title: Bile acids initiate cholestatic liver injury by triggering a hepatocyte-specific inflammatory response.
abstract: Mechanisms of bile acid-induced (BA-induced) liver injury in cholestasis are controversial, limiting development of new therapies. We examined how BAs initiate liver injury using isolated liver cells from humans and mice and in-vivo mouse models. At pathophysiologic concentrations, BAs induced proinflammatory cytokine expression in mouse and human hepatocytes, but not in nonparenchymal cells or cholangiocytes. These hepatocyte-specific cytokines stimulated neutrophil chemotaxis. Inflammatory injury was mitigated inCcl2-/-mice treated with BA or after bile duct ligation, where less hepatic infiltration of neutrophils was detected. Neutrophils in periportal areas of livers from cholestatic patients also correlated with elevations in their serum aminotransferases. This liver-specific inflammatory response required BA entry into hepatocytes via basolateral transporter Ntcp. Pathophysiologic levels of BAs induced markers of ER stress and mitochondrial damage in mouse hepatocytes. Chemokine induction by BAs was reduced in hepatocytes fromTlr9-/-mice, while liver injury was diminished both in conventional and hepatocyte-specificTlr9-/-mice, confirming a role for Tlr9 in BA-induced liver injury. These findings reveal potentially novel mechanisms whereby BAs elicit a hepatocyte-specific cytokine-induced inflammatory liver injury that involves innate immunity and point to likely novel pathways for treating cholestatic liver disease.
authors.affiliation: Department of Internal Medicine and Yale Liver Center, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Shi-Ying
authors.initials: SY
authors.lastname: Cai
authors.affiliation: Department of Internal Medicine and Yale Liver Center, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Xinshou
authors.initials: X
authors.lastname: Ouyang
authors.affiliation: Department of Internal Medicine and Yale Liver Center, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Yonglin
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine and Yale Liver Center, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Soroka
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Juxian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine and Yale Liver Center, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Albert
authors.initials: A
authors.lastname: Mennone
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Yucheng
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine and Yale Liver Center, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Wajahat Z
authors.initials: WZ
authors.lastname: Mehal
authors.affiliation: Department of Internal Medicine and Yale Liver Center, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Dhanpat
authors.initials: D
authors.lastname: Jain
authors.affiliation: Department of Internal Medicine and Yale Liver Center, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Boyer
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000097:blood / Q000378:metabolism / Q000502:physiology*; D002779:Cholestasis / Q000503:physiopathology*; D016207:Cytokines / Q000502:physiology; D022781:Hepatocytes / Q000473:pathology*; D006801:Humans; D007249:Inflammation / Q000503:physiopathology*; D018836:Inflammation Mediators / Q000502:physiology; D008107:Liver Diseases / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout
chemical_list: D001647:Bile Acids and Salts; D016207:Cytokines; D018836:Inflammation Mediators