Cholesterol, bile acid, and lipoprotein metabolism in two strains of hamster, one resistant, the other sensitive (LPN) to sucrose-induced cholelithiasis

A comprehensive study of cholesterol, bile acid, and lipoprotein metabolism was undertaken in two strains of hamster that differed markedly in their r esponse to a sucrose-rich/low fat diet. Under basal conditions, hamsters fr om the LPN strain differed from Janvier hamsters by a lower cholesterolemia , a higher postprandial insulinemia, a more active cholesterogenesis in bot h liver [3- to 4-fold higher 3-hydroxy 3-methylglutaryl coenzyme A reductas e (HMG-CoAR) activity and mRNA] and small intestine, and a lower hepatic ac yl-coenzyme A:cholesterol acyltransferase activity. Cholesterol saturation indices in the gallbladder bile were similar for both strains, but the lipi d concentration was 2-fold higher in LPN than in Janvier hamsters. LPN hams ters had a lower capacity to transform cholesterol into bile acids, shown b y the smaller fraction of endogenous cholesterol converted into bile acids prior to fecal excretion (0.34 vs. 0.77). In LPN hamsters, the activities o f cholesterol 7 alpha -hydroxylase (C70Hase) and sterol 27-hydroxylase (S27 0Hase), the two rate-limiting enzymes of bile acid synthesis, were dispropo rtionably lower (by 2-fold) to that of HMG-CoAR. When fed a sucrose-rich di et, plasma lipids increased, dietary cholesterol absorption improved, hepat ic activities of HMG-CoA reductase, C70hase, and S270Hase were reduced, and intestinal S270Hase was inhibited in both strains. Despite a similar incre ase in the biliary hydrophobicity index due to the bile acid enrichment in chenodeoxycholic acid and derivatives, only LPN hamsters had an increased l ithogenic index and developed cholesterol gallstones (75% incidence), where as Janvier hamsters formed pigment gallstones (79% incidence). These studie s indicate that LPN hamsters have a genetic predisposition to sucrose-induc ed cholesterol gallstone formation related to differences in cholesterol an d bile acid metabolism.