantitative or definitive data on it. It could be an important mechanism, and then it could be more of a theoretical possibility.
[HMG-CoA](cytosolic) = kapp [acetyl-CoA]^3/[CoA]^2
(or, rather, is proportional to) [Acetyl-CoA]^3/[CoA]^2
So the author says that a doubling of the cytosolic acetyl-CoA concentration, without any change in the free CoA concentration, would cause the cytosolic HMG-CoA concentration to increase by a factor of 8. I think there's probably something to that, but I don't know why it's necessary to have an equation. The author also cites research showing that the flux of cytosolic acetyl-CoA into de novo fatty acid formation is ten times the flux, in the liver, of acetyl-CoA into cholesterol formation.
The author also mentions some interesting research on the regulation of HMG-CoA reductase, the so-called rate-limiting enzyme in de novo cholesterol formation, by AMPK. Evidently, pharmacological AMPK activation tends to decrease the HMG-CoA reductase activity in cells, such as the liver, and also decreases de novo fatty acid formation from acetyl-CoA. I haven't read much of the research on the interactions of AMPK and cholesterol metabolism, and it's a lot more complex than that. But that's an important mechanism.
That's relevant to research showing cholesterol depletion from the brains of people who died by violent suicide (there's a whole series of articles showing that violent suicide but not nonviolent suicide is associated with reductions in cholesterol levels in various parts of the brain, at autopsy). That doesn't necessarily mean that the reduction in cholesterol per se was the problem, however, because mitochondrial dysfunction in astrocytes, for example, could reduce citrate export from the mitochondria and hence reduce both astrocytic ketogenesis and cholesterol biosynthesis, etc. I came across this whole series of articles discussing the fact that plasma free fatty acids essentially don't reach neurons, to a significant extent, because the astrocytes utilize them and are in close apposition to the basolateral membranes of cerebral blood vessels. I don't have time to link to them now, but that's an important distinction, for a number of reasons. There are countless articles stating that FFAs are important energy substrates or even the most important energy substrates for astrocytes, and then there are articles that just proclaim that beta-oxidation doesn't occur in the adult brain. It just doesn't even sound plausible, from the standpoint of "common sense" or a general sense of the brain and of cells in general, to think that no cells in the brain would be capable of oxidizing fatty acids. Given that FFAs cross the blood brain barrier by passive diffusion (Cullingford et al., 1999, cited below), what would happen to all the FFAs entering the brain? Do they just accumulate in cells or diffuse back out? How is it that they don't form micelles? It just doesn't make sense, in my opinion, because all cholesterol would then have to be formed from glucose or amino acids, most of which are poor lipogenic substrates, or lactate, which is evidently a good lipogenic substrate, or from the relatively low levels of plasma ketones.
Whenever I see an article with a title saying something "does not" occur or a statement expressing a "strict rule," having to do with just about anything, I tend to immediately suspect that the statement or article will have major flaws, on closer examination of the issue. Things just do not tend to work in a rigid, "tightly-regulated," yes-or-no manner. That's just my obnoxious statement for the day, but it tends to be the case. Another possibility is that the statement itself is sort of correct but misses the point. For example, some of the research showing no passage of deuterium-labeled cholesterol from the blood to the brain seems to have given people the impression that changes in plasma cholesterol have no influence on brain functioning. That's not the case, and there are many mechanisms by which changes in serum cholesterol could strongly influence the brain. I've also read articles, related to Alzheimer's disease, in which the authors discuss their suspicion that some cholesterol does enter the brain from the blood. Researchers tend to dismiss the research (on the basis of 40-year-old studies using acute dosages of deuterium-labeled cholesterol) showing LDL translocation across both the luminal and abluminal membranes of cerebral vascular endothelial cells. I still think most cholesterol is made de novo in the brain, but the small fraction that may not be made in the brain could nonetheless become significant under some conditions. Moreover, researchers have almost always generalized from research in healthy animals to animals or humans in disease states. It may well be that there is an increase in the uptake, into the brain, of plasma lipoprotein-bound cholesterol in response to a brain injury, etc.
Another thing that is noteworthy is that plasma FFAs consist of mostly palmitate and oleate and one other common fatty acid. I forget which one, but plasma FFAs tend to be either saturated or at least "not-highly-unsaturated." In contrast, the FFAs that are liberated in response to cerebral ischemia can be these highly reactive, polyunsaturated fatty acids and can produce much more severe damage than saturated fatty acids can. That's my sense of it, anyway. This is one of the articles [Cullingford et al., 1999: (http://www.ncbi.nlm.nih.gov/pubmed/10709651)] that discusses the fact that astrocytes probably use a lot of plasma FFAs because of the close proximity of the astrocytes to cerebral blood vessels. The perivascular endfeet of astrocytes maintain and, to some extent, constitute part of the blood-brain barrier. That article also discusses research showing that meningeal fibroblasts can produce ketones, and meningeal fibroblasts are also present in the adult brain.
