title: LPS-TLR4 Pathway Mediates Ductular Cell Expansion in Alcoholic Hepatitis.
abstract: Alcoholic hepatitis (AH) is the most severe form of alcoholic liver disease for which there are no effective therapies. Patients with AH show impaired hepatocyte proliferation, expansion of inefficient ductular cells and high lipopolysaccharide (LPS) levels. It is unknown whether LPS mediates ductular cell expansion. We performed transcriptome studies and identified keratin 23 (KRT23) as a new ductular cell marker. KRT23 expression correlated with mortality and LPS serum levels. LPS-TLR4 pathway role in ductular cell expansion was assessed in human and mouse progenitor cells, liver slices and liver injured TLR4 KO mice. In AH patients, ductular cell expansion correlated with portal hypertension and collagen expression. Functional studies in ductular cells showed that KRT23 regulates collagen expression. These results support a role for LPS-TLR4 pathway in promoting ductular reaction in AH. Maneuvers aimed at decreasing LPS serum levels in AH patients could have beneficial effects by preventing ductular reaction development.
authors.affiliation: Division of Gastroenterology and Hepatology, Departments of Medicine and Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Gemma
authors.initials: G
authors.lastname: Odena
authors.affiliation: Division of Gastroenterology and Hepatology, Departments of Medicine and Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Jiegen
authors.initials: J
authors.lastname: Chen
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain.
authors.forename: Juan Jose
authors.initials: JJ
authors.lastname: Lozano
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: Altamirano
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rodrigo-Torres
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Affo
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain.
authors.forename: Oriol
authors.initials: O
authors.lastname: Morales-Ibanez
authors.affiliation: Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Matsushita
authors.affiliation: Bowles Center For Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Zou
authors.affiliation: UNC Human Pluripotent Stem Cell Core, Neuroscience Center and Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Raluca
authors.initials: R
authors.lastname: Dumitru
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain.|Liver Unit, Hospital Clínic, Barcelona, Catalonia, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Caballeria
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain.|Liver Unit, Hospital Clínic, Barcelona, Catalonia, Spain.
authors.forename: Pere
authors.initials: P
authors.lastname: Gines
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain.|Liver Unit, Hospital Clínic, Barcelona, Catalonia, Spain.
authors.forename: Vicente
authors.initials: V
authors.lastname: Arroyo
authors.affiliation: Department of Pharmaceutical Sciences, College of Pharmacy, Northeast Ohio Medical University, Rootstown, OH, USA.
authors.forename: Min
authors.initials: M
authors.lastname: You
authors.affiliation: Service d'Hépatologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France; INSERM, U773, Centre de Recherche Biomédicale Bichat-Beaujon CRB3, Université Paris-Diderot-Paris 7, Hôpital Bichat, Paris, France.|INSERM, U970, Paris Cardiovascular Research Center-PARCC, and Université Paris Descartes, Sorbonne Paris Cité, UMR-S970, Paris, France.
authors.forename: Pierre-Emmanuel
authors.initials: PE
authors.lastname: Rautou
authors.affiliation: Service d'Hépatologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Clichy, France; INSERM, U773, Centre de Recherche Biomédicale Bichat-Beaujon CRB3, Université Paris-Diderot-Paris 7, Hôpital Bichat, Paris, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Valla
authors.affiliation: Bowles Center For Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Fulton
authors.initials: F
authors.lastname: Crews
authors.affiliation: Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors.forename: Ekihiro
authors.initials: E
authors.lastname: Seki
authors.affiliation: Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain.
authors.forename: Pau
authors.initials: P
authors.lastname: Sancho-Bru
authors.affiliation: Division of Gastroenterology and Hepatology, Departments of Medicine and Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain.|Bowles Center For Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Ramon
authors.initials: R
authors.lastname: Bataller
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006500:Hepatic Duct, Common / Q000473:pathology*; D006519:Hepatitis, Alcoholic / Q000276:immunology*; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D053530:Keratins, Type I / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008875:Middle Aged; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
chemical_list: C420247:KRT23 protein, human; D053530:Keratins, Type I; D008070:Lipopolysaccharides; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D003094:Collagen