This article [Relas et al., 2000: (http://www.sinoas.com/journal/UploadFiles/200706/20070625110816450.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/10998465)] shows that even 500 mg of oral squalene can acutely increase cholesterol biosynthesis, by serving as a precursor of cholesterol. That might be another approach to increasing cholesterol formation extrahepatically (i.e. in the brain or other tissues). Obviously, this is an approach one would want to discuss with one's doctor before implementing. The research generally shows that squalene may or may not acutely increase plasma cholesterol slightly but does not usually elevate it, when given at doses between 500 mg and 1000 mg/d, in the long term. Some squalene is sold in combination with alkylglycerols (a.k.a. alkoxyglycerols), but I can't imagine why anyone would want to mess around with that type of thing. They're incorporated into phospholipids and have mysterious effects, etc., in my opinion, according to the research. People who eat diets high in olive oil (i.e. people who live around the "Mediterranean," etc.) can evidently obtain between 200 and 400 mg of squalene per day, from some types of olive oil [Newmark, 1997: (http://cebp.aacrjournals.org/cgi/reprint/6/12/1101.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/9419410)]. There's research showing "encephaloneuropathy" (abnormalities in the brain, etc.) from massive doses of squalene in rats [Gajkowska et al., 1999: (http://www.ncbi.nlm.nih.gov/pubmed/10048717)] [that dose of 20 grams squalene per kg bw (20,000 mg/kg bw) in rats is like 4,246 mg/kg bw in humans, which is a dose of 297,240 mg squalene per day]. I just mention that to provide basic, toxicological information.
It's not clear if squalene can cross the blood-brain barrier, but I would guess that it can. Free fatty acids can cross lipid bilayers by passive diffusion, by the "flip-flop" type of mechanism of crossing lipid bilayers (http://hardcorephysiologyfun.blogspot.com/2009/04/free-fatty-acid-transport-and.html), and squalene may behave similarly. It's a polymer of 6 isoprene units (30-carbons) but is not nearly as reactive as many polyunsaturated fatty acids, evidently because it does not contain bis-allylic hydrogens [Cho et al., 2009: (http://pt.wkhealth.com/pt/re/cdrm/abstract.00003050-200906000-00011.htm)] (hydrogens that are allylic to two double bonds, meaning that they're on the carbon in between two double bonds). Apart from that, though, it appears to be able to elevate cholesterol levels in the skin of humans (Cho et al., 2009) and, evidently, in the testes in rats, given that squalene supplementation increased plasma testosterone in rats [Liu et al., 2009: (http://icmr.nic.in/ijmr/2009/february/0206.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/19293441)]. That research on testosterone is reminiscent of research showing that serum testosterone concentrations increase as the dietary saturated fat intake increases [one of many articles showing that: Volek et al., 1997: (http://jap.physiology.org/cgi/content/full/82/1/49)(http://www.ncbi.nlm.nih.gov/pubmed/9029197); see some of the articles shown here: (http://scholar.google.com/scholar?q=Testosterone+and+cortisol+in+relationship+to+dietary+volek&hl=en&lr=)], but I don't know how much there is to that. It's probably only true up to a point, but it's consistent with the idea that some saturated fat is "required" for extrahepatic cholesterol biosynthesis. The effect would, in my opinion, eventually or sooner-than-eventually be opposed by, for example, the increase in aromatase activity, in adipocytes, in response to weight gain from massive amounts of saturated fat. Also, one would ask if downregulations in androgen receptor expression occur, etc. Normalizing the membrane or intracellular cholesterol concentration is likely to be possible, but upregulating the whole hypothalamic-pituitary-gonadal axis, in response to something like squalene alone, is unlikely to occur, in my opinion.
