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.
Fayard
Elisabeth
E
Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS/INSERM/Université Louis Pasteur, B.P. 10142, F-67404 Illkirch, C.U. de Strasbourg, France.
Schoonjans
Kristina
K
Annicotte
Jean-Sébastien
JS
Auwerx
Johan
J
D001483:Base Sequence; D001665:Binding Sites; D043182:Carboxylesterase; D002265:Carboxylic Ester Hydrolases / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D010179:Pancreas / Q000201:enzymology / Q000502:physiology*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D015183:Restriction Mapping; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D014158:Transcription, Genetic
C431936:Nr5a2 protein, mouse; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D002265:Carboxylic Ester Hydrolases; D043182:Carboxylesterase