HMB (3-hydroxyisovalerate)

I was reading about beta-hydroxy-beta-methylbutyrate (HMB) (a.k.a. 3-hydroxyisovaleric acid or 3-hydroxy-3-methylbutyrate or beta-hydroxyisovaleric acid, etc.) again and was thinking it might be useful as an adjuctive for neuroprotective/neurotrophic or other applications. There are a few articles showing mood improvements in people taking HMB (http://scholar.google.com/scholar?q=methylbutyrate+mood+OR+%22well+being%22&hl=en&lr=), evidently for "muscle building" purposes or prevention of trauma-induced muscle wasting, and it would stand to reason that it could have some effect in that regard or produce "indirect ketogenesis" by sparing acetyl-CoA that would otherwise be used for cholesterol biosynthesis, etc. The reports of mood improvement sound bogus to me, but it's not always wise to dismiss these things. I just put these things up on the "blog" and try to give my impressions. But the absence of research, in the form of a big 10,000-person study that provides no information but that hypes up some compound, is not, in any way, evidence of the absence of validity of a compound. I don't know if HMB would have any usefulness at all for brain-related applications, but it's supposedly converted, primarily, into hydroxymethylglutaryl-CoA (HMG-CoA) in skeletal muscle myocytes and other cell types and promotes satellite cell proliferation and increases IGF-1 mRNA in satellite cells, etc. It's supposedly useful for treating catabolic conditions by virtue of its capacity to serve as a cholesterol precursor (HMG-CoA is a precursor or "building block" of cholesterol). My guess is that it may very well not be useful for brain-related applications and may, in my opinion, cause the accumulation of HMB-CoA, which could inhibit the enzymes of the glycine cleavage system or other enzymes, but I may be wrong about that.

I don't have to mention that brain cholesterol depletion (depletion of membrane cholesterol in axon terminals or postsynaptic membranes of neurons in the brain, etc.) is thought to potentially be one factor contributing to the association of low cholesterol with violent death or suicide or death by accidents [(http://scholar.google.com/scholar?num=100&hl=en&lr=&q=cholesterol+suicide); (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=cholesterol+murder); (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=cholesterol+%22violent+death%22); (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=cholesterol+accident)]. I know this research is disturbing, but I didn't come up with the research. Don't shoot the messenger. There's considerable research suggesting that very low cholesterol levels cause people to become clumsy or impulsive or reckless and die by accidents or to kill themselves violently or to essentially be at a greater "risk" of being murdered, for unknown reasons. Presumably it's because they become aggressive or impulsive and get into some sort of confrontation that ultimately results in their being murdered, in my opinion. Violent death also includes death by suicide, and there's research showing unusually violent suicides among people with very low cholesterol. I know it's quite an unpleasant topic, but I'm just including this information to explain my reasons for not immediately dismissing something like HMB. I don't think it's possible to just dismiss such large numbers of articles, in any event. It's also relevant that cholesterol is degraded into propionate, and propionate can be anaplerotic and enter the tricarboxylic acid cycle as succinate, via succinyl-CoA. So HMB could conceivably be indirectly anaplerotic, but it could also not be. HMB could indirectly enhance ketogenesis by some mechanism, and increases in ketone availability have been suggested as approaches to treating mood disorders (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=mood+ketogenic+OR+ketone).

HMB wouldn't have to elevate plasma cholesterol to conceivably contribute to cholesterol biosynthesis in the brain. Most (80+ percent) of the cholesterol in the brain is made in situ, in astrocytes and oligodendrocytes, and low plasma cholesterol could just be a sign of generalized mitochondrial dysfunction, causing impairments in beta-oxidation (fatty acid oxidation) and therefore in acetyl-CoA availability for cholesterol biosynthesis. But the extents to which plasma cholesterol normally correlates with synaptosomal cholesterol or with other variables related to brain lipid metabolism are not even known. My sense is that low plasma cholesterol can be part and parcel of HPA axis activation and could result from glucocorticoid resistance, but it may also just be a sign of mitochondrial dysfunction (derangements in energy metabolism). I know those aren't very mechanistically-rich statements.

