Moderate increase of <scp>MET</scp> in hepatocytes protects against cholestatic liver injury by promoting an effective antioxidant response

Hepatocyte growth factor (HGF)/hepatocyte growth factor receptor (MET) signaling plays a critical role during liver regeneration upon acute and chronic damage, and is therefore an interesting target for therapeutic intervention. Nevertheless, the molecular mechanisms underlying the pro-regenerative effects of HGF/MET signaling are not fully elucidated, particularly during cholestatic injury. Our aim was to analyze the impact of moderately enhanced MET on the hepatic response to cholestatic injury, and uncover the mechanisms behind it. For that, Alb-R26^Met mice expressing a wild-type Met transgene in albumin-positive liver cells were fed with a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-supplemented diet, used as a model simulating human primary sclerosing cholangitis. Results indicate that increased MET expression diminished liver damage in DDC-fed mice, evidenced by lower serum levels of bilirubin and alkaline phosphatase, and decreased cell apoptosis. However, decreased ductular expansion was observed, which together with enhanced hepatocyte proliferation suggests that hepatocytes act as the main cellular defense. Both in vivo and in vitro studies using Alb-R26^Met liver-derived hepatocytes under cholestasis-simulated in vitro conditions demonstrated an enhanced upregulation of nuclear factor erythroid 2-related factor 2 (NRF2; encoded by the Nfe2l2 gene), parallel to an upregulation of glutathione biosynthesis enzymes, increased levels of glutathione, and decreased reactive oxygen species, along with decreased activation of transforming growth factor beta (TGF-β)-induced signaling. Consistently, MET transgenic hepatocytes were protected against TGF-β-induced oxidative stress and apoptosis in vitro. In conclusion, our work evidences that moderate upregulation of wild-type MET in hepatocytes is sufficient to promote a strong antioxidant response in the liver that efficiently protects against chronic cholestasis, thus allowing optimal liver regeneration.