Evidence for regulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and cholesterol synthesis in nonhepatic tissues of rat.

Abstract

The adenine analogue 4-aminopyrazolopyrimidine reduced the hepatic secretion of plasma lipoproteins in rats, thereby lowering the plasma cholesterol level. In the current studies, reduction of the plasma cholesterol level by 90% in rats through the administration of aminopyrazolopyrimidine was associated with a 5- to 30-fold increase in the activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase [mevalonate:NADP+ oxidoreductase (CoA-acylating), EC 1.1.1.34, HMG coA red.] in kidney and lung. In both tissues, the enhanced activity of this microsomal enzyme was associated with a 3-fold elevation in the rate of cholesterol synthesis from either [14C]acetate or [14C]octanoate. Comparable increases were not observed in the activities of several other microsomal enzymes or in the rates of [14C]acetate incorporation into saponifiable lipids or CO2. When administration of 4-aminopyrazolopyrimidine was terminated, plasma cholesterol levels rose and HMG coA red activity declined in the kidney in a reciprocal manner. These data are consistent with the hypothesis that the low levels of HMG coA red activity and cholesterol synthesis that are normally observed in certain nonhepatic tissues of the rat are due to an active form of feedback regulation mediated by cholesterol carried in plasma lipoproteins.