FAILURE OF INTRAVENOUS-INFUSION OF TAUROCHOLATE TO DOWN-REGULATE CHOLESTEROL 7-ALPHA-HYDROXYLASE IN RATS WITH BILIARY FISTULAS

Background/Aims: The decrease in cholesterol 7 alpha-hydroxylase induc ed by intraduodenal infusion of taurocholate in bile fistula vats may be indirect, i.e., mediated through release or absorption of an intest inal factor in response to the presence of bile salts in the intestine . The aim of this study was to determine if negative feedback regulati on of cholesterol 7 alpha-hydroxylase can be shown when equimolar conc entrations of taurocholate are administered intravenously, thus bypass ing the intestine. Methods: After 96 hours of biliary diversion, tauro cholate (36 mu mol.h(-1).100 g rat(-1)) was infused into the rats eith er intravenously or intraduodenally for the final 24 hours. Livers wer e then harvested for analysis of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase specific activity, cholesterol 7 alpha-hydroxylas e specific activity, messenger RNA levels, and transcriptional activit y. Results: Intra-duodenally administered taurocholate significantly d ecreased HMG-CoA reductase and cholesterol 7 alpha-hydroxyfase specifi c activity by more than 50% and cholesterol 7 alpha-hydroxylase steady -state messenger RNA levels and transcriptional activity by 50%-75%. I n contrast, intravenous administration of taurocholate failed to down- regulate either cholesterol 7 alpha-hydroxylase or HMG-CoA reductase. Conclusions: Passage of taurocholate through the intestine strongly po tentiates negative feedback regulation of cholesterol 7 alpha-hydroxyl ase. A putative intestinal factor, released or absorbed in the presenc e of bile acids in the intestinal lumen, may play a role in the regula tion of bile acid synthesis.