Chunk #19 — Epigenetics-Relevant Consequences of Oxidative Alcohol Metabolism — Increases in NADH/NAD+ Ratio and Their Consequences — Derangement of Carbohydrate Metabolism
NAD+ mediates cytosolic energy metabolism by influencing the breakdown of glucose molecules (i.e., glycolysis) and by modulating the lactate–pyruvate conversion by lactate dehydrogenase (LDH). An increase in the NADH/NAD+ ratio interferes with both of these processes. NAD+ depletion also causes inhibition of the later steps of glucose metabolism (i.e., the tricarboxylic acid [TCA]) cycle. As NADH accumulates, NAD+ becomes depleted. As a result, oxidation of acetyl-CoA by the TCA cycle is inhibited because of a lack of oxidized coenzymes. In addition, NADH accumulation inhibits pyruvate dehydrogenase (PDH), thus decreasing the conversion of pyruvate to acetyl-CoA. Instead, NADH accumulation in the cytosol favors the conversion of pyruvate to lactate by LDH. This lowers the concentration of pyruvate, which in turn decreases the pyruvate carboxylase reaction, one of the rate limiting steps of gluconeogenesis (Krebs et al. 1969). Collectively, the increase in NADH results in the inhibition of gluconeogenesis and, during starvation, can cause clinically significant hypoglycemia.