There is, however, the fact that intermediates in cholesterol biosynthesis tend to cause problems, when they accumulate, and so the provision of a lot of ketones or FFAs might, under some circumstances, just cause a lot of intermediates in cholesterol biosynthesis to accumulate and cause problems.
Gibbons (2003) also mentioned that an increase in membrane cholesterol is thought to reduce the membrane "permeability" to sodium and reduce ATP consumption by that "mechanism," but I'm not sure how that's supposed to occur. I remember reading that, many years ago, but I'm not sure if there's any quantitative or definitive data on it. It could be an important mechanism, and then it could be more of a theoretical possibility.
Wednesday, June 17, 2009
Perspectives on Physiology
These are some perspectives on physiology, posted by a dilettante.
"They clung together in that bright moment of wonder, there on the magic island, where the world was quiet, believing all they said. And who shall say--whatever disenchantment follows--that we ever forget magic, or that we can ever betray, on this leaden earth, the apple-tree, the singing, and the gold? Far out beyond that timeless valley, a train, on the rails for the East, wailed back its ghostly cry: life, like a fume of painted smoke, a broken wrack of cloud, drifted away. Their world was a singing voice again: they were young and they could never die. This would endure."
Thomas Wolfe
"I slept my sleep. From deepest dream I've woke, and plead. The world is deep, and deeper than the day could read. Deep is its woe. Joy deeper still than grief can be. Woe saith: Hence, Go! But joys all want eternity, want deep, profound eternity."
Friedrich Nietzsche
"There lies the port: the vessel puffs her sail:
There gloom the dark broad seas. My mariners,
Souls that have toil'd and wrought, and thought with me--
That ever with a frolic welcome took
The thunder and the sunshine, and opposed
Free hearts, free foreheads--you and I are old;
Old age hath yet his honour and his toil;
Death closes all; but something ere the end,
Some work of noble note, may yet be done,
Not unbecoming men that strove with Gods.
The lights begin to twinkle from the rocks:
The long day wanes: the slow moon climbs: the deep
Moans round with many voices. Come, my friends,
'Tis not too late to seek a newer world.
Push off, and sitting well in order smite
The sounding furrows; for my purpose holds
To sail beyond the sunset, and the baths
Of all the western stars, until I die.
It may be that the gulfs will wash us down:
It may be we shall touch the Happy Isles,
And see the great Achilles, whom we knew.
Tho' much is taken, much abides; and tho'
We are not now that strength which in old days
Moved earth and heaven; that which we are, we are;
One equal temper of heroic hearts,
Made weak by time and fate, but strong in will
To strive, to seek, to find, and not to yield."
Alfred Tennyson
"They clung together in that bright moment of wonder, there on the magic island, where the world was quiet, believing all they said. And who shall say--whatever disenchantment follows--that we ever forget magic, or that we can ever betray, on this leaden earth, the apple-tree, the singing, and the gold? Far out beyond that timeless valley, a train, on the rails for the East, wailed back its ghostly cry: life, like a fume of painted smoke, a broken wrack of cloud, drifted away. Their world was a singing voice again: they were young and they could never die. This would endure."
Thomas Wolfe
"I slept my sleep. From deepest dream I've woke, and plead. The world is deep, and deeper than the day could read. Deep is its woe. Joy deeper still than grief can be. Woe saith: Hence, Go! But joys all want eternity, want deep, profound eternity."
Friedrich Nietzsche
"There lies the port: the vessel puffs her sail:
There gloom the dark broad seas. My mariners,
Souls that have toil'd and wrought, and thought with me--
That ever with a frolic welcome took
The thunder and the sunshine, and opposed
Free hearts, free foreheads--you and I are old;
Old age hath yet his honour and his toil;
Death closes all; but something ere the end,
Some work of noble note, may yet be done,
Not unbecoming men that strove with Gods.
The lights begin to twinkle from the rocks:
The long day wanes: the slow moon climbs: the deep
Moans round with many voices. Come, my friends,
'Tis not too late to seek a newer world.
Push off, and sitting well in order smite
The sounding furrows; for my purpose holds
To sail beyond the sunset, and the baths
Of all the western stars, until I die.
It may be that the gulfs will wash us down:
It may be we shall touch the Happy Isles,
And see the great Achilles, whom we knew.
Tho' much is taken, much abides; and tho'
We are not now that strength which in old days
Moved earth and heaven; that which we are, we are;
One equal temper of heroic hearts,
Made weak by time and fate, but strong in will
To strive, to seek, to find, and not to yield."
