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 (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.

• Authors: S Shefer, L Nguyen, G Salen, A K Batta, D Brooker, F G Zaki, I Rani, G S Tint
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 85 Issue 4 Pg. 1191-8 (Apr 1990) ISSN: 0021-9738 [Print] United States
• PMID: 2318973 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Bile Acids and Salts
• Taurocholic Acid
• Hydroxymethylglutaryl CoA Reductases
• Cholesterol 7-alpha-Hydroxylase
• Mevalonic Acid

Topics

• Animals
• Bile Acids and Salts (biosynthesis)
• Cholesterol 7-alpha-Hydroxylase (analysis)
• Feedback
• Hydroxymethylglutaryl CoA Reductases (analysis)
• Male
• Mevalonic Acid (pharmacology)
• Rats
• Rats, Inbred Strains
• Structure-Activity Relationship
• Taurocholic Acid (pharmacology)