Pravastatin sodium, a competitive inhibitor of hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase, decreases the cholesterol content of newly secreted very-low-density lipoprotein in Watanabe heritable hyperlipidemic rabbits

We examined the secretion of very-low-density lipoprotein (VLDL) when hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, a rate-limiting Enzyme of Cholesterol biosynthesis, was inhibited. To inhibit HMG-CoA reductase in liver, pravastatin sodium, a competitive inhibitor of HMG-CoA reductase, was administered to homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits, a low-density lipoprotein receptor-deficient animal model, at a dosage of 50 mg/kg per day for 5 weeks. Although triglyceride levels were not changed, total Cholesterol levels of sera and each atherogenic lipoprotein were decreased by approximately 30%. As a result, the percentage of Cholesterol concentration in newly secreted VLDL was significantly decreased by 24%. The VLDL secretion rate was determined by intravenous injection of Triton WR-1339. The VLDL secretion rate was significantly decreased by 23% using Cholesterol as an index, but it did not change using triglyceride, phospholipid, or protein as an index. It is concluded that one of the mechanisms of serum total Cholesterol decrease due to reduction of the putative Cholesterol pool of the liver in homozygous WHHL rabbits is caused by a decrease of Cholesterol content in newly secreted VLDL particles.