Human and experimental evidence supporting a role for osteopontin in alcoholic hepatitis

Authors

  • Oriol Morales-Ibanez,

    1. Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
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  • Marlene Domínguez,

    1. Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
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  • Sung H. Ki,

    1. Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD
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  • Miguel Marcos,

    1. Alcoholism Unit, Department of Internal Medicine, IBSAL-University Hospital of Salamanca, Salamanca, Spain
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  • Javier F. Chaves,

    1. Genotyping and Genetic Diagnosis Unit, Research Foundation of Hospital Clínico, Valencia, Spain
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  • Eric Nguyen-Khac,

    1. Service d'Hépato-Gastroentérologie, Amiens University Hospital and Groupe de Recherche sur l'Alcool et les Pharmacodépendances (INSERM ERI 24, GRAP), Picardie University, Amiens, France
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  • Hakim Houchi,

    1. Service d'Hépato-Gastroentérologie, Amiens University Hospital and Groupe de Recherche sur l'Alcool et les Pharmacodépendances (INSERM ERI 24, GRAP), Picardie University, Amiens, France
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  • Silvia Affò,

    1. Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
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  • Pau Sancho-Bru,

    1. Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
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  • José Altamirano,

    1. Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
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  • Javier Michelena,

    1. Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
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  • Juan Carlos García-Pagán,

    1. Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
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  • Juan G. Abraldes,

    1. Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
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  • Vicente Arroyo,

    1. Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
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  • Juan Caballería,

    1. Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
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  • Francisco-Javier Laso,

    1. Alcoholism Unit, Department of Internal Medicine, IBSAL-University Hospital of Salamanca, Salamanca, Spain
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  • Bin Gao,

    1. Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD
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  • Ramón Bataller

    Corresponding author
    1. Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain
    2. Division of Gastroenterology and Hepatology, Departments of Medicine and Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC
    • Address reprint requests to: Ramón Bataller, M.D., Division of Gastroenterology and Hepatology, Departments of Medicine and Nutrition, University of North Carolina at Chapel Hill, 2209 McGavran-Greensberg, Chapel Hill, NC 27599. E-mail: ramon_bataller@med.unc.edu; fax: 919-966-7216.

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  • Potential conflict of interest: Nothing to report.

  • This work was supported by grants from the Instituto de Salud Carlos III (FIS PI080237 and FIS PS09/01164; to R.B. and J.C., respectively). S.A. received a grant from IDIBAPS. P.S.-B. received grants from Instituto Carlos III, Miguel Servet (CP11/00071), and from the European Commission (within its FP7 Cooperation Program) and the European Cosmetics Association (COLIPA; °HeMiBio-HEALTH-F5-2010-266777). J.A. received a grant from Fundación Banco Bilbao Vizcaya Argentaria.

Abstract

We identified, in the transcriptome analysis of patients with alcoholic hepatitis (AH), osteopontin (OPN) as one of the most up-regulated genes. Here, we used a translational approach to investigate its pathogenic role. OPN hepatic gene expression was quantified in patients with AH and other liver diseases. OPN protein expression and processing were assessed by immmunohistochemistry, western blotting and enzyme-linked immunosorbent assay. OPN gene polymorphisms were evaluated in patients with alcoholic liver disease. The role of OPN was evaluated in OPN−/− mice with alcohol-induced liver injury. OPN biological actions were studied in human hepatic stellate cells (HSCs) and in precision-cut liver slices. Hepatic expression and serum levels of OPN were markedly increased in AH, compared to normal livers and other types of chronic liver diseases, and correlated with short-term survival. Serum levels of OPN also correlated with hepatic expression and disease severity. OPN was mainly expressed in areas with inflammation and fibrosis. Two proteases that process OPN (thrombin and matrix metalloproteinase 7) and cleaved OPN were increased in livers with AH. Patients with AH had a tendency of a lower frequency of the CC genotype of the +1239C single-nucleotide polymorphism of the OPN gene, compared to patients with alcohol abuse without liver disease. Importantly, OPN−/− mice were protected against alcohol-induced liver injury and showed decreased expression of inflammatory cytokines. Finally, OPN was induced by lipopolysaccharide and stimulated inflammatory actions in HSCs. Conclusion: Human and experimental data suggest a role for OPN in the pathogenesis of AH. Further studies should evaluate OPN as a potential therapeutic target. (Hepatology 2013;58:1742–1756)

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