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

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.

• Authors: Daniela C Kroy, Fabienne Schumacher, Pierluigi Ramadori, Maximilian Hatting, Ina Bergheim, Nikolaus Gassler, Mark V Boekschoten, Michael Müller, Konrad L Streetz, Christian Trautwein
• Journal: Journal of hepatology (J Hepatol) Vol. 61 Issue 4 Pg. 883-90 (Oct 2014) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 24845607 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Chemical References

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

Topics

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