Liver receptor homolog 1 is a negative regulator of the hepatic acute-phase response.
The orphan nuclear receptor liver receptor homolog 1 (LRH-1) has been reported to play an important role in bile acid biosynthesis and reverse cholesterol transport. Here, we show that LRH-1 is a key player in the control of the hepatic acute-phase response. Ectopic expression of LRH-1 with adenovirus resulted in strong inhibition of both interleukin-6 (IL-6)- and IL-1beta-stimulated haptoglobin, serum amyloid A, and fibrinogen beta gene expression in hepatocytes. Furthermore, induction of the hepatic inflammatory response was significantly exacerbated in HepG2 cells expressing short hairpin RNA targeting LRH-1 expression. Moreover, transient-transfection experiments and electrophoretic mobility shift and chromatin immunoprecipitation assays revealed that LRH-1 regulates this cytokine-elicited inflammatory response by, at least in part, antagonizing the CCAAT/enhancer binding protein beta signaling pathway. Finally, we show, by using LRH-1 heterozygous mice, that LRH-1 is involved in the control of the inflammatory response at the hepatic level in vivo. Taken together, our results outline an unexpected role for LRH-1 in the modulation of the hepatic acute-phase response.
Venteclef
Nicolas
N
GlaxoSmithKline R&D, CVU CEDD, 25 Avenue du Quebec, 91951 Les Ulis, France.
Smith
Jason C
JC
Goodwin
Bryan
B
Delerive
Philippe
P
D000210:Acute-Phase Reaction / Q000276:immunology*; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000378:metabolism; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D015870:Gene Expression; D006242:Haptoglobins / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D007375:Interleukin-1 / Q000494:pharmacology; D015850:Interleukin-6 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000276:immunology; D008099:Liver / Q000187:drug effects / Q000276:immunology*; D008252:Macaca fascicularis; D051379:Mice; D011485:Protein Binding / Q000187:drug effects; D034622:RNA Interference; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*
D022782:CCAAT-Enhancer-Binding Protein-beta; D006242:Haptoglobins; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; C431936:Nr5a2 protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D004247:DNA