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

Abstract EN

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-Metmut and MxCre/c-Metmut 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.