Regulation of Hepatic Sterol Metabolism in The Rat

In vivo regulation of hepatic sterol metabolism was examined in the rat. Sodium cholate markedly suppressed hepatic 7a-hydroxylase mRNA levels and activity when fed to rats on a low cholesterol diet. Sterol balance was maintained solely by decreasing hepatic cholesterol synthesis. Compensatory mechanisms were inadequate when cholate was fed to rats on a high cholesterol diet and massive amounts of cholesterol accumulated in the liver and plasma. Suppression of bile salt synthesis was not responsible since cholate did not suppress 7a-hydroxylase activity when fed to rats on a high cholesterol diet. Moreover, total hepatic low density lipoprotein receptor activity was not suppressed even though liver cholesteryl ester levels were increased more than 360-fold. Changes in 7a-hydroxylase activity were always accompanied by parallel changes in mRNA, whereas mRNA levels for 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase were reduced by 60% or less, even when cholesterol synthesis was suppressed by 98%. HMG-CoA reductase and low density lipoprotein receptor activities were regulated independently although mRNA levels for these two proteins were coordinately regulated. These findings indicate that 7a-hydroxylase is controlled by mRNA levels, whereas in vivo cholesterol synthesis is predominantly controlled by posttranscriptional regulation of HMG-CoA reductase activity.