There's a considerable amount of research that shows an association of very low plasma total cholesterol levels with an increase in the risk of death by suicide (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=cholesterol+suicide) or, disturbingly, by murder ("violent death") (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=cholesterol+%22violent+death%22). This is a disturbing topic, and there's also quite a bit of research that associates very low plasma cholesterol levels with an increase in the risk of hemorrhagic stroke (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=cholesterol+hemorrhage). The arguments that researchers have made, in their attempts to explain these associations, have not been very compelling to me, for the most part. Many people seem to have bought in to the idea that low omega-3 fatty acid intake was some sort of "surrogate marker" for low plasma cholesterol and that the apparent increases in suicidality, in the context of low cholesterol levels, are actually a result of low omega-3 intakes. This makes no sense, in my opinion, and it's never made any sense to me. That explanation for the association of low cholesterol with suicide would, in fact, directly conflict with other research that relates to the association of low cholesterol with hemorrhage. Specifically, researchers have found a positive association of high omega-3 fatty acid intakes with risk of hemorrhage (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=%22omega-3%22+hemorrhage), and researchers have also found that low saturated fat intakes are associated with an increased risk of hemorrhage (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=%22saturated+fat%22+hemorrhage). (Note that researchers sometimes use the term "intraparenchymal hemorrhage" to refer to an intracranial hemorrhage into the central nervous system parenchyma, as opposed to the hepatic, or liver, parenchyma, etc.)
I think all of these associations could be explained in terms of decreases in saturated free fatty acid availability to the brain and endothelial cells lining the blood vessels supplying the brain. Saturated free fatty acids behave quite differently from the ways unsaturated fatty acids behave, and there's considerable research showing that elevations in free fatty acids, following exercise, contribute strongly to glycogen replenishment in the liver and skeletal muscles. High-intensity exercise can elevate fasting plasma free fatty acids for four or more days post-exercise. Kiens et al. (1998) [Kiens et al., 1998: (http://ajpendo.physiology.org/cgi/content/full/275/2/E332)(http://www.ncbi.nlm.nih.gov/pubmed/9688636)] found, similarly, that fasting FFAs (note that the FFA measurements in the evening, at 30 hours post-exercise, was approximately a fasting measurement but might have been expected to be even higher in the true, fasted state, meaning in the morning) were still elevated at 42 hours post-exercise. And strength training, performed correctly, as a form of high-intensity exercise, generally produces the greatest elevations in FFAs. There's increasing evidence that impairments in cellular energy metabolism may be at the root of some psychiatric conditions, such as depression, and astrocytes and endothelial cells are capable of oxidizing palmitate and other free fatty acids, in addition to ketones, as energy substrates. Additionally, there is research showing that fasting is beneficial to animals with traumatic brain injuries (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=%22Fasting+Is+Neuroprotective+Following%22). Everyone assumes that this is because fasting can elevate ketones (acetoacetate and beta-hydroxybutyrate, primarily), and ketones have been shownt to exert neuroprotective effects in many articles (http://scholar.google.com/scholar?num=100&hl=en&lr=&q=ischemia+%22beta-hydroxybutyrate%22+OR+acetoacetate). But my sense is that ketone levels do not reliably correlate with plasma cholesterol levels. I'm not sure if *saturated* free fatty acid levels correlate with plasma cholesterol levels, but my sense is that the proportion of saturated free fatty acids would increase as plasma cholesterol increased. Saturated fatty acids are preferentially used for cholesterol biosynthesis, in comparison to monounsaturated (and, obviously, omega-3) fatty acids. Also, fasting for even short periods of time elevates plasma free fatty acids, but I think ketones do not necessarily become elevated to very significant levels until one has fasted for a fairly prolonged period of time. My reason for not focusing on ketones is that I've seen articles showing very inconsistent relationships between serum ketone levels and serum cholesterol levels, but this does not mean that ketones would not be important as energy substrates for neurons and astrocytes. But even the overnight fast, during sleep, elevates free fatty acids substantially, an effect that is thought to partly be due to the nighttime growth hormone release. Nonetheless, high-intensity exercise elevates both FFAs and ketones [Walsh et al., 1998: (http://www.ncbi.nlm.nih.gov/pubmed/9562294)]. But the assumption in the research looking at associations of factors with plasma cholesterol did not, in general, assume that the people were exercising, etc. And increasing one's omega-3 fatty acid intake is thought to potentially increase ketone formation (by the liver, etc.), and that's not an effect one would expect to see if, as I'm assuming in the context of this discussion, an increase in omega-3 intake and a decrease in saturated fat intake were predisposing to hemorrhage [Freemantle et al., 2006: (http://www.ncbi.nlm.nih.gov/pubmed/16829066)]. The authors of many of the articles on fat intake have suggested that the supposed protective effect of saturated fat intake, in the context of the risk of hemorrhage, might have more to do with the ratio of saturated fat to omega-3 fats. In other words, a person who eats more saturated fats will, at a given caloric intake and dietary composition, tend to eat fewer grams of omega-3 fats and have a higher percentage of saturated fatty acids in erythrocyte membrane phospholipids than a person who eats fish three times a day would, etc. Other researchers have suggested that a higher saturated fat intake simply increases cholesterol levels and thereby produces the supposed protection against intracranial hemorrhage. Although saturated fats (palmitate, etc.) are generally thought to be utilized more for cholesterol biosynthesis than many other fatty acids, I don't think that small increments in saturated fatty acid intake (I think even something like an increment, or increase, of 18 grams per day of saturated fats was found to be associated with protection from hemorrhage in some articles, and that's not some kind of enormous intake level) would produce large and incremental increases in plasma cholesterol. That's my sense of it, at least. But increasing the ratio of dietary saturated fat to polyunsaturated fats would, in my opinion, be expected to increase the "percentages" of erythrocyte phospholipids containing saturated fatty "acyl" side chains and, by extension, in my opinion, increase the saturated fraction of the plasma FFA pool.
