Toxicological sciences : an official journal of the Society of ToxicologySep 9, 2026

Loss of a Liver Cell Membrane Protein May Protect Against Acetaminophen Liver Damage by Changing Inflammation and Cell Growth

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Updated Sep 10, 2026

Abstract

Increased lipid-laden macrophages (foam cells) were present in Vmp1LKO livers following acetaminophen (APAP) treatment.

VMP1 expression and autophagy-related gene levels were elevated in human acetaminophen acute liver failure (ALF) samples.
Wild-type mice exhibited significant liver injury and necrosis after APAP administration, with increased serum ALT levels.
VMP1 protein levels decreased in wild-type mouse livers post-APAP treatment, while autophagy markers LC3B-II and p62 increased.
Liver injury was significantly less severe in liver-specific Vmp1 knockout mice compared to their wild-type counterparts.
APAP protein adduct formation was reduced in Vmp1LKO mouse livers, although mitochondrial damage was similar in both genotypes.
GSH replenishment and liver regeneration were enhanced in Vmp1LKO mouse livers, suggesting protective mechanisms against APAP-induced injury.

Simplified

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, human APAP ALF RNA sequencing database was analyzed. Liver-specific Vmp1 knockout (Vmp1LKO) and matched wild-type (Vmp1LWT) mice were administered with 500 mg/kg APAP. Liver injury, necrosis and other biochemistry 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 APAP-induced liver injury by replenishing GSH, modulating inflammation and enhancing liver regeneration.

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Loss of a Liver Cell Membrane Protein May Protect Against Acetaminophen Liver Damage by Changing Inflammation and Cell Growth

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