Alfred Tennyson
Provocative Articles Showing Effects of Dietary Cholesterol Intake on the Brain or Interesting Associations That Relate to Cholesterol Metabolism
These are some articles that show that increases in the dietary cholesterol intakes of animals can influence the animals' brain functions or behaviors or neurotransmission in the brain or cognitive functioning, etc. (some of these articles purport to show positive or beneficial effects of cholesterol intake) [Dufour et al., 2006: (http://www.ncbi.nlm.nih.gov/pubmed/16814755); Schreurs et al., 2007a: (http://www.ncbi.nlm.nih.gov/pubmed/17539481); Schreuers et al., 2007b: (http://www.ncbi.nlm.nih.gov/pubmed/18019398); Kanat et al., 2007: (http://www.ncbi.nlm.nih.gov/pubmed/17234355); Micale et al., 2008: (http://www.ncbi.nlm.nih.gov/pubmed/18222653); Li et al., 2008: (http://www.ncbi.nlm.nih.gov/pubmed/18972185); Pond, 2003: (http://www.ingentaconnect.com/content/tandf/gctb/2003/00000008/00000001/art00002); Pond et al., 2008: (http://jn.nutrition.org/cgi/content/full/138/2/282)(http://www.ncbi.nlm.nih.gov/pubmed/18203892); Boleman et al., 1998: (http://jn.nutrition.org/cgi/content/full/128/12/2498)(http://www.ncbi.nlm.nih.gov/pubmed/9868199)]. The article by Li et al. (2008) looks interesting and could conceivably relate to the inhibition of the proteasomal degradation of GTP cyclohydrolase I, in response to an increase in cellular cholesterol, but that's not a very thoroughly-developed hypothesis. I can't get the full text of that article, at the moment. Some of those articles used dietary copper supplementation that may be a confounding variable, and I haven't looked at the full texts of those articles by Schreuers et al. yet. The increases in dietary cholesterol could modify brain functioning without producing increases in the (supposedly-minimal) transport of cholesterol from the blood to the brain, as discussed below. This article [Ravnskov, 2003: (http://qjmed.oxfordjournals.org/cgi/content/full/96/12/927?ijkey=172mwKXqzgmtE&keytype=ref)(http://www.ncbi.nlm.nih.gov/pubmed/14631060)] discusses evidence that high total cholesterol levels are protective against infections or damage due to infections.
A general point I'd make is that it's important to try to distinguish among different factors, such as dietary cholesterol vs. de novo cholesterol formation in the liver or other tissues vs. the uptake of lipoprotein-bound cholesterol from the plasma to target tissues, that may be producing a given concentration of serum cholesterol. For example, high dietary cholesterol intakes can increase serum cholesterol but suppress cholesterol formation in the liver and reduce some concentrations of "postsqualene" sterols in the blood. Those effects could produce different effects on mitotic cells, such as lymphocytes, by reducing the availabilities of some of the intermediates in cholesterol biosynthesis (even the availabilities of "presqualene" intermediates). In contrast, a person who has high cholesterol levels and obtains no cholesterol from his or her diet may have higher levels of plasma cholesterol precursors, and this could increase lymphocyte proliferation during infections, etc. But the higher serum cholesterol might also increase the uptake of lipoprotein-bound cholesterol by cells in extrahepatic tissues and thereby suppress de novo cholesterol biosynthesis in the skin and other tissues. That effect would be similar, in the skin or other extrahepatic sites of de novo cholesterol formation, to the the effects of dietary cholesterol on cholesterol formation at extrahepatic sites, but the effects of dietary vs. endogenously-driven hypercholesterolemia (or elevations in cholesterol) would diverge in the liver, as discussed previously.
McNamara (2000) [McNamara, 2000: (http://www.ncbi.nlm.nih.gov/pubmed/11111098)] makes a compelling case that, when the data from association studies are examined by multivariate analysis, cholesterol intake is a surrogate marker for saturated fat intake and that saturated fat intake per se is responsible for the associations of high-fat diets with cardiovascular disease. This tells me that past a certain point, any supposed health benefits of omega-3-fatty-acid-containing eggs would be expected to be offset and ultimately negated by the effects of the excessive increase in fat intake from the eggs. Teunissen et al. (2003) [Teunissen et al., 2003: (http://arno.unimaas.nl/show.cgi?fid=4701)(http://www.ncbi.nlm.nih.gov/pubmed/12493560)] found that the serum concentrations of lathosterol and lanosterol were negatively correlated with cognitive functioning, and the authors attributed the elevations in those cholesterol precursors to higher rates of de novo cholesterol formation in the liver. Dietary cholesterol could conceivably decrease the levels of those or other plasma cholesterol precursors (by suppressing de novo cholesterol biosynthesis), but dietary cholesterol could also worsen atherosclerosis, past a certain point. In any case, these articles are interesting, but one would obviously want to talk with one's doctor before doing anything. Cholesterol metabolism is very complex, and it's difficult to predict, with any degree of certainty, the effects, on the brain, of any changes in cholesterol intake or transport.
