Hepatic cholesterol synthesis from mevalonate and squalene in rats: Effect of feeding cholesterol supplemented diet during weaning and following starvation

Abstract

The conversion of squalene to digitonin precipitable sterols by microsomes and soluble fractions from liver and the incorporation of mevalonate into nonsaponifiable lipids and digitonin precipitable sterols by 5000 g liver supernatant was studied in suckling rats and rats weaned on diet (Purina chow) supplemented with varying levels of cholesterol. The results indicate that the conversion of squalene to digitonin precipitable sterols was low in suckling rats and high in rats weaned on Purina chow diet. Weaning rats on 1% cholesterol supplemented diet effectively eliminated the post-weaning increase in mevalonate incorporation into nonsaponifiable and digitonin precipitable sterols, and in the conversion of squalene to digitonin precipitable sterols. The incorporation of mevalonate into nonsaponifiable lipids and digitonin precipitable sterols, and of squalene into digitonin precipitable sterols also was studied in liver preparations from adult rats which were starved and refed control or cholesterol supplemented diet. It was observed that the conversion of squalene to digitonin precipitable sterols by liver fractions from fasted rats was low, while that by liver fractions from rats refed control diet was higher. Furthermore, the post-fasting increase in the conversion of mevalonate to nonsaponifiable lipids and digitonin precipitable sterols and in squalene to digitonin precipitable sterols conversion essentially was eliminated by refeeding a 1% cholesterol supplemented diet. The low conversion of squalene to digitonin precipitable sterols in suckling rats, rats weaned on cholesterol supplemented diet, and adult rats that were starved, or starved and refed cholesterol supplemented diet, was due to the reduced activity of microsomal enzymes. It is concluded from this study that dietary cholesterol prevents the increase in cholesterol synthesis observed in developing and regenerating liver by suppressing the activities of one or more enzymes between mevalonate and squalene and between squalene and cholesterol.