title: FXR ligands protect against hepatocellular inflammation via SOCS3 induction.
abstract: Because of the anti-inflammatory actions of farnesoid X receptor (FXR) agonists, FXR has received much attention as a potential therapeutic target. However, the molecular mechanisms of actions have not yet been elucidated. In the present study, we reported that in the animal model of LPS-induced liver injury, administration of the FXR natural ligand CDCA could attenuate hepatocyte inflammatory damage, reduce transaminase activities, suppress inflammation mediators (IL-6, TNF-α and ICAM-1) expression and inhibit STAT3 phosphorylation. These protective effects of FXR were accompanied by an increased expression of suppressor of cytokine signaling 3 (SOCS3), which is a negative feedback regulator of cytokine-STAT3 signaling. We then demonstrated that the beneficial effects of FXR agonist in STAT3 activation were weakened by small interfering RNA-mediated SOCS3 knockdown in hepacytes. Moreover we observed both natural ligand CDCA and synthetic ligand GW4064 could upregulate SOCS 3 expression by enhancing the promoter activity in hepatocytes. These results suggest modulation of SOCS3 expression may represent a novel mechanism through which FXR activation could selectively affect cytokine bioactivity in inflammation response. FXR ligands may be potentially therapeutic in the treatment of liver inflammatory diseases via SOCS3 induction.
authors.affiliation: Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing 400038, China.
authors.forename: Zhizhen
authors.initials: Z
authors.lastname: Xu
authors.forename: Gang
authors.initials: G
authors.lastname: Huang
authors.forename: Wei
authors.initials: W
authors.lastname: Gong
authors.forename: Peng
authors.initials: P
authors.lastname: Zhou
authors.forename: Yuanyin
authors.initials: Y
authors.lastname: Zhao
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhang
authors.forename: Yijun
authors.initials: Y
authors.lastname: Zeng
authors.forename: Min
authors.initials: M
authors.lastname: Gao
authors.forename: Zhisheng
authors.initials: Z
authors.lastname: Pan
authors.forename: Fengtian
authors.initials: F
authors.lastname: He
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D002635:Chenodeoxycholic Acid / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D007249:Inflammation / Q000188:drug therapy* / Q000276:immunology; D008024:Ligands; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000276:immunology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000276:immunology*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D002635:Chenodeoxycholic Acid; D008024:Ligands; D008070:Lipopolysaccharides; D018160:Receptors, Cytoplasmic and Nuclear; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D000099150:Receptor, Farnesoid X-Activated; C491411:Socs3 protein, mouse