Regulation of Squalene Epoxidase in Cholesterol Biosynthesis and Metabolism

Abstract

Regulation of squalene epoxidase in the cholesterol biosynthetic pathway was studied in human hepatoma cell line, Hep G2 and in rat liver. Incubation of Hep G2 cells with L-654, 969, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, increased squalene epoxidase activity, whereas low-density-lipoprotein (LDL) decreased it. In rat liver microsomes, cholestyramine feeding and the administration of reductase inhibitor to rats increased the epoxidase activity. Cholesterol feeding reduced it. These results demonstrate that squalene epoxidase is regulated by endogenous and exogenous sterols in Hep G2 cells and in rat liver. NB-598, a specific inhibitor of mammalian squalene epoxidase, was used to investigate the regulatory mechanism of cholesterol metabolism in Hep G2 cells. The inducibility by NB-598 in HMG-CoA reductase activity was rather low as compared to that by L-654, 969, though NB-598 inhibited cholesterol synthesis more potently than L-654, 969. On the other hand, the reductase mRNA was increased to the same extent. Therefore, NB-598 is thought to have no effect on the synthesis of nonsterol suppressor derived from mevalonate. NB-598 strongly increased LDL receptor activity. These observations indicate that squalene epoxidase inhibitor is expected to be highly effective in the treatment of hypercholesterolemia.