Activation of PPARα-catalase pathway reverses alcoholic liver injury via upregulating NAD synthesis and accelerating alcohol clearance

Alcohol metabolism in the liver simultaneously generates toxic metabolites and disrupts redox balance, but the regulatory mechanisms have not been fully elucidated. The study aimed to characterize the role of PPAR alpha in alcohol detoxification. Hepatic PPAR alpha and catalase levels were examined in patients with severe alcoholic hepatitis. Mouse studies were conducted to determine the effect of PPAR alpha reactivation by Wy14,643 on alcoholic hepatotoxicity and how catalase is involved in mediating such effects. Cell culture study was conducted to determine the effect of hydrogen peroxide on cellular NAD levels. We found that the protein levels of PPAR alpha and catalase were significantly reduced in the livers of patients with severe alcoholic hepatitis. PPAR alpha reactivation by Wy14,643 effectively reversed alcohol-induced liver damage in mice. Global and targeted metabolites analysis revealed a fundamental role of PPAR alpha in regulating the tryptophan-NAD pathway. Notably, PPAR alpha activation completely switched alcohol metabolism from the CYP2E1 pathway to the catalase pathway along with accelerated alcohol clearance. Catalase knockout mice were incompetent in alcohol metabolism and hydrogen peroxide clearance and were more susceptible to alcohol-induced liver injury. Hydrogen peroxide-treated hepatocytes had a reduced size of cellular NAD pool. These data demonstrate a key role of PPAR alpha in regulating hepatic alcohol detoxification. Catalase-mediated hydrogen peroxide removal represents an underlying mechanism of how PPAR alpha preserves the NAD pool. The study provides a new angle of view about the PPAR alpha-catalase pathway in combating alcohol toxicity.

Automated summary

The study revealed the significant role of PPAR alpha in hepatic alcohol detoxification, with PPAR alpha reactivation reversing alcohol-induced liver damage and accelerating alcohol clearance. Catalase plays multiple roles in maintaining NAD levels and clearing hydrogen peroxide against alcohol-induced liver injury.