Lecithin:cholesterol acyltransferase gene expression is regulated in a tissue-selective manner by fibrates.

Abstract

Plasma lipoprotein metabolism is influenced by several factors that may act by regulating the expression of proteins involved in lipoprotein metabolism, such as lecithin:cholesterol acyltransferase (LCAT). We determined the influence of several hormones and hypolipidemic drugs on hepatic LCAT gene expression and plasma LCAT activity. Liver LCAT mRNA levels were resistant to regulation by the hormones ethinylestradiol, L-thyroxine, hydrocortisone, or by the hypolipidemic drugs probucol, simvastatin, and nicotinic acid. In contrast, hepatic LCAT mRNA levels decreased to 67%, 64%, and 46% of the control levels after treatment with the fibric acid derivatives clofibrate, gemfibrozil, and fenofibrate, respectively. Fenofibrate lowered liver LCAT mRNA levels in a dose-dependent manner, which was paralleled by a decrease in plasma LCAT activity to 54% of the controls at a dose of 0.5% (w/w) in rat chow. The decrease in liver LCAT mRNA levels was maximal after 1 day, whereas the fall in plasma LCAT activity trailed by 2 days. Cessation of treatment with fenofibrate restored liver LCAT mRNA levels to control levels within 1 week. The transcription rate of the LCAT gene decreased by 25% in nuclei isolated from fenofibrate-treated rat liver, thereby indicating that hepatic LCAT gene expression is, at least partly, regulated at a transcriptional level. In contrast to the liver, brain and testis LCAT mRNA levels remained constant after treatment with fenofibrate, indicating that fibrates regulate LCAT gene expression in a tissue-selective manner.