Feedback regulation of bile-acid synthesis in the rat. Differing effects of taurocholate and tauroursocholate

We studied the effect of the orientation of the 7-hydroxyl group in taurocholate (7 alpha) and tauroursocholate (7 beta) on the feedback regulation of bile-acid synthesis and its rate-controlling enzyme, cholesterol 7 alpha-hydroxylase, in bile-fistula rats. To ensure a constant supply of cholesterol and to label newly synthesized bile acids, RS[2-14C]mevalonolactone was infused intraduodenally at 154 mumol/h before and during bile-acid infusion. Mevalonolactone inhibited hydroxymethyl-glutaryl CoA reductase activity 90% but did not increase bile-acid synthesis and cholesterol 7 alpha-hydroxylase activity. When sodium taurocholate was infused at the rate of 27 mumol/100 g rat per h (equivalent to the hourly hepatic bile-acid flux), bile-acid synthesis decreased 82% and cholesterol 7 alpha-hydroxylase activity declined 78%. This inhibitory effect was observed in the absence of hepatic damage. In contrast, sodium tauroursocholate infused at the same rate did not decrease bile-acid synthesis nor cholesterol 7 alpha-hydroxylase activity. Hepatic cholesterol content rose 36% with sodium taurocholate but did not change during sodium tauroursocholate administration. These results demonstrate that the feedback inhibition of bile-acid synthesis is mediated through the regulation of cholesterol 7 alpha-hydroxylase. In these experiments, taurocholate was a far more potent inhibitor than its 7 beta-hydroxy epimer, tauroursocholate.