A general point I'd make is that it's important to try to distinguish among different factors, such as dietary cholesterol vs. de novo cholesterol formation in the liver or other tissues vs. the uptake of lipoprotein-bound cholesterol from the plasma to target tissues, that may be producing a given concentration of serum cholesterol. For example, high dietary cholesterol intakes can increase serum cholesterol but suppress cholesterol formation in the liver and reduce some concentrations of "postsqualene" sterols in the blood. Those effects could produce different effects on mitotic cells, such as lymphocytes, by reducing the availabilities of some of the intermediates in cholesterol biosynthesis (even the availabilities of "presqualene" intermediates). In contrast, a person who has high cholesterol levels and obtains no cholesterol from his or her diet may have higher levels of plasma cholesterol precursors, and this could increase lymphocyte proliferation during infections, etc. But the higher serum cholesterol might also increase the uptake of lipoprotein-bound cholesterol by cells in extrahepatic tissues and thereby suppress de novo cholesterol biosynthesis in the skin and other tissues. That effect would be similar, in the skin or other extrahepatic sites of de novo cholesterol formation, to the the effects of dietary cholesterol on cholesterol formation at extrahepatic sites, but the effects of dietary vs. endogenously-driven hypercholesterolemia (or elevations in cholesterol) would diverge in the liver, as discussed previously.
McNamara (2000) [McNamara, 2000: (http://www.ncbi.nlm.nih.gov/pubmed/11111098)] makes a compelling case that, when the data from association studies are examined by multivariate analysis, cholesterol intake is a surrogate marker for saturated fat intake and that saturated fat intake per se is responsible for the associations of high-fat diets with cardiovascular disease. This tells me that past a certain point, any supposed health benefits of omega-3-fatty-acid-containing eggs would be expected to be offset and ultimately negated by the effects of the excessive increase in fat intake from the eggs. Teunissen et al. (2003) [Teunissen et al., 2003: (http://arno.unimaas.nl/show.cgi?fid=4701)(http://www.ncbi.nlm.nih.gov/pubmed/12493560)] found that the serum concentrations of lathosterol and lanosterol were negatively correlated with cognitive functioning, and the authors attributed the elevations in those cholesterol precursors to higher rates of de novo cholesterol formation in the liver. Dietary cholesterol could conceivably decrease the levels of those or other plasma cholesterol precursors (by suppressing de novo cholesterol biosynthesis), but dietary cholesterol could also worsen atherosclerosis, past a certain point. In any case, these articles are interesting, but one would obviously want to talk with one's doctor before doing anything. Cholesterol metabolism is very complex, and it's difficult to predict, with any degree of certainty, the effects, on the brain, of any changes in cholesterol intake or transport.
Tuesday, June 16, 2009
Approaches to Resistance Exercise/Strength Training
The authors of this article [Avery et al., 2003: (http://www.fittech.com.au/downloads/bmsdocs/AveryKraemer.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/14636105)] discuss the fact that, as shown by their research and the research of others, 6 or more days are required for a given muscle group to recover from a strength-training workout. Avery et al. (2003) used people who had not been doing weight training, but their statements about the recovery time being 6 days, ideally, are consistent with the anecdotal statements, with regard to recovery time, that people with expertise in sports nutrition and training have been giving for many years. I can't provide any citations to support the statements, but people who have considerable expertise in this area have generally said that a person can wait one week between strength-training/resistance-training workouts of a given muscle group. This article [Tidball, 2005: (http://ajpregu.physiology.org/cgi/content/full/288/2/R345)(http://www.ncbi.nlm.nih.gov/pubmed/15637171)] cites research (reference 23) showing that neutrophil infiltration in exercised muscles may continue for up to 5 days post-exercise. Neutrophil infiltration is not "bad" and can actually help the repair/recovery process, etc. For example, the authors of this article [Lennon et al., 1998: (http://jem.rupress.org/cgi/content/full/188/8/1433)(http://www.ncbi.nlm.nih.gov/pubmed/9782120)] cite research (reference 8 on p. 1439) estimating that 100 billion neutrophils (polymorphonuclear leukocytes are neutrophils and are usually identified by myeloperoxidase expression) migrate from the blood to the extracellular fluid, by the whole rolling/adhesion process (I forget the details), every day in a person in the absence of inflammation, and the neutrophils release adenosine monophosphate that's converted into adenosine and promotes endothelial cell proliferation and barrier function, etc. In any case, one approach would be to allow 5-7 days between workouts of one muscle group and separate the exercises into 3 workouts per week, etc.
