Failure of intravenous infusion of taurocholate to down-regulate cholesterol 7 alpha-hydroxylase in rats with biliary fistulas.
OBJECTIVE
The decrease in cholesterol 7 alpha-hydroxylase induced by intraduodenal infusion of taurocholate in bile fistula rats may be indirect, i.e., mediated through release or absorption of an intestinal factor in response to the presence of bile salts in the intestine. The aim of this study was to determine if negative feedback regulation of cholesterol 7 alpha-hydroxylase can be shown when equimolar concentrations of taurocholate are administered intravenously, thus bypassing the intestine.


METHODS
After 96 hours of biliary diversion, taurocholate (36 mumol.h-1.100 g, rat-1) was infused into the rats either intravenously or intraduodenally for the final 24 hours. Livers were then harvested for analysis of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase specific activity, cholesterol 7 alpha-hydroxylase specific activity, messenger RNA levels, and transcriptional activity.


RESULTS
Intraduodenally administered taurocholate significantly decreased HMG-CoA reductase and cholesterol 7 alpha-hydroxylase specific activity by more than 50% and cholesterol 7 alpha-hydroxylase steady-state messenger RNA levels and transcriptional activity by 50%-75%. In 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 potentiates negative feedback regulation of cholesterol 7 alpha-hydroxylase. A putative intestinal factor, released or absorbed in the presence of bile acids in the intestinal lumen, may play a role in the regulation of bile acid synthesis.
Department of Medicine, Medical College of Virginia, Virginia Commonwealth University, Richmond.
W M
WM
Pandak
D M
DM
Heuman
P B
PB
Hylemon
J Y
JY
Chiang
Z R
ZR
Vlahcevic
D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis; D001658:Biliary Fistula / Q000201:enzymology* / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000187:drug effects / Q000378:metabolism*; D015536:Down-Regulation; D006903:Hydroxymethylglutaryl CoA Reductases / Q000187:drug effects / Q000378:metabolism; D007262:Infusions, Intravenous; D008297:Male; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013656:Taurocholic Acid / Q000008:administration & dosage* / Q000494:pharmacology; D013997:Time Factors
D001647:Bile Acids and Salts; D012333:RNA, Messenger; D013656:Taurocholic Acid; D006903:Hydroxymethylglutaryl CoA Reductases; D002790:Cholesterol 7-alpha-Hydroxylase