Bile acid synthesis in humans: regulation of hepatic microsomal cholesterol 7 alpha-hydroxylase activity.
The present work tested the hypothesis that portal venous bile acids regulate the activity of the cholesterol 7 alpha-hydroxylase and studied the influence of hepatic microsomal free cholesterol concentration on the enzyme activity. Operative liver biopsies and samples of portal venous blood were obtained from a total of 61 patients with gallstones who were undergoing cholecystectomy. Fifteen of the patients were treated with cholestyramine (16 g/day) for 2-3 wk before operation and 23 patients with chenodeoxycholic acid (15 mg/kg.day) or ursodeoxycholic acid (15 mg/kg.day) for 3-4 wk before operation. Highly accurate methods based on isotope dilution-mass spectrometry were used for assay of the cholesterol 7 alpha-hydroxylase activity, the concentration of free cholesterol in the microsomes, and the levels of individual bile acids in portal venous blood. Cholestyramine treatment increased the cholesterol 7 alpha-hydroxylase activity about sixfold, from 7.6 +/- 1.1 (mean +/- SEM) to 45.7 +/- 6.7 pmol/min.mg protein. Administration of chenodeoxycholic acid reduced the enzyme activity considerably to 1.0 +/- 0.3 pmol/min.mg protein, whereas ursodeoxycholic acid did not significantly affect the enzyme activity (7.9 +/- 2.2 pmol/min.mg protein). The concentration of microsomal free cholesterol remained essentially unchanged in spite of a 45-fold variation in enzyme activity. There was a negative correlation between the absolute as well as the relative concentration of chenodeoxycholic acid in portal blood and the activity of the cholesterol 7 alpha-hydroxylase, whereas there was no correlation between the total concentration of bile acids and the enzyme activity. It is concluded that the composition of individual bile acids may be more important than the total concentration of bile acids in the portal vein for the regulation of the cholesterol 7 alpha-hydroxylase activity in humans. It is further concluded that chenodeoxycholic acid is a considerably stronger suppressor of bile acid synthesis than ursodeoxycholic acid.
Reihnér
E
E
Department of Surgery, Karolinska Institutet, Huddinge University Hospital, Sweden.
Björkhem
I
I
Angelin
B
B
Ewerth
S
S
Einarsson
K
K
D000328:Adult; D000368:Aged; D001646:Bile / Q000032:analysis; D001647:Bile Acids and Salts / Q000032:analysis / Q000096:biosynthesis; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D002784:Cholesterol / Q000032:analysis; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism*; D002792:Cholestyramine Resin / Q000494:pharmacology; D005260:Female; D006801:Humans; D008055:Lipids / Q000032:analysis; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology*; D008875:Middle Aged; D013250:Steroid Hydroxylases / Q000378:metabolism*; D014580:Ursodeoxycholic Acid / Q000494:pharmacology
D001647:Bile Acids and Salts; D008055:Lipids; D002635:Chenodeoxycholic Acid; D002792:Cholestyramine Resin; D014580:Ursodeoxycholic Acid; D002784:Cholesterol; D013250:Steroid Hydroxylases; D002790:Cholesterol 7-alpha-Hydroxylase