It's very important to talk to one's doctor before beginning any exercise program, in part because of the risk of exertional rhabdomyolysis (RBM) (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=exertional+rhabdomyolysis). RBM can be life-threatening and can cause kidney failure and death, as a result of myoglobinuria [myoglobin from lysed (necrotic) muscle cells produces oxidative injury to the kidneys] and disseminated intravascular coagulopathy (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=disseminated+intravascular+coagulation+rhabdomyolysis). If one has any disease or health condition or viral illness or is taking any drug, one should be especially careful to do fewer sets or repetitions than one thinks one can, for the first several workouts, and gradually increase the intensity, etc. It's not muscle soreness or muscle fatigue but is the loss of muscle cells by an undesirable mode of cell death (necrosis) (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=exertional+rhabdomyolysis+necrosis). Necrotic cells dump intracellular antigens (proteins, lipids, etc.) that are usually somewhat shielded from immune recognition, etc. The proteins can also become insoluble as a result of necrotic cell death and cause insoluble immune complexes to form (to precipitate) and cause thromboses (disseminated intravascular coagulation, etc.) (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=%22immune+complex%22+insoluble+OR+precipitate). The mechanisms are really complex, but necrotic cell death can, for example, promote dendritic cell maturation and thereby increase the costimulatory capacities of dendritic cells (increasing their antigen-presenting capacities) [Basu et al., 2000: (http://intimm.oxfordjournals.org/cgi/content/full/12/11/1539)(http://www.ncbi.nlm.nih.gov/pubmed/11058573?dopt=Abstract)]. Many IgG antibodies normally bind to intracellular antigens to suppress viral infections, etc., but the loss of skeletal muscle myocytes by necrosis is not desirable.
I don't feel like going into any more detail, but that sort of research and information seems not to be very well-known, still. There's still a widespread belief that resistance exercise is secondary to endurance exercise, in terms of importance and biological effects (on the brain, etc.), but the reverse is actually true, in my opinion. There's no substitute for resistance exercise, as far as many different effects go.
It's always necessary to completely exhaust the muscle group, during a set of repetitions, and the negative (eccentric) contraction should be controlled or be about 2 seconds or even longer. It makes no sense, in my opinion and others' opinions, to try to control one's breathing with each repetition. The muscle group has to be completely exhausted with each set, if one wants to provide a stimulus and produce all of the other biological effects I've discussed in past postings. As far as the repetitions themselves go, people were promoting "slow negatives," which are 4-6 second eccentric contractions (the lowering of the weight in a repetition) for awhile but are not promoting or doing them, to a large extent, anymore. There isn't as much adrenergic activation (and, hence, not as much growth hormone release, etc.) with very slow negatives (eccentric contractions/eccentric work). Some people do some sets with 2-second eccentric contractions and then some with eccentric contractions that are not restricted, in terms of duration, on arm exercises, etc. There aren't that many different ways to do it, and I've never quite understood all of the "programs" and "fad methods." It's my suspicion that the real "secret" behind many "programs" is that the person providing the program is, in fact, taking massive amounts of androgenic steroids, etc. That's just my opinion, though.
Experts generally advise doing no more than 5 sets on a given muscle per workout, but many people do more sets than that. Also, it is not efficient or effective, in my opinion, to wait and do all of the sets sequentially. Many people do one or two sets on a muscle group and then do one or two on an opposing muscle group or other exercise and then return to the first exercise, etc. Up to four minutes are required for 90+ percent recovery of the phosphocreatine (PCr) concentrations (or PCr/Cr ratio, etc.) in a muscle, following a set to exhaustion. Waiting one minute or two minutes between sets means that the muscle is being exercised at 60 percent capacity, essentially. There's no way to avoid that, to some extent, because no one can wait four minutes between every set. But the point is that the muscle is going to be capable of progressively and drastically less work, if one does all sets, on a given exercise, sequentially and waits a minute or two between sets. I can only think of a couple of other things, off the top of my head. The leg-extension machine is an example of a machine that many people would suggest avoiding the use of, given that it can put shear stress on the knee at some points in the range of motion. The behind-the-neck pulldown is also supposed to not be a good exercise, and I forget the reasons for that. The proper way to do that one is to pull the bar down "in front of" the "face." This posting is obviously degenerating rapidly.
In my opinion, these are important considerations, though, if one is trying to actually get something out of exercise, in terms of disease prevention or whatever else. The information on the recovery time is also not intuitive and seems to not be widely known.
It's very important to talk to one's doctor before beginning any exercise program, in part because of the risk of exertional rhabdomyolysis (RBM) (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=exertional+rhabdomyolysis). RBM can be life-threatening and can cause kidney failure and death, as a result of myoglobinuria [myoglobin from lysed (necrotic) muscle cells produces oxidative injury to the kidneys] and disseminated intravascular coagulopathy (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=disseminated+intravascular+coagulation+rhabdomyolysis). If one has any disease or health condition or viral illness or is taking any drug, one should be especially careful to do fewer sets or repetitions than one thinks one can, for the first several workouts, and gradually increase the intensity, etc. It's not muscle soreness or muscle fatigue but is the loss of muscle cells by an undesirable mode of cell death (necrosis) (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=exertional+rhabdomyolysis+necrosis). Necrotic cells dump intracellular antigens (proteins, lipids, etc.) that are usually somewhat shielded from immune recognition, etc. The proteins can also become insoluble as a result of necrotic cell death and cause insoluble immune complexes to form (to precipitate) and cause thromboses (disseminated intravascular coagulation, etc.) (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=%22immune+complex%22+insoluble+OR+precipitate). The mechanisms are really complex, but necrotic cell death can, for example, promote dendritic cell maturation and thereby increase the costimulatory capacities of dendritic cells (increasing their antigen-presenting capacities) [Basu et al., 2000: (http://intimm.oxfordjournals.org/cgi/content/full/12/11/1539)(http://www.ncbi.nlm.nih.gov/pubmed/11058573?dopt=Abstract)]. Many IgG antibodies normally bind to intracellular antigens to suppress viral infections, etc., but the loss of skeletal muscle myocytes by necrosis is not desirable.
