Taurocholate infusion

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 mechanism of the inhibition of the HMG-CoA reductase by bile adds shown in Fig. 14 is a matter of controversy. Weis and Dietschy did not observe any influence of taurocholate on cholesterol synthesis in bile fistula rats fed a cholesterol-free diet, and concluded that the inhibitory effect of bile acids on cholesterol synthesis may be related to the increased absorption of cholesterol by the presence of bile acids in the intestine [247]. However, Hamprecht et al. were able to demonstrate a reduction of HMG-CoA reductase activity in lymph fistula rats infused with cholate [248]. Results by Shefer et al. also indicate that bile acids inhibit HMG-CoA reductase directly [212]. It seems likely that the inhibitory effect of the bile acids on HMG-CoA reductase may involve both direct and indirect effects. It was recently established that the stimulation of HMG-CoA reductase activity in response to treatment with cholestyramine is associated with an increase of the specific mRNA [258]. 

The major rate-determining step in the biosynthesis of bile acids appears to be the 7a-hydroxylation of cholesterol. The rate of this reaction is increased manyfold by biliary drainage and cholestyramine feeding (17,18,20,21,23,24). Several other reactions in the biosynthesis and metabolism of bile acids are unaffected or only moderately stimulated by biliary drainage and cholestyramine feeding (23,24). The half-life time of the 7a-hydroxylase in rats with a biliary fistula has been estimated to be about 2-3 hr (153), and a preliminary report (154) indicates the same short half-life time for the 7a-hydroxylase in intact rats. Further evidence for the role of the 7a-hydroxylase as a ratedetermining step has been presented by Shefer et al. (155), who have found that infusion of taurocholic acid does not affect the rate of conversion of cholest-5-ene-3)5,7a-diol into bile acids in rats with a biliary fistula. 

Myant and Eder (156) found that the increase in biosynthesis of cholesterol elicited by biliary drainage preceded the increase in biosynthesis of bile acids. This finding and those of Back et al. (167) appear to disprove the double feedback mechanism suggested by Beher et al. (142-144). However, it is not thereby excluded that bile acids may influence both the biosynthesis of cholesterol and the conversion of cholesterol into bile acids in the liver. Shefer et al. (155) have found that infusion of taurocholic acid into rats with a biliary fistula leads to inhibition not only of the conversion of labeled acetate into bile acids but also of the conversion of labeled mevalonate and cholesterol. These results indicate that the homeostatic regulation of bile... 

Table 1. Cell Migration in Bile-diverted Rats Infused Without and With Sodium Taurocholate (30 ijM). 

It has been shown that simultaneous infusion of taurocholic acid overcomes the cholestatic effect of lithocholic and taurolithocholic acid[2,32,33], possibly by micellar solubilization of the toxic molecules and promotion of their excretion into bile. Therefore, in situations that are characterized by low biliary bile acid output rates, the liver may be more susceptible to the hepatoxic action of monohydroxy bile acids. We studied the effects of endogenous bile acids on the cholestatic action of SGLC in rats. For this purpose we used an animal model in which the enterohepatic circulation (EHC) can be interrupted and restored without direct surgical intervention. 

Taurocholate is able to form micelles infusion of TC has been shown [232] to increase output of phospholipid and cholesterol with which it forms mixed micelles. Dehydrocholate has a low tendency to micelle formation and has little influence on the biliary excretion of cholesterol and phospholipid. However, Hardison and Apter [233] have found that while micelle formation is an important factor in the biliary excretion of lipids, it cannot alone explain the results they have obtained. Dehydrocholate, a synthetic agent, is a potent choleretic presumably because its osmotic activity in bile is not diminished by micelle formation and it may therefore exert an osmotic force in biliary canaliculae approximately equal to its concentration. As a result, bile flow is increased more by this substance than by micelle-forming bile salts. Some metabolites of dehydrocholate are, however, capable of micelle formation [234,235]. 

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