Effects of fibrate drugs on expression of ABCA1 and HDL biogenesis in hepatocytes

Abstract

Fibric acid-shaped drugs raise high-density lipoprotein (HDL) cholesterol by upregulating the HDL-related genes through activating peroxisome proliferater activated receptor (PPAR)-α. We investigated the effects of fibrates to induce expression of adenosine triphosphate-binding cassette transporter A1 (ABCA1) and increase HDL biogenesis in hepatocytes. Fenofibrate, bezafibrate, gemfibrozil, and LY518674 were tested for HepG2 cells and primary-cultured mouse hepatocytes. All the compounds examined increased ABCA1 expression and HDL biogenesis dependent on PPARα in association with the liver X receptor α upregulation. While fenofibrate and LY518674 showed exclusive dependency on PPARα for these activities, bezafibrate and gemfibrozil exhibited dependency on PPARβ/δ and PPARγ as well. On the other hand, cholesterol-enrichment of HDL may involve PPARγ for fenofibrate and bezafibrate, and PPARβ/δ for the fibrates examined except for bezafibrate. We concluded that fibrates enhance expression of ABCA1 in hepatocytes to contribute to increase of the HDL biogenesis in a PPAR-dependent manner, whether exclusively or nonexclusively on PPARα. © 2008 Lippincott Williams & Wilkins, Inc.