Someone should do research to see if it improves myelination or recovery from brain injuries in animals or something like that. Acetyl-L-carnitine, for example, has been shown to increase myelination or prevent the loss of myelin during aging in animals (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=%22acetyl-L-carnitine%22+myelin+OR+%22white+matter%22), but who knows if that type of effect, which is basically thought to result from its role in increasing "acetyl" group availability and maintaining beta-oxidation in astrocytes, in the brain, or in Schwann cells in the peripheral nervous system, would occur in humans. Someone should start by finding out what the actual mechanism of action is, though, because the research on HMB is astonishingly devoid of information on the actual mechanisms by which HMB even might regulate leucine metabolism. There's a recent article providing evidence that it doesn't inhibit the activity of the branched-chain alpha-keto acid dehydrogenase multienzyme complex in vivo, using labeled leucine, I think [Holecek et al., 2009: (http://www.ncbi.nlm.nih.gov/pubmed/19056452)]. But there must be some actual mechanism. Saying that it activates p70 S6 kinase is not saying anything about the mechanism, really (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=p70+methylbutyrate). How does it activate the p38 MAPK and p70 S6 kinase cascades?

HMB appears to lower plasma cholesterol very slightly in humans, but my main concern with it would be the potential to either disrupt phosphate homeostasis [Sousa et al., 1996: (http://www.ncbi.nlm.nih.gov/pubmed/8852485)] or, as HMB-CoA/3-hydroxyisovaleryl-CoA (not HMG-CoA), inhibit the enzymes of the glycine cleavage system, etc. Alpha-keto acids produced by the metabolism of leucine, isoleucine, and valine are thought to be capable of inhibiting the glycine cleavage system (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=%22glycine+cleavage%22+hydroxyisovaleric+OR+hydroxyisovalerate). 2-ketoisocaproate (a.k.a alpha-ketoisocaproate or 4-methyl-2-oxovaleric acid) is an example of a ketoacid metabolite (formed from leucine). Of course, the accumulation of those compounds occurs, in part, because many different inhibitory effects of toxic intermediate metabolites occur in people with genetic defects (which cause the accumulation of 3-hydroxyisovalerate). So there is likely to be not only a defect leading to overproduction of 3-hydroxyisovalerate but also a defect in the utilization of 3-hydroxyisovalerate (HMB) in people with genetic diseases. But it's still something to be aware of, in my opinion.

A lot of ketoacids, which are similar to but not the same as HMB/3-hydroxyisovalerate, can decrease serum phosphate (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=ketoacid+hyperphosphatemia), and it's fairly clear, in my opinion, that they don't exert these effects just by existing as calcium salts (such as calcium beta-hydroxy-beta-methylbutyrate) in the GI tract and "binding up" phosphate (preventing phosphate absorption) or by stimulating phosphate uptake into cells (the "refeeding" syndrome or phenomenon). They use some ketoacids to treat hyperphosphatemia, and the ketoacids decrease serum phosphate and can, as a result, decrease parathyroid hormone levels, etc. There seems to be an effect of some ketoacids on acid-base regulation in the kidneys, but that's just my opinion. HMB apparently has a net charge of -1 at physiological pH values, and that would tend to suggest that it's not going to cause the kinds of issues that something like, for example, 2-oxoglutarate, which supposedly has a -2 charge in neutral solution, could cause, in my opinion. There's a toxicological study in rats [Baxter et al., 2005: (http://www.ncbi.nlm.nih.gov/pubmed/16006030)] that shows elevations in serum inorganic phosphorus, which would suggest that HMB does not cause hypophosphatemia and may actually increase serum phosphate. But I'm just saying that it's the type of thing to be aware of and discuss with one's doctor.

I hope I don't need to say this, but attempting to increase the serum cholesterol level would not be a wise or effective approach to treating brain disorders or depression. Some research shows that it's almost impossible to increase one's serum cholesterol past a certain point, with diet alone. Some people do experience increases in serum total cholesterol in response to increases in dietary cholesterol, partly because of deficient feedback inhibition of HMG-CoA reductase activity by exogenous cholesterol. Some "graphs" of LDL-cholesterol changes in response to dietary cholesterol intake show some effects [Weggemans et al., 2001: (http://www.ajcn.org/cgi/content/full/73/5/885)(http://www.ncbi.nlm.nih.gov/pubmed/11333841)], but the authors of other articles make the argument that there's very little effect of dietary cholesterol on serum cholesterol [McNamara, 2000: (http://www.jacn.org/cgi/content/full/19/suppl_5/540S)(http://www.ncbi.nlm.nih.gov/pubmed/11023005?dopt=Abstract)]. In any case, the notion that an increase in cholesterol per se would automatically exert effects on the brain doesn't make sense to me, because very little cholesterol is thought to be transported from the blood to the brain. The more likely outcome is that one would worsen atherosclerosis. The researchers studying HMB make the argument that it could be protective against cardiovascular disease. I don't know if it's true, but I just throw these suggestions out there and offer my thoughts. Extremely low cholesterol levels, in the context of some types of neurodegenerative diseases or depression, are, in my opinion, one manifestation of some other metabolic disturbance.