The Orphan Nuclear Receptor LRH-1 Potentiates the Sterol-mediated Induction of the Human CETP Gene by Liver X Receptor

Abstract

The human cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from high density lipoproteins to triglyceride-rich lipoproteins, indirectly facilitating cholesteryl esters uptake by the liver. Hepatic CETP gene expression is increased in response to dietary hypercholesterolemia, an effect that is mediated by the activity of liver X receptor/retinoid X receptor (LXR/RXR) on a direct repeat 4 element in the CETP promoter. In this study we show that the orphan nuclear receptor LRH-1 also transactivates the CETP promoter by binding to a proximal promoter element distinct from the DR4 site. LRH-1 potentiates the sterol-dependent regulation of the wild type CETP promoter by LXR/RXR. Small heterodimer partner, a repressor of LRH-1, abolishes the potentiation effect of LRH-1 but not its basal transactivation of the CETP promoter. Since this mode of regulation of CETP is very similar to that recently reported for the bile salt-mediated repression of Cyp7a (encoding the rate-limiting enzyme for conversion of cholesterol into bile acid in the liver), we examined the effects of bile salt feeding on CETP mRNA expression in human CETP transgenic mice. Hepatic CETP mRNA expression was repressed by a diet containing 1% cholic acid in male mice but was induced by the same diet in female mice. Microarray analysis of hepatic mRNA showed that about 1.5% of genes were repressed, and 2.5% were induced by the bile acid diet. However, the sexually dimorphic regulatory pattern of the CETP gene was an unusual response. Our data provide further evidence for the regulation of CETP and Cyp7a genes by similar molecular mechanisms, consistent with coordinate transcriptional regulation of sequential steps of reverse cholesterol transport. However, differential effects of the bile salt diet indicate additional complexity in the response of these two genes.