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.
Shefer
S
S
Department of Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark 07103.
Nguyen
L
L
Salen
G
G
Batta
A K
AK
Brooker
D
D
Zaki
F G
FG
Rani
I
I
Tint
G S
GS
D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000032:analysis; D005246:Feedback; D006903:Hydroxymethylglutaryl CoA Reductases / Q000032:analysis; D008297:Male; D008798:Mevalonic Acid / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D013656:Taurocholic Acid / Q000494:pharmacology*
D001647:Bile Acids and Salts; D013656:Taurocholic Acid; D006903:Hydroxymethylglutaryl CoA Reductases; D002790:Cholesterol 7-alpha-Hydroxylase; D008798:Mevalonic Acid