title: Loss of Gab1 adaptor protein in hepatocytes aggravates experimental liver fibrosis in mice.
abstract: Grb2-associated binder 1 (Gab1) adaptor protein amplifies signals downstream of a broad range of growth factors/receptor tyrosine kinases. Although these signals are implicated in liver fibrogenesis, the role of Gab1 remains unclear. To elucidate the role of Gab1, liver fibrosis was examined in hepatocyte-specific Gab1-conditional knockout (Gab1CKO) mice upon bile duct ligation (BDL). Gab1CKO mice developed exacerbated liver fibrosis with activation of hepatic myofibroblasts after BDL compared with control mice. The antifibrotic role of hepatocyte Gab1 was further confirmed by another well-established mouse model of liver fibrosis using chronic injections of carbon tetrachloride. After BDL, Gab1CKO mice also displayed exacerbated liver injury, decreased hepatocyte proliferation, and enhanced liver inflammation. Furthermore, cDNA microarray analysis was used to investigate the potential molecular mechanisms of the Gab1-mediated signal in liver fibrosis, and the fibrosis-promoting factor chemokine (C-C motif) ligand 5 (Ccl5) was identified as upregulated in the livers of Gab1CKO mice following BDL. Interestingly, in vitro studies using primary hepatocytes isolated from control and Gab1CKO mice revealed that the loss of Gab1 resulted in increased hepatocyte CCL5 synthesis upon lipopolysaccharide stimulation. Finally, pharmacological antagonism of CCL5 reduced BDL-induced liver fibrosis in Gab1CKO mice. In conclusion, our results demonstrate that hepatocyte Gab1 is required for liver fibrosis and that hepatocyte CCL5 could be an important contributor to this process. Thus, we present a novel antifibrotic function of hepatocyte Gab1 in liver fibrogenesis.
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan;
authors.forename: Takashi
authors.initials: T
authors.lastname: Kizu
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan;
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Yoshida
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan;
authors.forename: Kunimaro
authors.initials: K
authors.lastname: Furuta
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan;
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ogura
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan;
authors.forename: Mayumi
authors.initials: M
authors.lastname: Egawa
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan;
authors.forename: Norihiro
authors.initials: N
authors.lastname: Chatani
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan;
authors.forename: Mina
authors.initials: M
authors.lastname: Hamano
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan;
authors.forename: Takayo
authors.initials: T
authors.lastname: Takemura
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan;
authors.forename: Hisao
authors.initials: H
authors.lastname: Ezaki
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan;
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kamada
authors.affiliation: Laboratory for Homeostatic Network, RCAI, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa, Japan; and.
authors.forename: Keigo
authors.initials: K
authors.lastname: Nishida
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Nakaoka
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan;
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kiso
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan; takehara@gh.med.osaka-u.ac.jp.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takehara
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002251:Carbon Tetrachloride; D049109:Cell Proliferation; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D018946:Chemokine CCL5 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D010750:Phosphoproteins / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction; D015854:Up-Regulation
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; C490897:Gab1 protein, mouse; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D010750:Phosphoproteins; D002251:Carbon Tetrachloride
keywords: Grb2-associated binder 1; bile duct ligation; chemokine (C-C motif) ligand 5; cholestasis