Liver receptor homolog 1 controls the expression of carboxyl ester lipase

The orphan nuclear receptor liver receptor homolog 1 (LRH-1) plays a central role in cholesterol homeostasis by regulating a number of hepatic and intestinal genes critical for reverse cholesterol transport and bile acid homeostasis. Herein, we describe the identification of carboxyl ester lipase (CEL) as a novel target of LRH- 1 in pancreas, a tissue in which LRH- 1 is abundantly expressed. In situ hybridization and gene expression studies demonstrate that both LRH- 1 and CEL are co- expressed and confined to the exocrine pancreas. LRH- 1 interacts with a consensus LRH- 1 response element in the human CEL promoter, which is perfectly conserved in the rat gene, and induces CEL promoter activity in cotransfection assays. As reported for other LRH- 1 target genes, the nuclear receptor short heterodimer partner represses LRH- 1-induced CEL promoter activity. Chromatin immunoprecipitation demonstrates that binding of LRH- 1 to the CEL promoter increases histone H4 acetylation corresponding with the activation of endogenous CEL gene transcription. Our data, identifying CEL as the first pancreatic LRH- 1 target gene, indicate that LRH- 1 is an important player in enterohepatic cholesterol homeostasis.