c-Met Signaling Protects from Nonalcoholic Steatohepatitis- (NASH-) Induced Fibrosis in Different Liver Cell Types

Abstract

Nonalcoholic steatohepatitis (NASH) is the most common chronic, progressive liver disease in Western countries. The significance of cellular interactions of the HGF/c-Met axis in different liver cell subtypes and its relation to the oxidative stress response remains unclear so far. Hence, the present study is aimed at investigating the role of c-Met and the interaction with the oxidative stress response during NASH development in mice and humans. Conditional c-Met knockout (KO) lines (LysCre for Kupffer cells/macrophages, GFAPCre for α-SMA⁺ and CK19⁺ cells and MxCre for bone marrow-derived immune cells) were fed chow and either methionine-choline-deficient diet (MCD) for 4 weeks or high-fat diet (HFD) for 24 weeks. Mice lacking c-Met either in Kupffer cells, α-SMA⁺ and CK19⁺ cells, or bone marrow-derived immune cells displayed earlier and faster progressing steatohepatitis during dietary treatments. Severe fatty liver degeneration and histomorphological changes were accompanied by an increased infiltration of immune cells and a significant upregulation of inflammatory cytokine expression reflecting an earlier initiation of steatohepatitis development. In addition, animals with a cell-type-specific deletion of c-Met exhibited a strong generation of reactive oxygen species (ROS) by dihydroethidium (hydroethidine) (DHE) staining showing a significant increase in the oxidative stress response especially in LysCre/c-Met^mut and MxCre/c-Met^mut animals. All these changes finally lead to earlier and stronger fibrosis progression with strong accumulation of collagen within liver tissue of mice deficient for c-Met in different liver cell types. The HGF/c-Met signaling pathway prevents from steatosis development and has a protective function in the progression to steatohepatitis and fibrosis. It conveys an antifibrotic role independent on which cell type c-Met is missing (Kupffer cells/macrophages, α-SMA⁺ and CK19⁺ cells, or bone marrow-derived immune cells). These results highlight a global protective capacity of c-Met in NASH development and progression.