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

Ruichao Yue, Guan yuan Chen, Guoxiang Xie, Liuyi Hao, Wei Guo, Xinguo Sun, Wei Jia, Qibin Zhang, Zhanxiang Zhou, Wei Zhong*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)

Abstract

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 PPARα in alcohol detoxification. Hepatic PPARα and catalase levels were examined in patients with severe alcoholic hepatitis. Mouse studies were conducted to determine the effect of PPARα 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 PPARα and catalase were significantly reduced in the livers of patients with severe alcoholic hepatitis. PPARα reactivation by Wy14,643 effectively reversed alcohol-induced liver damage in mice. Global and targeted metabolites analysis revealed a fundamental role of PPARα in regulating the tryptophan-NAD pathway. Notably, PPARα 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 PPARα in regulating hepatic alcohol detoxification. Catalase-mediated hydrogen peroxide removal represents an underlying mechanism of how PPARα preserves the NAD pool. The study provides a new angle of view about the PPARα-catalase pathway in combating alcohol toxicity.

Original languageEnglish
Pages (from-to)249-263
Number of pages15
JournalFree Radical Biology and Medicine
Volume174
DOIs
Publication statusPublished - Oct 2021

Scopus Subject Areas

  • Biochemistry
  • Physiology (medical)

User-Defined Keywords

  • Alcohol-related liver disease
  • Catalase
  • NAD biosynthesis
  • PPARα

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