This article [Lumeng et al., 1976: (http://www.jbc.org/cgi/reprint/251/2/277.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/1245472)] is interesting. The authors show that increasing glutamate availability in mitochondria, in vitro, increases beta-oxidation and ketogenesis in the absence of a high concentration of malate but suppresses beta-oxidation when the concentration of malate is high. This is somewhat reminiscent of the effects of exogenous glutamine on fatty acid oxidation in humans. There was an initial suppression of lipolysis but a subsequent acceleration of postprandial fatty acid oxidation [Iwashita et al., 2006: (http://www.ncbi.nlm.nih.gov/pubmed/16517950)]. The suppression of lipolysis presumably occurs in the adipocytes, and the fatty acid oxidation occurs in the liver or skeletal muscles, primarily. But the point is that there glutamine-derived glutamate can serve as either a lipogenic substrate or as a TCA cycle intermediate that accelerates beta-oxidation, etc. The authors are saying that, assuming the glutamate-oxaloacetate transaminase (GOT) activity is not being inhibited, an increase in intramitochondrial glutamate will, in the presence of malate (as a precursor to oxaloacetate formation by malate dehydrogenase), undergo transamination by GOT and decrease the availability of oxaloacetate as a substrate for citrate synthase. This will drive acetyl-CoA groups into ketone formation and increase the intramitochondrial NADH/NAD+ ratio, as a result of the increase in malate availability. The authors aren't clear, though, on what the mechanism is by which glutamate, in the absence of malate, increases beta-oxidation. The authors say that glutamate increases ketone formation by increasing beta-oxidation, but then the authors say that an increase in the intramitochondrial NADH/NAD+ (redox potential) occurs in association with the inhibition of beta-oxidation. But they say that glutamate augments ketogenesis by increasing beta-oxidation, and their argument is that an increase in the intramitochondrial NADH/NAD+ ratio occurs as a result of an increase in glutamate availability and in close association with the suppression of beta-oxidation. The authors note, though, that an increase in the intramitochondrial 2-oxoglutarate content will tend to limit the flux through malate dehydrogenase and thereby disinhibit beta-oxidation by preventing an excessive increase in the intramitochondrial NADH/NAD+ ratio (as a result of malate dehydrogenase activity). So that could explain the increase in beta-oxidation produced by glutamate, in the absence of malate (the authors suggest that the inhibition of beta-hydroxyacyl-CoA dehydrogenase activity by excessively-high NADH levels could account for the inhibition of beta-oxidation). But Iwashita et al. (2006) noted that an increase in the NADH/NAD+ ratio (they don't specify the location as being intramitochondrial or cytosolic) has been associated with an increase in beta-oxidation in other articles. The increase in beta-oxidation induced by glutamine, in that article, as in the other article, seems to have been the result of an increase in glutamate-derived 2-oxoglutarate in the mitochondria.
A major finding of that article, though, is that the activity and equilibrium of GOT essentially can determine the availability of oxaloacetate to citrate synthase, and the authors note that that means the overall malate-aspartate shuttle flux, as driven by GOT activity, may determine the balance between ketogenesis and beta-oxidation. That's relevant to an understanding of vitamin B6-induced peripheral neuropathy and to an understanding of its neuroprotective effects. Vitamin B6 deficiency has been shown to increase the beta-oxidation of palmitate in animals (i.e. in the liver) [Dussault and Lepage, 1979: (http://jn.nutrition.org/cgi/reprint/109/1/138.pdf)(http://www.ncbi.nlm.nih.gov/pubmed/430206)], and an excess of vitamin B6 could conceivably produce neuropathy, in part, by suppressing astrocytic beta-oxidation of free fatty acids, derived from the blood, etc. The effect could be in schwann cells or astrocytes, etc. People don't seem to realize that GOT activity is not saturated in erythrocytes, even at 150-200 mg/day of B6. I think the activity of GOT could partially account for the beneficial effects of B6 on peripheral neuropathy at doses in the range of 50-75 mg/day (50 mg/d of B6 has been shown to improve peripheral neuropathy in humans, and I don't feel like looking up the article) and also for the peripheral neuropathy that tends to develop in people taking doses that are higher than 100-125 mg/d, in the long term. When one considers that exogenous glutamate has been shown to alleviate B6-induced peripheral neuropathy in animals (I've discussed that article in past postings) but that the neuroprotective effects of B6 are dependent on transaminase activity (they can be inhibited by amino-oxyacetic acid, an inhibitor of GOT and other transaminases), it should be clear, in my opinion, that small changes in GOT activity can have profound metabolic effects. This is consistent with the content in the papers by Yudkoff and colleagues, and I've discussed their articles in past postings. They think that increases in ketone oxidation produce anticonvulsant effects by shifting the equilibrium of GOT toward glutamate formation and increasing citrate availability. That seems, at first glance, to be the opposite of the effect of glutamate, but glutamate and glutamine actually have been shown to increase citrate levels in many articles. The net effect depends on the conditions and on malate availability and GOT activity. But the point I would make is that an increase in GOT activity (and in the overall flux of substrates through the malate-aspartate shuttle) is not necessarily going to be beneficial. Although B6 is viewed as being "anaplerotic," these articles imply that there can also be a kind of "substrate-wasting anaplerosis" at high B6 intakes, given the fact that B6-induced neuropathy can be partially ameliorated by increases in intramitochondrial glutamate availability. Another way of looking at it is to say that B6-induced increases in GOT activity produce a transient, "stopgap anaplerosis" that is not true anaplerosis. In true anaplerosis, there has to be a net influx of TCA cycle intermediates other than acetyl-CoA. The adverse effects that excessive intakes of B6 can produce could be a consequence of this "disposal" and excessive efflux of TCA cycle intermediates from the mitochondria. The inhibition of beta-oxidation could also be problematic in the brain and peripheral nervous system, past a certain point. Part of this capacity of GOT activity to determine the rate of citrate formation stems from the fact that oxaloacetate is the least abundant TCA cycle intermediate, essentially all of the time. It's rapidly converted into citrate or transaminated with glutamate by GOT, to form aspartate and 2-oxoglutarate. So its steady-state level is almost always very low, and anaplerosis is most traditionally or classically defined as being a net increase in the influx of oxaloacetate into the TCA cycle.
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