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

Abstract

We studied the effect of the orientation of the 7-hydroxyl group in taurocholate (7a) and tauroursocholate (7ft) on the feedback regulation of bile-acid synthesis and its rate-controlling enzyme, cholesterol 7a-hydroxylase, in bile-fistula rats. To ensure a constant supply of cholesterol and to label newly synthesized bile acids, RS[2-'4Clmevalonolactone was infused intraduodenally at 154 ,imol/h before and during bile-acid infusion. Mevalonolactone inhibited hydroxymethyl-glutaryl CoA reductase activity 90% but did not increase bile-acid synthesis and cholesterol 7a-hydroxylase activity. When sodium taurocholate was infused at the rate of 27 ,umol/100 g rat per h (equivalent to the hourly hepatic bile-acid flux), bile-acid synthesis decreased 82% and cholesterol 7a-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 7a-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 7a-hydroxylase. In these experiments, taurocholate was a far more potent inhibitor than its 70-hydroxy epimer, tauroursocholate. (J.

Regulation of cholesterol and bile acid homoeostasis in bile-obstructed rats

“…In regard to the first possibility, Heuman et al [38] have shown that the hydrophilic bile acid ursodeoxycholic acid does not inhibit 7a-hydroxylase, whereas more hydrophobic bile acids do. These data have been confirmed by others [39]. Our data show that the relatively hydrophilic bile acid ,3-muricholic acid accumulates in the greatest quantities (10-fold increase) in the livers of bile-duct-ligated rats.…”

Coenzyme Q in pregnant women and rats with intrahepatic cholestasis

“…Furthermore, it may be related to a hepatic paradox previously described in animal models of cholestasis including EE‐cholestasis. Despite increased hepatic BA, the activity of HMG‐CoA reductase and 7alpha hydroxylase is increased . These authors explained this paradox by showing that increased hydrophilic BA in cholestatic livers do not result in enzyme inhibition.…”

Biliary lipids, cholesterol and bile synthesis: different adaptive mechanisms to dietary cholesterol in lean and obese subjects

“…Until recently, bile acids were considered to be produced via a single so‐called classic or neutral pathway. The first and rate‐controlling reaction, the conversion of cholesterol to 7 α ‐hydroxy‐cholesterol, is catalysed by the microsomal enzyme cholesterol 7 α ‐hydroxylase (CYP7A1), 8 which is feedback controlled by the hepatic bile acid flux 9, 10 . Lately, it has become evident 11, 12 that a fraction of bile acids may be synthesized via an alternative pathway.…”