| First Author | Yue R | Year | 2021 |
| Journal | Free Radic Biol Med | Volume | 174 |
| Pages | 249-263 | PubMed ID | 34390780 |
| Mgi Jnum | J:313590 | Mgi Id | MGI:6789391 |
| Doi | 10.1016/j.freeradbiomed.2021.08.005 | Citation | Yue R, et al. (2021) Activation of PPARalpha-catalase pathway reverses alcoholic liver injury via upregulating NAD synthesis and accelerating alcohol clearance. Free Radic Biol Med 174:249-263 |
| abstractText | 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 PPARalpha in alcohol detoxification. Hepatic PPARalpha and catalase levels were examined in patients with severe alcoholic hepatitis. Mouse studies were conducted to determine the effect of PPARalpha 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 PPARalpha and catalase were significantly reduced in the livers of patients with severe alcoholic hepatitis. PPARalpha reactivation by Wy14,643 effectively reversed alcohol-induced liver damage in mice. Global and targeted metabolites analysis revealed a fundamental role of PPARalpha in regulating the tryptophan-NAD pathway. Notably, PPARalpha 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 PPARalpha in regulating hepatic alcohol detoxification. Catalase-mediated hydrogen peroxide removal represents an underlying mechanism of how PPARalpha preserves the NAD pool. The study provides a new angle of view about the PPARalpha-catalase pathway in combating alcohol toxicity. |
