High-fat diet triggers Mallory-Denk body formation through misfolding and crosslinking of excess keratin 8

Authors

  • Ozlem Kucukoglu,

    1. Department of Internal Medicine I, Center for Internal Medicine, University Medical Center Ulm, Ulm, Germany
    Search for more papers by this author
  • Nurdan Guldiken,

    1. Department of Internal Medicine I, Center for Internal Medicine, University Medical Center Ulm, Ulm, Germany
    2. Department of Internal Medicine III and IZKF, University Hospital Aachen, Aachen, Germany
    Search for more papers by this author
  • Yu Chen,

    1. Department of Internal Medicine I, Center for Internal Medicine, University Medical Center Ulm, Ulm, Germany
    2. Department of Internal Medicine III and IZKF, University Hospital Aachen, Aachen, Germany
    Search for more papers by this author
  • Valentyn Usachov,

    1. Department of Internal Medicine I, Center for Internal Medicine, University Medical Center Ulm, Ulm, Germany
    2. Department of Internal Medicine III and IZKF, University Hospital Aachen, Aachen, Germany
    Search for more papers by this author
  • Amin El-Heliebi,

    1. Institute of Pathology, Medical University of Graz, Graz, Austria
    Search for more papers by this author
  • Johannes Haybaeck,

    1. Institute of Pathology, Medical University of Graz, Graz, Austria
    Search for more papers by this author
  • Helmut Denk,

    1. Institute of Pathology, Medical University of Graz, Graz, Austria
    Search for more papers by this author
  • Christian Trautwein,

    1. Department of Internal Medicine III and IZKF, University Hospital Aachen, Aachen, Germany
    Search for more papers by this author
  • Pavel Strnad

    Corresponding author
    1. Department of Internal Medicine I, Center for Internal Medicine, University Medical Center Ulm, Ulm, Germany
    2. Department of Internal Medicine III and IZKF, University Hospital Aachen, Aachen, Germany
    • Address reprint requests to: Pavel Strnad, University Medical Center Aachen, Department of Internal Medicine III and IZKF, University Hospital Aachen, Pauwelsstr. 30, D-52074, Aachen, Germany. E-mail: pstrnad@ukaachen.de; fax: + 49 241 8082455.

    Search for more papers by this author

  • Potential conflict of interest: Nothing to report.

  • Supported by the German Research Foundation grants STR 1095/2-1, STR 1095/4-1, SFB TRR57 and the Interdisciplinary Center for Clinical Research (IZKF) in Aachen.

Abstract

Mallory-Denk bodies (MDBs) are protein aggregates consisting of ubiquitinated keratins 8/18 (K8/K18). MDBs are characteristic of alcoholic and nonalcoholic steatohepatitis (NASH) and discriminate between the relatively benign simple steatosis and the more aggressive NASH. Given the emerging evidence for a genetic predisposition to MDB formation and NASH development in general, we studied whether high-fat (HF) diet triggers MDB formation and liver injury in susceptible animals. Mice were fed a high-fat (HF) or low-fat (LF) diet plus a cofactor for MDB development, 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC). Additionally, we fed nontransgenic and K8 overexpressing mice (K8tg) with the HF diet. The presence of MDB and extent of liver injury was evaluated using biochemical markers, histological staining, and immunofluorescence microscopy. In DDC-fed animals, an HF diet resulted in greater liver injury and up-regulation of inflammation-related genes. As a potential mechanism, K8/K18 accumulation and increased ecto-5′-nucleotidase (CD73) levels were noted. In the genetically susceptible K8tg mice, HF diet triggered hepatocellular injury, ballooning, apoptosis, inflammation, and MDB development by way of 1) decreased expression of the major stress-inducible chaperone Hsp72 with appearance of misfolded keratins; 2) elevated levels of the transglutaminase 2 (TG2); 3) increased K8 phosphorylation at S74 with subsequent TG2-mediated crosslinking of phosphorylated K8; and 4) higher production of the MDB-modifier gene CD73. Conclusion: Our data demonstrate that HF diet triggers aggregate formation and development of liver injury in susceptible individuals through misfolding and crosslinking of excess K8. (Hepatology 2014;60:169–178)

Ancillary