This article [King et al., 2001: (http://ajpheart.physiology.org/cgi/content/full/280/3/H1173)(http://www.ncbi.nlm.nih.gov/pubmed/11179061?dopt=Abstract)] is interesting, and the authors found that exogenous palmitate, a saturated free fatty acid, was able to protect against damage to the hearts of diabetic rats during partial ischemia. King et al. (2001) also found that exogenous ketones were not protective. This type of research is consistent with one interpretation, as discussed previously (http://hardcorephysiologyfun.blogspot.com/2009/04/low-cholesterol-levels-and-risk-of.html), of research showing that very low cholesterol levels have been associated with higher incidences of intracranial hemorrhages/hemorrhagic strokes and deaths by suicide. King et al. (2001) found that exogenous palmitate had exerted an inhibitory influence on the overall rate of glycolysis, during ischemia, but had nonetheless been oxidized, even during ischemia, so as to produce a net augmentation of ATP production. The authors also noted that palmitate may have produced even more inhibition of the pyruvate dehydrogenase (PDH) multienzyme complex than had already been produced, in the diabetic rat hearts, from the effects of diabetes per se. The authors, additionally, discussed the fact that ketone-metabolizing enzymes are likely to be inhibited during ischemia, particularly in cardiac myocytes of diabetic rats, for various reasons. The ischemia-associated (and streptozotocin-induced) inhibition of ketone utilization may have contributed to the failure of exogenous beta-hydroxybutyrate to provide protection against ischemic/postischemic injuries (King et al., 2001).
Another specific factor the authors were getting at is that an elevation of lactate, which the authors found had occurred during ischemia, especially in the diabetic rats' hearts, tends to elevate the cytosolic NADH/NAD+ ratio, and this can, in cells with diminished oxidative capacity, lead to a decrease in the intramitochondrial NAD+/NADH ratio and inhibit enzymes whose activities are sensitive to changes in the NAD+/NADH ratio. This "translation" of the cytosolic redox state into the mitochondria occurs via the transport of substrates, such as aspartate and malate, into and out of the mitochondria, such as through the transporters that comprise the malate-aspartate shuttle. King et al. (2001) discuss research showing that the oxidation of lactose in cells from diabetic animals and humans is inhibited in a "specific" manner.
One thing that the authors may be getting at is that elevations in lactate and the lactate/pyruvate ratio, such as occur during the activation of anaerobic glycolysis during ischemia, can lead to the inhibition of the TCA cycle. An elevation in the lactate/pyruvate ratio is accompanied by an elevation in the NADH/NAD+ ratio and can, via the exchange of substrates across the outer mitochondrial membrane, decrease the intramitochondrial NAD+/NADH ratio and thereby inhibit the activities of TCA cycle enzymes. By inhibiting glycolysis, palmitate and, as the authors mention, hexanoate, may be essentially buffering the cytosolic NADH/NAD+ ratio. The authors also noted that the overall activity of the pyruvate dehydrogenase (PDHC) complex tends to be lower in the cardiac cells (and other cell types) of rats and humans with diabetes and that, in the face of a limited capacity of the cells to oxidize glucose, the exogenous palmitate had at least served as a substrate that the cells could oxidize. In other words, the PDHC activity would ideally have been higher and have allowed the cells to use glucose instead of palmitate, but the cells could only oxidize so much glucose and metabolize so much glucose, by glycolysis, without deranging the cytosolic redox state. In a context, such as the ischemic, diabetic heart, in which glucose metabolism is necessarily going to be deranged, fatty acid oxidation can evidently ameliorate the postischemic damage. King et al. (2001) also noted that other researchers had previously found exacerbations in postischemic injuries in response to exogenous palmitate, in part, as suggested by the authors, because other researchers had typically used total ischemia in their animal models. Total ischemia obviously prevents any oxidative metabolism from proceeding and prevents the utilization of palmitate or other saturated FFAs. Lloyd et al. (2004) found that the oxidative metabolism of many substrates, including palmitate, can make an important contribution to ATP production during ischemia that is even relatively severe [Lloyd et al., 2004: (http://ajpheart.physiology.org/cgi/content/full/287/1/H351)(http://www.ncbi.nlm.nih.gov/pubmed/15001444?dopt=Abstract)].
These articles [Bastiaanse et al., 1997: (http://cardiovascres.oxfordjournals.org/cgi/content/full/33/2/272)(http://www.ncbi.nlm.nih.gov/pubmed/9074689?dopt=Abstract); Bastiaanse et al., 1994: (http://www.ncbi.nlm.nih.gov/pubmed/8072018); Vauthey et al., 2000: (http://www.ncbi.nlm.nih.gov/pubmed/10822434); Olsen et al., 2007: (http://www.ncbi.nlm.nih.gov/pubmed/17761907); Zuliani et al., 2004: (http://www.ncbi.nlm.nih.gov/pubmed/15031316)] show that higher serum cholesterol levels or cell-membrane cholesterol levels (sarcolemmal cholesterol is plasma membrane cholesterol in cardiac myocytes) are associated with improvements in the tolerance of the cultured cells or various cell types, subjected to ischemia in vivo, to anoxia or ischemia. Three of those articles provide evidence that higher serum cholesterol levels are associated with the occurrence of less severe strokes and with decreases in the risk of post-stroke death. It's important to note that those studies do not evidently show that higher cholesterol levels reduce the risk of stroke, and it may be the case, in my opinion, that a person with "higher" cholesterol levels could have "more strokes" but have "less severe strokes," etc. The articles don't really show, in my opinion, that cholesterol is "good," and Bastiaanse et al. (1997) discuss research showing that higher plasma membrane cholesterol concentrations, in smooth muscle cells, can increase calcium influx. That would be undesirable both under "baseline," day-to-day conditions and during a stroke. Bastiaanse et al. (1997) also discuss research showing that plasma membrane cholesterol is degraded en masse, during ischemia, and that some of that cholesterol that isn't degraded is transported to the mitochondrial membranes, etc. It sounds as if some of it is, in fact, degraded to propionate and oxidized, in my opinion.
