Venteclef Nicolas, Smith Jason C, Goodwin Bryan, Delerive Philippe
GlaxoSmithKline R&D, CVU CEDD, 25 Avenue du Quebec, 91951 Les Ulis, France.
Mol Cell Biol. 2006 Sep;26(18):6799-807. doi: 10.1128/MCB.00579-06.
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.
据报道，孤儿核受体肝受体同源物1（LRH-1）在胆汁酸生物合成和逆向胆固醇转运中发挥重要作用。在此，我们表明LRH-1是肝脏急性期反应调控中的关键因子。用腺病毒异位表达LRH-1可强烈抑制肝细胞中白细胞介素6（IL-6）和IL-1β刺激的触珠蛋白、血清淀粉样蛋白A和纤维蛋白原β基因的表达。此外，在表达靶向LRH-1表达的短发夹RNA的HepG2细胞中，肝脏炎症反应的诱导明显加剧。此外，瞬时转染实验、电泳迁移率变动分析和染色质免疫沉淀分析表明，LRH-1至少部分通过拮抗CCAAT/增强子结合蛋白β信号通路来调节这种细胞因子引发的炎症反应。最后，我们通过使用LRH-1杂合小鼠表明，LRH-1在体内参与肝脏水平的炎症反应调控。综上所述，我们的结果概述了LRH-1在调节肝脏急性期反应中的意外作用。