I don't feel like going into any more detail, but that sort of research and information seems not to be very well-known, still. There's still a widespread belief that resistance exercise is secondary to endurance exercise, in terms of importance and biological effects (on the brain, etc.), but the reverse is actually true, in my opinion. There's no substitute for resistance exercise, as far as many different effects go.
It's always necessary to completely exhaust the muscle group, during a set of repetitions, and the negative (eccentric) contraction should be controlled or be about 2 seconds or even longer. It makes no sense, in my opinion and others' opinions, to try to control one's breathing with each repetition. The muscle group has to be completely exhausted with each set, if one wants to provide a stimulus and produce all of the other biological effects I've discussed in past postings. As far as the repetitions themselves go, people were promoting "slow negatives," which are 4-6 second eccentric contractions (the lowering of the weight in a repetition) for awhile but are not promoting or doing them, to a large extent, anymore. There isn't as much adrenergic activation (and, hence, not as much growth hormone release, etc.) with very slow negatives (eccentric contractions/eccentric work). Some people do some sets with 2-second eccentric contractions and then some with eccentric contractions that are not restricted, in terms of duration, on arm exercises, etc. There aren't that many different ways to do it, and I've never quite understood all of the "programs" and "fad methods." It's my suspicion that the real "secret" behind many "programs" is that the person providing the program is, in fact, taking massive amounts of androgenic steroids, etc. That's just my opinion, though.
Experts generally advise doing no more than 5 sets on a given muscle per workout, but many people do more sets than that. Also, it is not efficient or effective, in my opinion, to wait and do all of the sets sequentially. Many people do one or two sets on a muscle group and then do one or two on an opposing muscle group or other exercise and then return to the first exercise, etc. Up to four minutes are required for 90+ percent recovery of the phosphocreatine (PCr) concentrations (or PCr/Cr ratio, etc.) in a muscle, following a set to exhaustion. Waiting one minute or two minutes between sets means that the muscle is being exercised at 60 percent capacity, essentially. There's no way to avoid that, to some extent, because no one can wait four minutes between every set. But the point is that the muscle is going to be capable of progressively and drastically less work, if one does all sets, on a given exercise, sequentially and waits a minute or two between sets. I can only think of a couple of other things, off the top of my head. The leg-extension machine is an example of a machine that many people would suggest avoiding the use of, given that it can put shear stress on the knee at some points in the range of motion. The behind-the-neck pulldown is also supposed to not be a good exercise, and I forget the reasons for that. The proper way to do that one is to pull the bar down "in front of" the "face." This posting is obviously degenerating rapidly.
In my opinion, these are important considerations, though, if one is trying to actually get something out of exercise, in terms of disease prevention or whatever else. The information on the recovery time is also not intuitive and seems to not be widely known.
Monday, June 15, 2009
Different Effects of Sodium Butyrate on Hepatic Energy Metabolism
This article [Beauvieux et al., 2008: (http://www.biomedcentral.com/content/pdf/1472-6793-8-19.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/18847460)] shows that the administration of butyrate (1.90 mg butyrate/g bw or 1900 mg/kg bw) and 14 mg/g bw (this is 14 g/kg bw, and I don't know why the doses were given in mg/g bw) to rats increased their liver glycogen concentrations, measured 8 hours after a meal, in comparison to the mean glycogen concentration in rats fed only 14 g/kg bw glucose. That dose of butyrate of 1900 mg/kg bw is like a dose of about 28.2 grams for a 70-kg human [(1900/4.71) x 70 = 28238 mg], and that's a really high dosage of sodium butyrate. Beauvieux et al. (2001) [Beauvieux et al., 2001 (http://jn.nutrition.org/cgi/content/full/131/7/1986)(http://www.ncbi.nlm.nih.gov/pubmed/11435518?dopt=Abstract)] found that infusion of sodium butyrate into the portal vein, so as to maintain relatively high concentrations for prolonged periods of time, impaired energy metabolism, and decreased the intracellular pH in cells (measured in the whole liver, evidently--site unspecified). Those authors (evidently some of the same researchers who did the more recent experiments and article) discuss the fact that butyrate from the colon, according to research cited on the first page), is thought to reach the liver in significant amounts and contribute to energy provision, etc. I've read about that in other articles, but I think it's a much lower concentration. The authors themselves cite research estimating that short-chain fatty acids, including butyrate, are produced by microorganisms, in the colon, at a rate 400-800 mmol/day. The (not sure if this is extracellular or intracellular--I'm assuming intracellular) "cellular" butyrate concentration in the liver is thought to be about 148 uM, normally, according to the authors. I think that using those concentrations for prolonged periods of time is not likely to be physiological, and the concentrations, based on my crude reading of a paper that provides pharmacological data on sodium butyrate in rodents, would probably not be that high, in response to something like 4 g of sodium butyrate, for very long (if they ever reached that concentration). But that article (Beauvieux et al., 2001) is still really good and sheds light on the pH changes produced in response to beta-oxidation.
