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.
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