Feedback Regulation of Cholesterol Biosynthesis

Abstract

Regulation of hepatic cholesterol biosynthesis is thought to occur at the step involving formation of mevalonate from 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA); this reaction is catalyzed by HMG-CoA reductase. Oral administration of cholestyramine, an agent that interferes with cholesterol reabsorption and is associated with a compensatory increase in hepatic cholesterol synthesis, was used to evaluate feedback regulation of cholesterol biosynthesis. Liver slices and cell-free fractions were prepared from control rats and rats fed 3% cholestyramine for 3-7 days. Cholestyramine feeding was associated with a four- to eightfold increase in incorporation of [ 14 C]acetate into cholesterol and mevalonate. However, there was no effect on incorporation of [ 14 C]acetate into CO 2 , fatty acids, or acetoacetate or on incorporation of [ 14 C]mevalonate into cholesterol, indicating stimulation at an early regulatory site prior to mevalonate formation. In fractionated liver homogenates, incorporation of [ 14 C] acetate, [ 14 C]acetyl-CoA, and [ 14 C]HMG-CoA into mevalonate increased markedly following cholestyramine administration. In the absence of microsomes, incorporation of [ 14 C]acetate and [ 14 C]acetyl-CoA into HMG was also increased. Changes in incorporation of [ 14 C]acetate into HMG, mevalonate, and cholesterol corresponded to changes in product synthesis. I concluded that (1) interruption of the enterohepatic circulation of cholesterol causes a release of feedback inhibition of cholesterol synthesis, (2) mevalonate synthesis catalyzed by HMG-CoA condensing enzyme and HMG-CoA reductase, and (3) HMG-CoA condensing enzyme, by limiting the availability of HMG-CoA, may have an important regulatory function in cholesterol biosynthesis.