Cholesterol degradation can contribute to the propionate pool, and propionate can serve, via its metabolism into succinyl-CoA, as an anaplerotic substrate, but I'm not sure if the amounts of cholesterol-derived propionate would be large enough to contribute meaningfully to ATP production. The oxidation of cholesterol-derived propionate, a saturated, odd-chain "free fatty acid" (the term does not really apply to fatty acids that are formed intracellularly and oxidized in an autocrine manner), could conceivably help to maintain ATP production during partial ischemia. Again, I'm not sure if a significant amount would be formed from cholesterol. My guess is that it would, but I can't provide quantitative support of that supposition.
Another possibility is that the membrane cholesterol content exerts some regulatory effect on AMPK expression or on energy metabolism, etc. A lot of the research on that type of regulation has been centered around the feedback suppression of HMG-CoA reductase activity by cholesterol itself, in the liver. One reason I suggested that increases, past some critical level, in saturated FFAs as a factor that could mediate protection against hemorrhage or "suicidal-depression-associated" impairments in astrocyte energy metabolism is that most of the cholesterol in the brain is thought to be made in situ, or locally in the brain. It's conceivable that there's some combination of an impairment in the oxidation of fatty acids, derived from the blood, and intracellular fatty acid synthesis, from glucose or glutamine or other substrates, in astrocytes or cerebral capillary endothelial cells, in people who become suicidally depressed. These are just my opinions and thoughts, but it's interesting that, for example, glutamine can serve as an energy substrate for astrocytes, a role that tends to be accompanied by the transient or partial inhibition of lipolysis and beta-oxidation of FFAs, a "lipogenic" substrate, and a factor that has been shown to increase the oxidation of fatty acids [Iwashita et al., 2006: (http://www.ncbi.nlm.nih.gov/pubmed/16517950); (http://hardcorephysiologyfun.blogspot.com/2009/02/glutamine-decreases-plasma-free-fatty.html)]. A pronounced decrease in plasma FFAs might produce more of a decrease in brain cholesterol levels than a reduction in plasma cholesterol per se would, in my opinion. My current sense of the relationships is that a higher saturated fat intake will not especially reliably increase total serum cholesterol levels (via an increase in LDL cholesterol levels) in people with extremely low cholesterol levels, even though high saturated fat intakes do seem to be associated with higher total cholesterol levels. I would think that glucocorticoid resistance, in the context of chronic stress and depression, would impair the regulation of energy metabolism, via AMPK phosphorylation or dephosphorylation, for example, and confound a lot of these attempts to apply experimental results from nondepressed people to an understanding of the physiology at work in suicidal depression. But the presence of high cholesterol levels, from any cause, seems to be associated with higher FFA levels. Plasma ketone levels do not seem to reliably correlate with cholesterol levels, as shown in this article [Fukuda et al., 1991: (http://www.ncbi.nlm.nih.gov/pubmed/1897904)]. That's not a good example, but my point is that some kind of predictable relationship between plasma FFA levels and total cholesterol may be absent among severely depressed people, across a lower range of cholesterol levels, but may be present among people who are at the upper ranges of total cholesterol levels. And the extents to which FFAs are available for utilization (referring to the rate of uptake into the brain) or are utilized as energy substrates (referring to the rate at which they are oxidized) or cholesterol precursors by, for example, astrocytes, may not show reliable relationships with changes in the plasma FFA level.
Given the associations of depression with cardiovascular disease, it's conceivable to me that impairments in energy metabolism in the brain or cerebral vascular endothelial cells could impair the utilization of blood-borne FFAs, and so the issue might be as much about the rate of utilization of FFAs by astrocytes as it might be about the rate of uptake of FFAs into the brain. Even in the face of this poor utilization, it's conceivable that ATP production in astrocytes or endothelial cells could be very sensitive to small changes in plasma FFAs. I can't think or read about this topic any more right now. Obviously, these are only my opinions, and I'm not attempting to view any of this research in the context of any particular value system. Maybe the endothelial cells metabolize FFAs poorly in people who experience depression and allow saturated acyl-CoAs to accumulate, thereby interfering with oxidative metabolism and contributing to atherosclerosis. This accumulation could simultaneously restrict the transport of FFAs and other substrates into the brain, thereby leading to reductions in ATP production or membrane cholesterol biosynthesis in situ, etc. I think it's also likely to be important to differentiate, in research on these topics and associations, between people who have severe depression and may be suicidally depressed and those who have less severe depression. In any case, it's not a pleasant topic to think about or discuss.
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