One concern would be the potential for induced vitamin K deficiency (in addition to the concern that squalene could, in my opinion, conceivably produce pathological effects by mimicking vitamin K), given the research showing this can occur in rodents and other animals (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=squalene+%22vitamin+K%22), and other potential problems include the possibility that squalene could increase "post-squalene-and-pre-cholesterol" sterols to excessive levels (these can cause problems by exerting inappropriate, feedback inhibition of HMG-CoA reductase and producing all sorts of other effects) or produce direct and "undesirable" regulatory effects (such as by displaying vitamin K activity, in my opinion). There's research showing that geranylgeraniol and related "pre-squalene" isoprenoids can produce apoptotic effects in many cell types (http://scholar.google.com/scholar?q=apoptosis+farnesol+OR+geranylgeraniol&hl=en&lr=), but my sense is that squalene tends to be more of a cholesterol precursor than those isoprenoids (given, in part, that they can be converted into substrates for protein isoprenylation, etc.). But who knows. For all I know, epoxidized squalene could accumulate and exert vitamin K activity or produce some other bizarre effect like that, as discussed below. One reason I throw these suggestions out is that squalene is epoxidized by an enzyme or enzymes that catalyzes a reaction that may be similar to the reaction that produces vitamin K epoxide.
A major reason squalene wouldn't be expected to increase plasma cholesterol much, though, at reasonable dosages, is that dietary cholesterol exerts feedback inhibition of HMG-CoA reductase activity, by various direct and indirect mechanisms, and dietary cholesterol doesn't increase plasma cholesterol in many people, in my opinion (and as shown in various articles, such as the one by McNamara, 2000: (http://hardcorephysiologyfun.blogspot.com/2009/05/hmb-3-hydroxyisovalerate.html)]. But at high doses, cholesterol-laden foods would probably start to contribute to atherosclerosis and other pathological processes, in my opinion.
I sort of doubt, at reasonable dosages, that serious vitamin K deficiency would occur in response to squalene, because, even with high-dose vitamin E supplementation, for example, the plasma under-gamma-carboxylated prothrombin (des-carboxyprothrombin) doesn't increase to anything comparing to the levels that occur with true vitamin K antagonists (such as warfarin). But I don't really know. But at first glance, this article [Booth et al., 2004: (http://www.ajcn.org/cgi/content/full/80/1/143)(http://www.ncbi.nlm.nih.gov/pubmed/15213041?dopt=Abstract)], for example, looks like it's showing that vitamin E behaves like a vitamin K antagonist (they're structurally similar). But there's one key sentence in the article, and it's the one in which the authors say that the PIVKA-II [this is the same as des-gamma-carboxyprothrombin or as des-carboxyprothrombin: (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=%22des-carboxy+prothrombin%22+OR+descarboxyprothrombin+OR+%22carboxyprothrombin%22)] concentrations in response to vitamin E were in the range of 2.4 ng/mL. The authors go on to say that the PIVKA-II levels in people on oral anticoagulants are 750 ng/mL, or 313 times the levels produced by vitamin E. So that's similar to saying warfarin and other anticoagulants are 313 times as potent as vitamin E in producing anticoagulant effects. Of course, vitamin E could, in my opinion, cause bleeding by causing its inhibitory effects on the activation of protein kinase C in platelets, etc. Also, Olestra evidently has been shown to not very readily cause vitamin K deficiency, and some of these articles discuss squalene in relation to compounds like Olestra [Koonsvitsky et al., 1997: (http://jn.nutrition.org/cgi/content/full/127/8/1636S)(http://www.ncbi.nlm.nih.gov/pubmed/9237960)]. I could be wrong about this vitamin K-depleting potential, though. I can't say, with much confidence, what the effects of squalene would be, and I'm just giving my initial impressions and guesses. Vitamin K metabolism is very strange and complex, but the coagulation system is somehow able to sustain itself with tiny, 15-microgram amounts of dietary vitamin K. It's partly that the coagulation cascade is so extremely potent and self-perpetuating and almost totally-unregulated, but I wonder if there isn't some other factor, produced endogenously, that has vitamin K activity.