Additionally, one explanation for the association of low cholesterol with hemorrhage was that a low cellular cholesterol content in smooth muscle cells made those cells less resistant to anoxia or hypoxia. Why would this be? Perhaps, during hypoxia or ischemia, cholesterol is degraded more extensively to propionate (cholesterol is, in fact, a source of odd-chain fatty acids, such as propionate, that can be metabolized to succinyl-CoA and thereby serve as anaplerotic substrates). I can't find the article discussing that, but I remember it. The researchers were saying that cerebral ischemia can produce localized, smooth-muscle-cell necrosis ("arterionecrosis"), by diminishing blood flow to a section of an artery (although, one would think , in my opinion, that low cholesterol would be associated with venous hemorrhage, also, and not just or even mainly with arterial hemorrhages), and that an "adequate" smooth-muscle-cell cholesterol content would reduce that arterionecrosis. The localized, necrotic death of smooth muscle cells is one explanation for reperfusion-induced or reperfusion-associated hemorrhage. It's possible that there is not a great deal of validity to that "explanation" for the association of low cholesterol with hemorrhage (the researchers' concept that a low smooth muscle cell cholesterol content might decrease the resistance of those cells to hypoxia/anoxia), and my suggestion that a "cellular-cholesterol-content-induced" increase in propionate oxidation may also not be valid. But finding evidence that would contradict those concepts would not negate the possibility that increases in, for example, the "area under the curve" for saturated, plasma free fatty acids could, for example, be associated with less depression or with improvements in the maintenance of astrocyte glycogen contents at different times during the day or during recovery from exercise, etc. There can be a tendency to view all free fatty acids as being always bad, and one could argue that this tendency has more to do with value-laden dogma about physiological processes being "good" or "bad" ("good fats" vs. "bad fats," etc.). If all free fatty acids, including palmitate and other saturated free fatty acids, are bad for cellular energy metabolism all the time, then why can resistance exercise, which elevates plasma free fatty acids significantly for prolonged periods of time but simultaneously tends to improve insulin sensitivity (elevations in FFAs normally are associated with a worsening of insulin sensitivity) and increase the capacity of skeletal muscle cells and other cell types to oxidize those fatty acids, produce improvements in mood in some people [Doyne et al., 1987: (http://www.runningtherapie.nl/Portals/0/ccp555748.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/3454786)]? I think an important distinction needs to be made, from the standpoint of energy metabolism, between saturated free fatty acids and unsaturated free fatty acids (a.k.a. nonesterified fatty acids). Saturated fatty acids do not produce all of the same inhibitory effects, on the activities of enzymes and on the binding of ligands to receptors, as unsaturated fatty acids produce. In many cases, saturated fatty acids do not produce any of the less-than-desirable "regulatory" or toxic effects, at least in experiments performed in vitro, that unsaturated fatty acids produce.
I'm not saying that elevating saturated free fatty acids is likely to be a particularly good strategy in any particular disease context, but, for example, endothelial cells in some blood vessels are known to depend on either glutamine or free fatty acids, to a significant extent, as energy substrates, particularly in the fasted state. Also, I think that inappropriate elevations in saturated plasma free fatty acids could reasonably be expected to contribute to atherosclerotic disease, particularly if those elevations occurred outside of the context of something like resistance training or some other form of exercise. But if the role of saturated free fatty acids could be investigated in some of these contexts that I've discussed, researchers might be able to develop alternative substrates for maintaining cellular energy metabolism, such as in astrocytes and neurons, and avoid the problems associated with beta-oxidation of fatty acids in the cells of adults. Beta-oxidation is not a particularly efficient or "clean" process and tends to be problematic, from the standpoint of the flux of substrates through the tricarboxylic acid cycle, etc. (problematic from the standpoint of carbohydrate metabolism). Nonetheless, I would argue that there is a need to face some of these disturbing associations. To acknowledge that free fatty acids may influence astrocyte energy metabolism in some positive ways, as, in my opinion, they may, is not to say or imply that this is "good" or that people should eat massive amounts of saturated fats or try to elevate free fatty acids artificially, outside of the context of something like strength training/resistance exercise. Rather, the idea, in my opinion, could be to research alternative cellular energy substrates, such as glutamine, etc., in those contexts.
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