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

J Hepatol. 2014 Oct;61(4):883-90. doi: 10.1016/j.jhep.2014.05.019. Epub 2014 May 15.

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-MetΔ(hepa)) using the cre-loxP system and wild type controls (c-Met(loxP/loxP)) were fed a methionine-choline deficient (MCD) diet.

Results: MCD feeding triggered massive steatosis, decreased survival and higher transaminases in c-MetΔ(hepa) livers compared to c-Met(loxP/loxP). Gene array analysis demonstrated that genes involved in fatty acid metabolism were strongly upregulated in c-MetΔ(hepa) livers correlating with higher amounts of hepatic free fatty acids. Consequently, c-MetΔ(hepa) mice showed significantly more TUNEL positive cells and more superoxide anion production than c-Met(loxPloxP) animals. Additionally, c-MetΔ(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-MetΔ(hepa) livers. As increased apoptosis was a prominent feature in c-MetΔ(hepa) livers, we generated c-Met/Casp8Δ(hepa) double knockout mice. In these animals compared to c-MetΔ(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.

Keywords: HGF; NASH; c-Met.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Caspase 8 / metabolism
  • Choline Deficiency* / metabolism
  • Diet* / adverse effects
  • Diet* / methods
  • Hepatocyte Growth Factor / metabolism*
  • Hepatocytes / metabolism
  • Inflammation / metabolism*
  • Lipotropic Agents / metabolism
  • Liver Cirrhosis* / etiology
  • Liver Cirrhosis* / metabolism
  • Liver Cirrhosis* / prevention & control
  • Methionine* / deficiency
  • Methionine* / metabolism
  • Mice
  • Mice, Knockout
  • Neutrophil Infiltration
  • Non-alcoholic Fatty Liver Disease* / complications
  • Non-alcoholic Fatty Liver Disease* / metabolism
  • Non-alcoholic Fatty Liver Disease* / pathology
  • Oxidative Stress*
  • Proto-Oncogene Proteins c-met / metabolism*

Substances

  • Lipotropic Agents
  • Hepatocyte Growth Factor
  • Methionine
  • Proto-Oncogene Proteins c-met
  • Caspase 8