Down-regulation of hepatic HMG-CoA reductase in mice by dietary cholesterol: importance of the delta 5 double bond and evidence that oxidation at C-3, C-5, C-6, or C-7 is not involved.

Abstract

It has been suggested that the down-regulation of hepatic HMG-CoA reductase by dietary cholesterol requires modification of the cholesterol molecule before it can exert its suppressive action. In a recent study [Lund, E., Breuer, O., & Björkhem, I. (1992) J. Biol. Chem. 267, 25092-25097], we showed that side-chain hydroxylation is not likely to be of importance for this down-regulation in male C57BL/6J mice. In this study, we studied the possibility that modification of cholesterol in the region around the delta 5 double bond is required for the suppression. It was shown that cholestanol, which does not have a delta 5 double bond but is otherwise identical to cholesterol, is a poor suppressor of HMG-CoA reductase activity. Groups of mice were fed with diets containing cholestanol, epicholesterol, 6-methylcholesterol, 6-fluorocholesterol, [3 alpha-2H]cholesterol, and [7,7-2H2]cholesterol with control groups fed cholesterol or a cholesterol-free diet. These cholesterol analogues were selected to interfere with potential in vivo modifications and to clarify structural requirements for the down-regulation. After sacrifice, the hepatic HMG-CoA reductase activity was assayed. Cholesterol, 6-methylcholesterol, and 6-fluorocholesterol were efficient suppressors whereas cholestanol and epicholesterol only had a low suppressive capacity. Differences in the degree of absorption from the intestine or degree of esterification were too small to explain the differences in HMG-CoA reductase suppressing capacity. The two deuterated cholesterol species had a suppressive capacity similar to that of unsubstituted cholesterol.(ABSTRACT TRUNCATED AT 250 WORDS)