STUDIES ON THE LINK BETWEEN HMG-COA REDUCTASE AND CHOLESTEROL 7-ALPHA-HYDROXYLASE IN RAT-LIVER

  • 1 February 1988
    • journal article
    • research article
    • Vol. 29  (2) , 136-143
Abstract
Under most experimental conditions, there is a covariation between the rate-limiting enzyme in cholesterol biosynthesis, HMG-CoA reductase, and the rate-limiting enzyme in bile acid biosynthesis, cholesterol 7.alpha.-hydroxylase. The most simple explanation for the coupling between the two enzymes is that newly synthesized cholesterol is a substrate for an unsaturated cholesterol 7.alpha.-hydroxylase and that substrate availability is of major regulatory importance for this enzyme. The following results seem, however, to rule out that such a simple regulatory mechanism is of major importance and the HMG-CoA reductase activity per se is of importance in the regulation of cholesterol 7.alpha.-hydroxylase. 1) The apparent degree of saturation of cholesterol 7.alpha.-hydroxylase, as measured in vitro in rat liver microsomes, was found to be relatively high (70-90%) under most experimental conditions, including starvation, cholestyramine treatment, and cholesterol treatment. A significant decrease in the degree of saturation was obtained first after a drastic reduction of total concentration of cholesterol in the microsomes by treatment with high doses of triparanol, an inhibitor of cholesterol biosynthesis. 2) The stimulatory effect of cholesterol feeding on cholesterol 7.alpha.-hydroxylase activity in rats seems to be an effect on the enzyme activity (enzyme induction ?) rather than an effect on substrate availability. Thus, the stimulatory effect of cholesterol feeding was retained also after almost complete removal of the endogenous cholesterol by extraction with acetone. 3) Biliary drainage leads to a several-fold increase in the activity of both HMG-CoA reductase and cholesterol 7.alpha.-hydroxylase. The latter increase, however, cannot be due to the increased HMG-CoA reductase activity per se since infusion of cholesterol-enriched Intralipid to bile fistula rats led to a depressed HMG-CoA reductase activity with little or no effect on cholesterol 7.alpha.-hydroxylase. Similarly, depression of HMG-CoA reductase by use of mevalonate in the drinking water had little or no effect on cholesterol 7.alpha.-hydroxylase. It is concluded that microsomal cholesterol concentration, degree of substrate saturation, and levels of HMG-CoA reductase are not major direct regulators for cholesterol 7.alpha.-hydroxylase activity in rat liver.

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