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.

Liver Receptor Homologue-1 Mediates Species- and Cell Line-specific Bile Acid-dependent Negative Feedback Regulation of the Apical Sodium-dependent Bile Acid Transporter

“…The resulting gene product contains bile acid and DNA binding domains, but lacks a functional transactivation motif, essentially making it a dominant-negative expression construct. pcDNA3.1/Myc-LRH (generous gift from Dr. Alan R. Tall, Columbia University, New York) directs expression of the mouse liver receptor homologue-1 gene, which is a homologue of the orphan nuclear receptor fushi tarazu F1 (Ftz-F1) from Drosophila (29). The effect of the orphan nuclear receptors on basal activity and bile acid-mediated responses was assessed by co-transfection of these constructs with pGL3-mASBT5Ј/P2 as described above.…”

The structure of corepressor Dax-1 bound to its target nuclear receptor LRH-1

“…LRH-1 was first discovered in the liver and intestine, where it regulates genes controlling bile acid synthesis and cholesterol homeostasis (21)(22)(23)(24). Recently, LRH-1 was found in human steroidogenic tissues and was shown to activate transcription of genes encoding steroidogenic enzymes (25).…”

LRH-1-mediated glucocorticoid synthesis in enterocytes protects against inflammatory bowel disease

“…Previously recognized as an orphan receptor, phospholipids, including the phosphatidyl inositol second messengers, have been proposed as ligands for the human form (2)(3)(4). Although the role of LRH-1 in cholesterol and bile acid homeostasis is relatively well established (5)(6)(7)(8)(9)(10)(11)(12)(13)(14), unanticipated actions of LRH-1 in the intestine have emerged, including control of cell renewal (15). This finding was shown to be the result of cross-talk between LRH-1 and the ␤-catenin pathway (15), through which LRH-1 contributes to tumorigenesis under pathophysiological conditions (16).…”