Loss of Vacuole Membrane Protein 1 protects against acetaminophen-induced liver injury by modulating inflammation and hepatocyte proliferation.

Acetaminophen (APAP) overdose is a leading cause of severe liver injury and acute liver failure (ALF). Increased hepatic macrophages promote inflammation and clear necrotic cell debris, thereby promoting a regenerative state for liver repair during APAP-induced liver injury. Vacuole membrane protein 1 (VMP1) is an ER transmembrane protein essential for autophagy. Deletion of VMP1 in the liver impairs autophagy. The role of VMP1 in APAP-induced liver injury is unknown. In this study, the human APAP ALF RNA sequencing database was analyzed. Liver-specific Vmp1 knockout (Vmp1LKO) and matched wild-type (Vmp1LWT) mice were administered 500 mg/kg APAP. Liver injury, necrosis, and other biochemical analyses were assessed. Increased mRNA levels of VMP1 and autophagy-related genes were found in human APAP ALF livers. Serum ALT and hepatic necrosis were increased in WT mice following APAP treatment. LC3B-II and p62 were increased, but VMP1 protein decreased in WT mouse livers following APAP treatment. Liver injury was markedly decreased in Vmp1LKO mice compared with their WT littermates. Basal hepatic CYP2E1 and glutathione (GSH) levels were similar between genotypes, but increased lipid-laden macrophages (foam cells) were present in Vmp1LKO livers. Interestingly, APAP protein adduct formation decreased in Vmp1LKO mouse livers, but mitochondrial damage was similar in both phenotypes. Peroxynitrite formation was observed in APAP-treated Vmp1LWT hepatocytes but was limited in foam cells of Vmp1LKO mouse livers. Furthermore, GSH replenishment and liver regeneration were enhanced in Vmp1LKO mouse livers. In conclusion, loss of hepatic VMP1 protects against APAP-induced liver injury by replenishing GSH, modulating inflammation, and enhancing liver regeneration.