Free fatty acids repress small heterodimer partner (SHP) activation and adiponectin counteracts bile acid-induced liver injury in superobese patients with nonalcoholic steatohepatitis

Authors

  • Lars P. Bechmann,

    1. Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Essen, Germany
    2. Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, NY
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  • Peri Kocabayoglu,

    1. Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Essen, Germany
    2. Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, NY
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  • Jan-Peter Sowa,

    1. Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Essen, Germany
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  • Svenja Sydor,

    1. Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Essen, Germany
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  • Jan Best,

    1. Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Essen, Germany
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  • Martin Schlattjan,

    1. Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Essen, Germany
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  • Anja Beilfuss,

    1. Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Essen, Germany
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  • Johannes Schmitt,

    1. Clinic for Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
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  • Rebekka A. Hannivoort,

    1. Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, NY
    2. Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
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  • Alpaslan Kilicarslan,

    1. Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Essen, Germany
    2. Department of Internal Medicine, Hacettepe University Hospital Ankara, Ankara, Turkey
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  • Christian Rust,

    1. Clinic for Gastroenterology and Hepatology, University Hospital Munich Grosshadern, Munich, Germany
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  • Frieder Berr,

    1. Department of Medicine I, Paracelsus Medical University/Salzburger Landeskliniken (SALK), Salzburg, Austria
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  • Oliver Tschopp,

    1. Department of Endocrinology & Diabetology, University Hospital Zurich, Zurich, Switzerland
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  • Guido Gerken,

    1. Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Essen, Germany
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  • Scott L. Friedman,

    1. Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, NY
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  • Andreas Geier,

    1. Clinic for Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
    2. Division of Hepatology, Department of Internal Medicine II, University Hospital Würzburg
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    • These authors equally contributed to this work.

  • Ali Canbay

    Corresponding author
    1. Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Essen, Germany
    • Professor of Medicine, University Hospital, University Duisburg-Essen, Hufelandstr. 55, 45122 Essen, Germany===

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    • These authors equally contributed to this work.

    • fax: +49 (201) 723-5719


  • Potential conflict of interest: Dr. Rust is on the speakers' bureau for Falk Foundation.

  • Supported by the Deutsche Forschungsgemeinschaft (DFG, grant 267/4-1 and 267/8-1; to A.C.), Swiss National Foundation (grant 310000-122310/1; to A.G.), the Wilhelm Laupitz Foundation (to A.C.), EASL Sheila Sherlock short-term fellowship (to L.P.B.), IFORES program of the University of Duisburg-Essen (to L.P.B.).

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in industrialized countries and may proceed to steatohepatitis (NASH). Apoptosis and free fatty acid (FFA)-induced lipotoxicity are important features of NASH pathogenesis. We have shown a hepatoprotective effect of adiponectin in steatotic livers of hepatitis C virus (HCV) patients and recent data links bile acid (BA) metabolism to the pathogenesis of NAFLD. The aim of this study was to identify potential interactions between BA and FFA metabolism in NAFLD. Liver biopsies and serum samples from 113 morbidly obese patients receiving bariatric surgery, healthy individuals, and moderately obese NAFLD patients were studied. Serum FFA, BA, and M30 were increased in NASH versus simple steatosis, while adiponectin was significantly decreased. The NAFLD activity score (NAS) score correlated with BA levels and reversely with adiponectin. Adiponectin reversely correlated with CD95/Fas messenger RNA (mRNA) and hepatocellular apoptosis. The BA transporter high-affinity Na+/taurocholate cotransporter (NTCP) and the BA synthesizing enzyme cholesterol 7 alpha-hydroxylase (CYP7A1) were significantly up-regulated in obese patients and hepatoma cells exposed to FFA. Up-regulation of NTCP and CYP7A1 indicate failure to activate small heterodimer partner (SHP) upon farnesoid X receptor (FXR) stimulation by increasing BA concentrations. In line with the NAS score, adiponectin levels were reversely correlated with BA levels. Adiponectin correlated with NTCP and affects Cyp7A1 expression both in vivo and in vitro. Conclusion: BA synthesis and serum BA levels correlated with disease severity in NAFLD, while adiponectin is reversely correlated. FFA exposure prevented SHP-mediated repression of NTCP and Cyp7A1 expression, which lead to increased BA synthesis and uptake. In NASH, BA accumulation induced hepatocyte cell death and late FXR activation failed to prevent hepatocyte injury due to decreased adiponectin levels. Early treatment with FXR ligands and/or adiponectin-receptor agonists might prevent NASH. (HEPATOLOGY 2013;57:1394–1406)

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