Those are two possible effects of sodium butyrate, and I think both sets of results have validity. Both of those experiments used either high doses or unusually-prolonged elevations in the butyrate concentrations (0.5 to 5 mM) in the hepatic portal venous blood, but there is the potential, in my opinion, for high doses of sodium butyrate to produce adverse effects on mitochondrial functioning, etc. As the authors of the 2008 paper discuss, however, free fatty acids, such as butyrate, generally do contribute to the replenishment of hepatic glycogen concentrations, in the hours after a meal, in part by decreasing the oxidation of glucose and allowing it to be diverted into glycogen formation.
Those are two possible effects of sodium butyrate, and I think both sets of results have validity. Both of those experiments used either high doses or unusually-prolonged elevations in the butyrate concentrations (0.5 to 5 mM) in the hepatic portal venous blood, but there is the potential, in my opinion, for high doses of sodium butyrate to produce adverse effects on mitochondrial functioning, etc. As the authors of the 2008 paper discuss, however, free fatty acids, such as butyrate, generally do contribute to the replenishment of hepatic glycogen concentrations, in the hours after a meal, in part by decreasing the oxidation of glucose and allowing it to be diverted into glycogen formation.
Sunday, June 14, 2009
Folate and UVB Papers in Pdf Format
Here are my old papers, with the diagrams included, in pdf format. I now think that reduced folates, such as L-leucovorin (L-folinic acid) and L-methylfolate, are far superior to folic acid, for many reasons, but the concepts discussed in the folic acid paper are still "valid." Here's the paper on folate metabolism in relation to purine and pyrimidine metabolism (http://www.mediafire.com/?zmfojwc4am2), and here's the paper on the effects of cutaneous UVB/UVA exposure on sensory neurons and projection neurons/wide-dynamic-range neurons in the dorsal horn and caudal trigeminal nucleus, etc. (http://www.mediafire.com/?410jmzmrjjm).
Note on Coenzyme A Precursors: Pantothenic Acid vs. Pantethine
I've been meaning to mention that, in my opinion, pantethine is not superior to pantothenic acid (B5, vitamin B5) as a coenzyme A precursor. In my opinion, the cysteamine formed by the enzymatic hydrolysis of pantethine produces effects that are potentially problematic and undesirable. Some popular sources of information about pantethine give the impression that it is "closer" to coenzyme A than B5 is, but this isn't actually true. Pantethine is metabolized into B5 and cysteamine. Cysteamine is quite reactive, as I recall, and can then form mixed disulfides with a variety of different thiol groups on enzymes and other proteins, etc. For example, oral cysteamine was found to inhibit cholesterol biosynthesis in rabbits, but B5 did not reduce plasma cholesterol levels [Wittwer et al., 1987: (http://www.ncbi.nlm.nih.gov/pubmed/3689482)]. So it's pretty clear from that and other articles (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=pantethine+cysteamine+) that taking pantethine is basically like taking B5 and cysteamine or the disulfide form of cysteamine (cystamine). Also, cysteamine can inhibit the activity of the P-protein of the glycine cleavage system (GCS) [Fujiwara and Motokawa, 1983: (http://www.jbc.org/cgi/reprint/258/13/8156.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/6863283?dopt=Abstract)] and thereby inhibit the overall activity of the GCS multienzyme complex [Hayasaka and Tada, 1983: (http://www.ncbi.nlm.nih.gov/pubmed/6679320); (http://scholar.google.com/scholar?num=100&hl=en&lr=&safe=off&q=cysteamine+%22glycine+cleavage%22)]. The fact that cysteamine can do that is not a good sign, in my opinion, for many reasons. Some cysteamine is formed endogenously during the turnover of coenzyme A, I think [it is: Dominy et al., 2007: (http://www.jbc.org/cgi/content/full/282/35/25189)(http://www.ncbi.nlm.nih.gov/pubmed/17581819?dopt=Abstract)], but the facts that cysteamine inhibits cholesterol biosynthesis in vivo, in rabbits, and that B5 does not would tend to suggest that the amounts of cysteamine formed endogenously, during CoA turnover, are small in comparison to the amounts derived from the hydrolysis of pantethine.