I mentioned the seemingly-bizarre possibility that squalene could have vitamin K activity, and there's an article showing that geranylgeraniol, which is essentially a 20-carbon chain of 4 isoprene units, appears to have vitamin K activity [Ronden et al., 1997: (http://www.ncbi.nlm.nih.gov/pubmed/9247360)]. Squalene generally doesn't seem to behave in quite the same ways as some of the pre-squalene-and-post-mevalonate isoprenoids, which include geranylgeraniol, do, but the research is very chaotic and difficult to interpret. The authors of that article also discuss the fact that rats have much higher vitamin K requirements than humans, even when one scales the dosages between species (their requirements are 50-100 times those of humans, evidently). That's just one of many totally bizarre aspects of vitamin K metabolism. That article (Ronden et al., 1997), though, as I've discussed in a past posting, shows, in a roudabout way, that increasing the vitamin K intakes of rats does produce thrombogenic effects (the "obstruction time"). The authors suggested that the thrombogenicity might have been secondary to the vitamins-K-induced macrophage apoptosis or osteoclast-precursor-cell apoptosis (programmed cell death). Geranylgeraniol certainly has been shown to produce apoptotic effects in macrophages and osteoclasts in many articles (http://scholar.google.com/scholar?q=geranylgeraniol+apoptosis+osteoclast+OR+macrophage&hl=en&lr=), but it's certainly conceivable that the doses used by the authors of that article (Ronden et al., 1997) are supraphysiological. Some articles have shown, on the other hand, that geranylgeraniol and other free isoprenoids can prevent apoptosis or stimulate cell proliferation and growth in those and other cell types.
In any case, I want to say that, in my opinion, vitamin K supplementation has the potential to be very dangerous, in many cases, especially in the absence of the concomitant use of an anticoagulant (low-dose vitamin K is sometimes given along with vitamin K antagonists, to minimize variation in the INR) or in the absence of instructions from one's doctor. One would obviously want to talk to his or her doctor before making any changes in any supplements or medications. I'm not going to go into a discussion of vitamin K, but, in my opinion, using supplemental vitamin K to compensate for some supposed vitamin-K-deficiency-inducing effect of squalene would be a terrible idea and could, in my opinion, produce life-threatening thrombogenicity or other effects (especially since there's this disturbing, vitamin-K-mimetic effect that some free isoprenoids, such as geranylgeraniol, can have). I've discussed vitamin K in past postings [(http://hardcorephysiologyfun.blogspot.com/2009/01/vitamin-b2-riboflavin-and-vitamin-k.html); (http://hardcorephysiologyfun.blogspot.com/2009/01/half-lives-of-clotting-factor-proteins.html); (http://hardcorephysiologyfun.blogspot.com/2009/01/vitamin-b2-riboflavin-and-vitamin-k.html); (http://hardcorephysiologyfun.blogspot.com/2009/01/another-chilling-article-on-vitamin-k.html); (http://hardcorephysiologyfun.blogspot.com/2009/01/different-perspectives-on-coq10-and.html); (http://hardcorephysiologyfun.blogspot.com/2009/01/vitamin-k-activity-and-coq10-concerns.html)]. Vitamin K compounds can produce macrophage apoptosis and may induce thrombogenicity by that mechanism, in my opinion, as discussed in past postings. It's more likely that it will just increase thrombin formation by increasing prothrombin levels, in my opinion. But the numbers of articles showing these apoptotic effects on osteoclasts, etc., are very disturbing to me (http://scholar.google.com/scholar?q=%22vitamin+K%22+apoptosis+osteoclast+OR+macrophage&hl=en&lr=). I know all about the supposedly-great effects of vitamin K and the way the vitamin-K2-series compounds supposedly act more extrahepatically than vitamin K1 does and supposedly play a role in the prevention of vascular calcification, etc. And some growth factors (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=Gas6+%22vitamin+K%22) and proteins involved in the clearance of apoptotic cells (Mer, etc.) (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=Mer+%22vitamin+K%22) contain glutamate residues that are post-translationally modified by vitamin-K-dependent gamma-carboxylation. But there are things that look good on paper, and then there's reality, in my opinion.
There seem to be lots of things about squalene that are not well-understood, but that's just my opinion. It may increase cholesterol levels and thereby lead to the suppression of the formation pre-squalene isoprenoids and isoprenylated proteins, etc., but then it seems like it might have some mysterious capacity to produce vitamin K activity. It could have the opposite effect and act as a vitamin K antagonist, but there's evidence that some compounds can act as both vitamin K antagonists and vitamin K mimetics. These are just my opinions, though, and squalene isn't sounding all that good to me, at the moment. I'll see if there are other articles showing apparent vitamin K activity or vitamin-K-mimetic effects of geranylgeraniol or other isoprenoids, but it's a really complicated area of research.
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