Ethanol is metabolized in the liver by NADH-producing oxidation reactions. Increase of the NADH/NAD+ ratio is responsible for hypoglycemia and hepatic fatty change following ethanol ingestion. Specifically, increased NADH/NADH+ ratio results in:
1. Decreased gluconeogenesis
2. Increased fatty acid synthesis, decreased fatty acid oxidation
due to increased conversion of oxaloacetate to malate by malate dehydrogenase
- excess NADH preferentially causes metabolism of oxaloacetate to malate, depleting
oxaloacetate and hindering gluconeogenesis
- excess NADH and acetyl-CoA stimulates fatty acid synthesis and inhibits fatty acid oxidation,
leading to fatty acid accumulation
- fatty acids combine with glycerol 3-P (also increased due to elevated NADH) to form
triacylglycerols
3. Lactic acidosis
due to increased conversion of pyruvate to lactate by lactate dehydrogenase
- pyruvate metabolism is preferably shunted to a lactate producing pathway that utilizes NADH, as opposed to entering the TCA cycle via conversion to acetyl-CoA which requires NAD+
- lactate is used for gluconeogenesis once EtOH is metabolized and NADH:NAD ratio normalizes; until then, excess lactate accumulates in serum
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