Hepatocyte specific deletion of c-Met leads to the development of severe non-alcoholic steatohepatitis in mice

D.C. Kroy, F. Schumacher, P. Ramadori, M. Hatting, I. Bergheim, N. Gassler, M.V. Boekschoten, M.R. Müller, K.L. Streetz, C. Trautwein

Research output: Contribution to journalArticleAcademicpeer-review

31 Citations (Scopus)

Abstract

Background & Aims Non-alcoholic-fatty-liver disease (NAFLD) is part of the metabolic syndrome. The spectrum of NAFLD includes NASH (non-alcoholic steatohepatitis), which is characterised by progressive inflammation associated with oxidative stress and apoptosis, finally triggering liver cirrhosis and hepatocellular carcinoma. HGF (hepatocyte growth factor)/mesenchymal-epithelial transition factor (c-Met) receptor signalling is known to activate distinct intracellular pathways mediating among others anti-apoptotic properties to hepatocytes. Therefore, the aim was to characterise the role of c-Met during NASH development. Methods Hepatocyte specific c-Met knockout mice (c-Met¿hepa) using the cre-loxP system and wild type controls (c-MetloxP/loxP) were fed a methionine-choline deficient (MCD) diet. Results MCD feeding triggered massive steatosis, decreased survival and higher transaminases in c-Met¿hepa livers compared to c-MetloxP/loxP. Gene array analysis demonstrated that genes involved in fatty acid metabolism were strongly upregulated in c-Met¿hepa livers correlating with higher amounts of hepatic free fatty acids. Consequently, c-Met¿hepa mice showed significantly more TUNEL positive cells and more superoxide anion production than c-MetloxPloxP animals. Additionally, c-Met¿hepa livers showed significantly larger fractions of infiltrating neutrophils, macrophages, and cytotoxic T cells. These changes correlated with an enhanced progression of liver fibrosis as evidenced by higher collagen deposition in c-Met¿hepa livers. As increased apoptosis was a prominent feature in c-Met¿hepa livers, we generated c-Met/Casp8¿hepa double knockout mice. In these animals compared to c-Met¿hepa animals the increase in apoptosis could be reverted. Conclusions c-Met deletion in hepatocytes triggers NASH progression. A prominent mechanism is higher fatty acid accumulation and increased apoptosis, which in part can be reverted by blocking caspase 8.
Original languageEnglish
Pages (from-to)883-890
JournalJournal of Hepatology
Volume61
Issue number4
DOIs
Publication statusPublished - 2014

Keywords

  • fatty liver-disease
  • growth factor/scatter factor
  • hepatocellular-carcinoma
  • natural-history
  • risk-factors
  • receptor
  • fas
  • progression
  • expression
  • steatosis

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