Feedback regulation of bile acid biosynthesis

The possibility that the biosynthesis of bile acids is regulated by a negative feedback mechanism was supported by early experiments by Thompson and Vars [206] and Eriksson [207], who showed that the rate of bile acid synthesis in rats increased about 10-fold when a bile fistula is made. Bergstrom and Danielsson demonstrated that duodenal infusion of taurochenodeoxycholic acid in bile fistula rats restored the increased synthesis to a normal rate [208]. Danielsson et al. [44] showed that the cholesterol 7a-hydroxylase activity increased in parallel with the bile acid synthesis after cannulation of the bile duct in rats. In a subsequent work by Mosbach et al., it was reported that the incorporation of isotope from labelled acetate, mevalonate and cholesterol but not from labelled 7a-hydroxycholesterol into bile acids was inhibited by duodenal infusion of taurocholate to bile fistula rats [209]. The incorporation of isotope from labelled acetate, mevalonate and cholesterol but not from labelled 7a-hydroxycholesterol was stimulated in perfused livers of cholestyramine-treated rabbits [210]. It was concluded that there are essentially no rate-limiting steps beyond 7a-hydroxycholesterol in the biosynthesis of bile acids from acetate. Since both cholesterol and bile acid biosynthesis was subjected to negative feedback inhibition by bile acids, it cannot be excluded that inhibition of cholesterol biosynthesis precedes inhibition of the bile acid biosynthesis, and that the latter inhibition is secondary to the former. 

The specificity of the inhibitory effect of bile acids on bile acid formation has been studied by Danielsson [110]. Taurocholic acid, taurochenodeoxycholic acid and taurodeoxycholic acid, fed at the 1% level in the diet for 3-7 days, were found to inhibit cholesterol 7a-hydroxylase activity. Feeding taurohyodeoxycholic acid and 

The possibility that cholesterol 7a-hydroxylase is directly inhibited by bile acids was studied by Mosbach et al. by addition of bile acids or bile salts to microsomal suspension [62]. An inhibition was observed, but this was probably due to non-specific detergent effects. From the time lag observed in the stimulation of bile acid biosynthesis after introduction of a bile fistula, it may be concluded that the effects of the bile acids most probably are mediated by effects on protein synthesis or protein catabolism. 

Dowling et al. and Small et al. have studied the effects of controlled interruption of the enterohepatic circulation in monkeys [216-218]. It was shown that the regulation of the bile acid biosynthesis was of all or none type. It was established that the increased bile acid biosynthesis in response to interruption of the enterohepatic circulation was limited and reached a maximum rate at only 20% interruption. Up to this level, the increased bile salt loss was compensated for by increased synthesis loss so that bile salt secretion and pool size were maintained at normal levels. With diversion of 37% or more, there was no further increase in hepatic bile salt synthesis to compensate for external loss, and a reduction in bile acid pool size and steathorrhoea were observed. 

Angelin et al. reported recently that treatment with a bile-salt-sequestering agent reduced the postprandial but not the fasting serum bile acid levels in human [219]. It was concluded that the postprandial bile acid inflow to the liver may be more important as a regulator of bile acid biosynthesis than the fasting level of bile acids, supporting the contention that a certain concentration of bile acids must be reached in the portal blood to obtain an efficient inhibition of the cholesterol 7a-hydroxyl-ase. 

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