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 a (PPARa) 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 (Pex16A(lb-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 Pex16A(lb-Cre) mice were mislocated in cytosol and microsomes, and the escalated ethanol clearance was not observed in the Pex16Alb-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 PPARa-absent Nrf2(-/-) mice (Ppara(-/-)/Nrf2(-/-)) mice, suggesting that WY-14,643 escalates ethanol clearance through PPARa but not through Nrf2.