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

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., & Bjorkhem, 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 DELTA5 double bond is required for the suppression. It was shown that cholestanol, which does not have a DELTA5 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, [3alpha-H-2]cholesterol, and [7,7-H-2(2)]cholesterol with control groups fed cholesterol or a cholesterol-free diet. These cholesterol analogues were selected to interefere 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. The results seem to exclude that a transformation of cholesterol in the region C-3 to C-7 is required for down-regulation of HMG-CoA reductase by dietary cholesterol and show that the DELTA5 double bond is essential. The results are consistent with the possibility that cholesterol itself is the most important suppressor of HMG-CoA reductase, at least in the specific strain of mice studied.