Hepatocyte-Specific MET Deletion Exacerbates Acetaminophen-Induced Hepatotoxicity in Mice.

Abstract

Despite the well-known role of MET in liver regeneration after partial hepatectomy, its role in the clinically relevant acetaminophen (APAP)-induced liver injury (AILI) model remains unexplored. AILI markedly differs from partial hepatectomy because it is associated with massive liver necrosis. This study aims to delineate the role of MET specifically in AILI. Hepatocyte-specific MET knockout (MET KO) mice were administered a toxic dose of APAP and assessed for liver injury/regeneration parameters. MET deletion strikingly exacerbated the initial hepatotoxicity and consequentially impaired the compensatory proliferative response, culminating in significant mortality. Mechanistically, MET deletion enhanced c-Jun N-terminal kinase (JNK) activation and its mitochondrial translocation, resulting in excessive mitochondrial oxidative damage, releasing apoptosis-inducing factor into cytosol. Excess JNK activation was attributed to reduced inhibitory activity of AKT on JNK in the absence of MET signaling. Pharmacologic activation of AKT reduced JNK activation and hepatotoxicity in MET KO mice. RNA-sequencing/immunoblotting not only showed repression of proliferative/survival signaling but also activation of cell death/senescence pathways along with an impaired unfolded protein response in MET KO mice. Analysis of published single-nucleus RNA-sequencing data showed that proliferation in livers from patients with APAP-induced acute liver failure was associated with strong activation of hepatocyte growth factor/MET signaling in hepatocytes, with spatial transcriptomics showing striking induction of hepatocyte growth factor surrounding the necrotic zones. Interestingly, 35% of the genes altered in human acute liver failure were regulated by MET in the mouse AILI model. The current study shows that MET is crucial for restraining hepatotoxicity after APAP overdose via inhibition of the mitochondrial cell death signaling pathway.