Abstract
Bile acid biosynthesis has been believed to be regulated by negative feedback control; however, recent experiments have cast considerable doubts on the concept. The aim of the study was to examine the consensus of the negative feedback regulation of bile acids by clarifying the correlation between the portal bile acids and the rate-limiting enzyme of bile acid biosynthesis, hepatic microsomal cholesterol 7 alpha-hydroxylase. We measured the enzyme activity and the portal bile acids in male Wistar rats that were orally administered three different bile acids or cholestyramine for 2 weeks. The serum level of 7 alpha-hydroxycholesterol was also determined to verify whether it would be a parameter of bile acid synthesis rate in the rat. The activity of cholesterol 7 alpha-hydroxylase increased about threefold in rats treated with cholestyramine when compared with controls. On the other hand, in rats fed ursodeoxycholic, chenodeoxycholic, and deoxycholic acids, the enzyme activities decreased to 40%, 26%, and 28%, respectively. Treatment with cholestyramine had no significant effect on the portal bile acid concentration. Administration of ursodeoxycholic and chenodeoxycholic acids resulted in a significant increase in the concentration of portal bile acids, whereas deoxycholic acid feeding did not significantly affect it. In the control group, conjugated cholic acid constituted a major part of the portal bile acids while the administered bile acid and its metabolites became predominant in each bile acid feeding group. Treatment with ursodeoxycholic acid made the portal bile acids more hydrophilic, but, by contrast, administration of chenodeoxycholic, deoxycholic acids, and cholestyramine made the portal bile acids more hydrophobic.(ABSTRACT TRUNCATED AT 250 WORDS)
Highlights
110 We conclude that bile acid synthesis is not regulated directly by the portal bile acids returning to the liver and that the serum level of 7a-hydroxycholesterol would be a good indicator of bile acid biosynthesis rate in the rat.- Fukushima, K., H
Treatments with different bile acids or cholestyramine, and the light-dark cycle affected the activities of cholesterol 7a-hydroxylase and the portal bile acids in rats
The enzyme activity of cholesterol7a-hydroxylase in the mid-dark group was twofold higher than that in the mid-light group. This was in agreement with other reports that bile acid synthesis exhibits a marked diurnal rhythm with a maximum occurring at midnight and a minimum at midday in normal [6, 32], cholestyraminefed [6], bile fistula [6], or bile acid-treated [33] rats
Summary
P < 0.01). 110 We conclude that bile acid synthesis is not regulated directly by the portal bile acids returning to the liver and that the serum level of 7a-hydroxycholesterol would be a good indicator of bile acid biosynthesis rate in the rat.- Fukushima, K., H. Regulation of bile acid synthesis in the rat: relationship between hepatic cholesterol 7a-hydroxylase activity and portal bile acids. It has been the belief that the activity of cholesterol 7a-hydroxylase is regulated by bile acids returning to the liver. Pandak et al [12] recently reported that administration of bile acid intraduodenally, but not intravenously, down-regulated cholesterol 7a-hydroxylase activity. Absence of negative feedback control of bile acid biosynthesis in cultured or freshly suspended hepatocytes has been reported [16,17,18], whereas more recent studies have shown down-regulation of cholesterol 7ahydroxylase activity, m-RNA levels, and transcriptional activity by bile acids in primary rat hepatocytes [19, 20]
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