In vivo regulation of canine intestinal 3-hydroxy-3-methylglutaryl coenzyme A reductase by cholesterol, lipoprotein, and fatty acids.

Thirty-Vella-isolated ileal segments in dogs were used to study the regulation of intestinal cholesterol synthesis. This excluded fistula enabled independent in vivo manipulation of luminal and vascular influences on mucosal cells. Segments were studied repeatedly and each animal served as its own control. Cholesterol synthesis rate was assessed by measuring mucosal activity of the rate-limiting enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase. Luminal cholesterol and 25-hydroxycholesterol were shown to reduce HMG CoA reductase activity to 64 +/- 7% and 42 +/- 4%, respectively, of control within 4 hr. Reductase activity in the excluded segment also responded to alterations in serum cholesterol produced by cholesterol or cholestyramine feeding. Similarly, in vitro studies showed that lipoprotein cholesterol inhibited HMG CoA reductase in mucosa from the excluded segment but not in mucosa from intact bowel. In contrast to sterols, fatty acids stimulated HMG CoA reductase activity by luminal contact. These findings suggest that the cholesterol needs of canine intestinal epithelial cells are acutely balanced by absorption and synthesis of cholesterol. Mucosal cells may also utilize lipoprotein cholesterol under certain conditions, perhaps via low density lipoprotein receptors. Fatty acid absorption stimulated cholesterol synthesis in the absence of luminal cholesterol, perhaps to facilitate chylomicron formation.