Saturday, June 13, 2009
Export of Mitochondrial Acetoacetate for Cytosolic Lipogenesis: Relevance to Interactions of Microsomal Cholesterogenesis & Mitochondrial Ketogenesis
This article [MacDonald et al., 2007: (http://www.jbc.org/cgi/content/full/282/42/30596)(http://www.ncbi.nlm.nih.gov/pubmed/17724028?dopt=Abstract)] is interesting, and the authors found that both citrate and acetoacetate could serve as "carriers" or could serve to "transfer" acetyl-CoA from the mitochondria to the cytosol in pancreatic beta cells. Citrate has traditionally been viewed as the only or primary tricarboxylic acid (TCA) cycle intermediate that could be transported across the inner mitochondrial membrane and, fairly directly, serve as a precursor for cytosolic acetyl-CoA and hence for lipogenesis. The authors found that acetoacetate was converted into acetyl-CoA in the cytosol by either of two cytosolic enzymes. Succinate evidently couldn't be converted into succinyl-CoA in the cytosol, but this may not be true in cell types other than beta cells.
This is relevant to an understanding of the ways dietary cholesterol or the cellular cholesterol concentration in general, both in cells within and outside the liver, could exert feedback inhibition of microsomal (endoplasmic-reticulum, cytosolic) HMG-CoA reductase activity, thereby increasing the microsomal/cytosolic HMG-CoA pool, and, in theory, exert some kind of influence on the availability of intramitochondrial HMG-CoA for ketogenesis in the mitochondria [the first page of this pdf is inaccessible, but the rest of the article is fine: Ott and Lachance, 1981: (http://www.ajcn.org/cgi/reprint/34/10/2295)(http://www.ncbi.nlm.nih.gov/pubmed/6170219?dopt=Abstract)]. The cytosolic and mitochondrial HMG-CoA pools are not thought to be interchangeable, and so it's not easy to see an obvious or simple mechanism by which an increase in the overall cellular cholesterol concentration could enhance ketogenesis. Part of the reason for this is that cholesterol biosynthesis and transport within cells are compartmentalized [Ott and Lachance, 1981; Liscum et al., 1995: (http://www.jbc.org/cgi/content/full/270/26/15443)(http://www.ncbi.nlm.nih.gov/pubmed/7797533)]. But the authors of that article mention the relationships between succinate transport across the inner mitochondrial membrane, anaplerosis, and mevalonate biosynthesis. I'll try to read some more about that, but it doesn't look like there's all that much information on it. My point is that, as with glutamine and many other compounds, the compartmentation complicates or makes impossible any attempt to draw simple or easy conclusions about enzyme regulation in response to changes in dietary or intracellular or extracellular cholesterol concentrations. I think there is some mechanism, though, because cholesterol biosynthesis is energetically very demanding, compared to many other small-molecule intermediates or regulatory compounds or whatever one wants to describe cholesterol as being.
This is relevant to an understanding of the ways dietary cholesterol or the cellular cholesterol concentration in general, both in cells within and outside the liver, could exert feedback inhibition of microsomal (endoplasmic-reticulum, cytosolic) HMG-CoA reductase activity, thereby increasing the microsomal/cytosolic HMG-CoA pool, and, in theory, exert some kind of influence on the availability of intramitochondrial HMG-CoA for ketogenesis in the mitochondria [the first page of this pdf is inaccessible, but the rest of the article is fine: Ott and Lachance, 1981: (http://www.ajcn.org/cgi/reprint/34/10/2295)(http://www.ncbi.nlm.nih.gov/pubmed/6170219?dopt=Abstract)]. The cytosolic and mitochondrial HMG-CoA pools are not thought to be interchangeable, and so it's not easy to see an obvious or simple mechanism by which an increase in the overall cellular cholesterol concentration could enhance ketogenesis. Part of the reason for this is that cholesterol biosynthesis and transport within cells are compartmentalized [Ott and Lachance, 1981; Liscum et al., 1995: (http://www.jbc.org/cgi/content/full/270/26/15443)(http://www.ncbi.nlm.nih.gov/pubmed/7797533)]. But the authors of that article mention the relationships between succinate transport across the inner mitochondrial membrane, anaplerosis, and mevalonate biosynthesis. I'll try to read some more about that, but it doesn't look like there's all that much information on it. My point is that, as with glutamine and many other compounds, the compartmentation complicates or makes impossible any attempt to draw simple or easy conclusions about enzyme regulation in response to changes in dietary or intracellular or extracellular cholesterol concentrations. I think there is some mechanism, though, because cholesterol biosynthesis is energetically very demanding, compared to many other small-molecule intermediates or regulatory compounds or whatever one wants to describe cholesterol as being.
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