Regulation of bile acid synthesis. I. Effects of conjugated ursodeoxycholate and cholate on bile acid synthesis in chronic bile fistula rat.
Bile acid synthesis is thought to be regulated by a negative feedback mechanism which is presumably dependent upon the flux of bile acids in the enterohepatic circulation. To characterize further the role of bile acids in regulation of bile acid synthesis, we have administered pure taurine or glycine conjugates of ursodeoxycholic acid or cholic acid to chronic bile fistula rats by continuous intraduodenal infusion, thus simulating restoration of the enterohepatic circulation. The effects of these bile salt infusions on bile acid synthesis, biliary cholesterol and phospholipid secretion and on the activities of the hepatic microsomal enzymes cholesterol 7 alpha-hydroxylase and HMG-CoA reductase were evaluated. Because the rate of biliary bile salt secretion in rats with intact exteriorized enterohepatic circulation averaged 27.1 +/- 1.4 mumoles per 100 gm rat per hr, infusion rates for bile fistula studies were chosen to match (24 to 36 mumoles per 100 gm rat per hr) or exceed (48 mumoles per 100 gm rat per hr) this physiological flux. Infusion of tauroursodeoxycholic acid for 48 hr at 24 and 48 mumoles per 100 gm rat per hr failed to suppress cholic acid synthesis. Bile flow and biliary cholesterol and phospholipid secretion exhibited small, dose-dependent increases with tauroursodeoxycholic acid infusions. No suppression of cholesterol 7 alpha-hydroxylase or HMG-CoA reductase activity was observed. By contrast, taurocholic acid inhibited synthesis of chenodeoxycholate and its metabolites alpha- and beta-muricholate by 10% (NS), 66% (p less than 0.05) and 75% (p less than 0.05) at infusion rates of 24, 36 and 48 mumoles per 100 gm rat per hr, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
Heuman
D M
DM
Division of Gastroenterology, McGuire Veterans Administration Medical Center, Richmond, Virginia 23249.
Hernandez
C R
CR
Hylemon
P B
PB
Kubaska
W M
WM
Hartman
C
C
Vlahcevic
Z R
ZR
D000818:Animals; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D001658:Biliary Fistula / Q000201:enzymology / Q000378:metabolism*; D002635:Chenodeoxycholic Acid / Q000096:biosynthesis / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism; D019826:Cholic Acid; D002793:Cholic Acids / Q000494:pharmacology*; D002908:Chronic Disease; D003840:Deoxycholic Acid / Q000031:analogs & derivatives*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D008297:Male; D010743:Phospholipids / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D013654:Taurine / Q000378:metabolism; D014580:Ursodeoxycholic Acid / Q000031:analogs & derivatives / Q000494:pharmacology*
D001647:Bile Acids and Salts; D002793:Cholic Acids; D010743:Phospholipids; D003840:Deoxycholic Acid; D002635:Chenodeoxycholic Acid; D013654:Taurine; C024033:glycoursodeoxycholic acid; D014580:Ursodeoxycholic Acid; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D002790:Cholesterol 7-alpha-Hydroxylase; D019826:Cholic Acid