Under peroxisome proliferation acyl-CoA oxidase coordinates with catalase to enhance ethanol metabolism

In peroxisomes, acyl-CoA oxidase (ACOX) oxidizes fatty acids and produces H₂O₂, and the latter is decomposed by catalase. If ethanol is present, ethanol will be oxidized by catalase coupling with decomposition of H₂O₂. Peroxisome proliferator-activated receptor α (PPARα) agonist WY-14,643 escalated ethanol clearance, which was not observed in catalase knockout (Cat^-/-) mice or partially blocked by an ACOX1 inhibitor. WY-14,643 induced peroxisome proliferation via peroxin 16 (PEX16). PEX16 liver-specific knockout (Pex16^Alb-Cre) mice lack intact peroxisomes in liver, but catalase and ACOX1 were upregulated. Due to lacking intact peroxisomes, the upregulated catalase and ACOX1 in the Pex16^Alb-Cre mice were mislocated in cytosol and microsomes, and the escalated ethanol clearance was not observed in the Pex16^Alb-Cre mice, implicating that the intact functional peroxisomes are essential for ACOX1/catalase to metabolize ethanol. Alcohol-associated liver disease (ALD) is a spectrum of liver disorders ranging from alcoholic steatosis to steatohepatitis. WY-14,643 ameliorated alcoholic steatosis but tended to enhance alcoholic steatohepatitis. In mice lacking nuclear factor erythroid 2-related factor 2 (Nrf2^-/-), WY-14,643 still induced PEX16, ACOX1 and catalase to escalate ethanol clearance and blunt alcoholic steatosis, which was not observed in the PPARα-absent Nrf2^-/- mice (Pparα^-/-/Nrf2^-/-) mice, suggesting that WY-14,643 escalates ethanol clearance through PPARα but not through Nrf2.