Possible mechanisms for regulation of cholesterol 7a-hydroxylase activity

The regulation of cholesterol 7 -hydroxylase may involve some of the following mechanisms  

Myant and Mitropoulos have discussed the possibility of a yet unidentified component that regulates the activity of the enzyme, and whose induction and repression are responsible for the different effects on the enzyme activity [59]. The unidentified component could be an inducible protein carrier that facilitates access of cholesterol to the catalytic site of the enzyme (cf. Chapter 3). 

The most important information concerning mechanisms of regulation of cholesterol 7a-hydroxylase is summarized in the model shown in Fig. 14. In view of the importance of HMG-CoA reductase for cholesterol 7a-hydroxylase activity, some important modulators of HMG-CoA reductase activity have also been included (cf. Chapter 2). It should be pointed out that the regulation of biosynthesis of cholesterol shown in Fig. 14 is oversimplified. For a discussion of the regulation of HMG-CoA reductase, the reader is referred to Chapter 2 and a recent review by Brown and Goldstein [246]. 

The bile acids returning to the liver in the portal blood inhibit both cholesterol 7a-hydroxylase and HMG-CoA reductase. Size, circulation rate and composition of the bile acid pool are of importance. The inhibitory effect of bile acids on cholesterol 7a-hydroxylase is mediated by an effect on synthesis or breakdown of proteins, most likely the specific species of cytochrome P-450 involved in the hydroxylation. Evidence that the rate of synthesis of the specific species of cytochrome P-450 is of major importance can be obtained only when it is possible to measure accurately the amount of specific cytochrome P-450 by means other than enzyme activity. Although less likely from the data available, it cannot be excluded at the present state of knowledge that the inhibitory effect of bile acids on cholesterol 7a-hydroxylase is mediated by the effect of bile acids on HMG-CoA reductase. Since the substrate pool for cholesterol 7 -hydroxylase does not seem to be affected [59,222], a hitherto unknown mechanism must then be responsible for the coupling between the two rate-limiting enzymes. 

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]. 

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Possible mechanisms for regulation of cholesterol 7a-hydroxylase activity... 

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