Regulation of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase and cholesterol synthesis.

Rat liver microsomal 3-hydroxy-3-methylglutaric acid (HMG)-coenzyme A reductase (mevalonate:NADP oxidoreductase (acylating CoA), EC 1.1.1.34) exhibits a cyclic rhythm with peak activity at midnight. HMG-CoA reductase from microsomes of rats killed at noon and midnight has similar properties. Cycloheximide completely prevents the 5to IO-fold rise in activity which occurs from 6 p.m. to midnight, suggesting that the rise in act‘ivity is due to synthesis of new enzyme. The effect of cycloheximide is paralleled by short duration cholesterol feeding, which blocks the cyclic rise in activity. Cholesterol does not appear to act as a feedback inhibitor of HMG-CoA reductase. Mixing experiments indicate that the livers of cholesterol-fed rats do not contain a soluble inhibitor of HMG-CoA reductase. Cholesterol-rich lipoproteins isolated from livers of cholesterol-fed rats and added to incubations at concentrations from 0.01 to 10 m&r cholesterol did not inhibit HMG-CoA reductase from control animals. After 4 hours of cholesterol feeding, liver cholesterol concentration begins to increase and acetate incorporation into cholesterol begins to decrease sharply. The decline in cholesterol synthesis measured in a liver mince closely parallels the decline in HMG-CoA reductase activity. The observed changes in HMG-CoA reductase activity thus appear to be an accurate reflection of changes in the intracellular rate of cholesterol synthesis. After 10 hours of cholesterol feeding, acetate incorporation into cholesterol and HMG-CoA reductase activity are 22% and 19% of control values, respectively. The incorporation of acetyl-CoA into HMG-CoA and of mevalonic acid into cholesterol is unchanged. Under these conditions HMGCoA reductase appears to be the sole regulatory site between acetyl-CoA and cholesterol.