title: Gas6 deficiency prevents liver inflammation, steatohepatitis, and fibrosis in mice.
abstract: The Gas6/Axl pathway has been increasingly implicated in regeneration and tissue repair and, recently, in the control of innate immunity. In liver, we have demonstrated that Gas6 and its receptor Axl are expressed in macrophages, progenitor cells, and myofibroblasts and that Gas6 deficiency reduced inflammation and myofibroblast activation, causing delayed liver repair in response to acute injury. All these data suggest a role of Gas6/Axl signaling in pathogenesis of chronic liver diseases. In the present study, we address the role of Gas6 in steatohepatitis and progression to liver fibrosis using Gas6-deficient mice fed a choline-deficient ethionine-supplemented diet (CDE) or receiving a chronic carbon tetrachloride (CCl(4)) treatment. Gas6 deficiency attenuated hepatic steatosis by limiting CDE-induced downregulation of genes involved in β-oxidation observed in wild-type animals. Moreover, Gas6-deficient mice displayed reduction of hepatic inflammation, revealed by limited F4/80-positive macrophage infiltration, decreased expression of IL-1β, TNF-α, lymphotoxin-β, and monocyte chemotactic protein-1, and attenuated hepatic progenitor cell response to CDE diet. Gas6 deficiency reduced CDE-induced fibrogenesis and hepatic myofibroblast activation and decreased expression of TGF-β and collagen 1 mRNAs. After chronic CCl(4) injury, Gas6-deficient mice also exhibited reduced liver fibrosis as a consequence of defective macrophage recruitment compared with wild-type animals. We conclude that improvement of steatohepatitis and fibrosis in Gas6(-/-) mice is linked to an inhibition of the inflammatory response that controls lipid metabolism and myofibroblast activation. This study highlights the deleterious effect of Gas6 in the progression of steatosis to steatohepatitis and fibrosis.
authors.affiliation: INSERM, UMR-S, Groupe Henri Mondor-Albert Chenevier, Département de Pathologie, Créteil, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Fourcot
authors.forename: Dominique
authors.initials: D
authors.lastname: Couchie
authors.forename: Marie-Noele
authors.initials: MN
authors.lastname: Chobert
authors.forename: Elie-Serge
authors.initials: ES
authors.lastname: Zafrani
authors.forename: Philippe
authors.initials: P
authors.lastname: Mavier
authors.forename: Yannick
authors.initials: Y
authors.lastname: Laperche
authors.forename: Arthur
authors.initials: A
authors.lastname: Brouillet
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride; D049109:Cell Proliferation; D002796:Choline Deficiency / Q000150:complications; D018450:Disease Progression; D005001:Ethionine; D005234:Fatty Liver / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D005786:Gene Expression Regulation; D006505:Hepatitis / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D013853:Thioacetamide; D013997:Time Factors; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D002251:Carbon Tetrachloride; D005001:Ethionine; D018836:Inflammation Mediators; D036341:Intercellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D013853:Thioacetamide; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C000722290:AXL receptor tyrosine kinase, mouse