Hepatic deletion of MET aggravates acetaminophen hepatotoxicity and impairs liver regeneration in mice

Abstract

MET is a receptor for hepatocyte growth factor (HGF) and is considered critical for liver regeneration after partial hepatectomy (Phx). Combined disruption of MET along with epidermal growth factor receptor (EGFR) signaling results in compete elimination of regenerative response after Phx, highlighting importance of these growth factor receptors in liver regeneration. A few studies also indicate a role of MET in cell survival signaling in hepatocytes. However, the role of MET in liver injury and compensatory regeneration after acetaminophen (APAP) overdose, a clinically significant model of acute liver failure (ALF), is not known, which was investigated in the current study. APAP (300 and 600 mg/kg) treatment in mice caused remarkable activation of MET in a dose‐dependent manner. Interestingly, MET activation was observed even at a very early stage (3 hr post‐APAP), prior to any observable necrosis or compensatory regenerative response, and was sustained during peak liver injury. Similar dose‐dependent activation of ERK1/2 signaling (one of the downstream mediators of MET) was also observed after APAP treatment. Next, albumin‐driven CRE approach was utilized for liver‐specific deletion of MET in order to study a causative role of MET in APAP‐induced liver injury and regeneration. WT or MET‐KO mice were treated with 300 mg/kg APAP and investigated at 0, 1, 3, 6, 12 and 24 hr post‐APAP. Liver‐specific MET deletion aggravated APAP‐induced liver injury as investigated by measuring serum ALT and AST levels, which was further corroborated by quantifying necrotic areas. Although, liver injury was not significantly different during early initiation phase, it was remarkably aggravated in MET‐KO mice during the progression phase of APAP hepatotoxicity (12 and 24 hr). Further, hepatocyte proliferation and activation of cell cycle machinery were strikingly lower in MET‐KO mice, indicating compensatory liver regeneration was compromised in these mice. While spontaneous recovery and 100% survival was observed in WT mice, significant mortality (67%) was observed in MET‐KO mice. Lastly, macrophage‐specific deletion of MET utilizing LysM‐CRE did not alter liver injury or regeneration after APAP overdose in mice, indicating macrophage‐specific MET is not involved. In conclusion, our study revealed a novel protective role of MET in liver injury and in promoting compensatory liver regeneration during APAP‐induced ALF.Support or Funding InformationThis study was supported by the Menten Endowment Foundation, University of Pittsburgh