Different feedback regulation of hepatic cholesterol and bile acid synthesis by glycodeoxycholic acid in rabbits.
BACKGROUND
To explore the sexual difference in the feedback regulation of hepatic bile acid synthesis, glycodeoxycholic acid (GDCA) was administered to 15 male and 14 female rabbits.


METHODS
After bile diversion, GDCA equivalent to the hepatic bile acid influx was infused intraduodenally. Biliary cholic acid output represented bile acid synthesis. Hepatic 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase and cholesterol 7 alpha-hydroxylase activities and steady state messenger RNA (mRNA) levels were determined.


RESULTS
GDCA inhibited bile acid synthesis less in female than in male rabbits. Hepatic HMG-CoA reductase activity decreased 39% in males, but increased 48% in females. Hepatic cholesterol 7 alpha-hydroxylase activity decreased similarly in males and females, and mRNA levels decreased 86% in males but were unchanged in females.


CONCLUSIONS
(1) Total bile diversion stimulated both hepatic cholesterol and bile acid synthesis by activating the rate-controlling enzymes and increasing mRNA levels. (2) GDCA decreased mRNA levels of HMG-CoA reductase and cholesterol 7 alpha-hydroxylase in males, but mRNA levels did not decrease in females. (3) Bile acid synthesis was sustained in females because continued biosynthesis of cholesterol provided a substrate for cholesterol 7 alpha-hydroxylase and stimulus for enzyme formation.
Xu
G
G
University of Medicine and Dentistry-New Jersey Medical School, Newark.
Salen
G
G
Shefer
S
S
Batta
A K
AK
Ness
G C
GC
Nguyen
L B
LB
Zhao
Z
Z
Chen
T S
TS
Niemann
W
W
Tint
G S
GS
D000818:Animals; D001646:Bile / Q000737:chemistry; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D002784:Cholesterol / Q000096:biosynthesis*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000032:analysis / Q000235:genetics; D002793:Cholic Acids / Q000032:analysis; D005246:Feedback; D005260:Female; D006002:Glycodeoxycholic Acid / Q000494:pharmacology*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000032:analysis / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D011817:Rabbits
D001647:Bile Acids and Salts; D002793:Cholic Acids; D012333:RNA, Messenger; D006002:Glycodeoxycholic Acid; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D002790:Cholesterol 7-alpha-Hydroxylase