p53 protects against alcoholic fatty liver disease via ALDH2 inhibition

Author:

Yao Pengbo12ORCID,Zhang Zhenxi1,Liu Hongchao3,Jiang Peng2ORCID,Li Wei1,Du Wenjing1ORCID

Affiliation:

1. State Key Laboratory of Medical Molecular Biology, Haihe Laboratory of Cell Ecosystem, Department of Cell Biology, School of Basic Medicine Peking Union Medical College Institute of Basic Medical Sciences Chinese Academy of Medical Sciences Beijing China

2. School of Life Sciences Tsinghua University Beijing China

3. Department of Laboratory Medicine Peking University Third Hospital Beijing China

Abstract

AbstractThe tumor suppressor p53 is critical for tumor suppression, but the regulatory role of p53 in alcohol‐induced fatty liver remains unclear. Here, we show a role for p53 in regulating ethanol metabolism via acetaldehyde dehydrogenase 2 (ALDH2), a key enzyme responsible for the oxidization of alcohol. By repressing ethanol oxidization, p53 suppresses intracellular levels of acetyl‐CoA and histone acetylation, leading to the inhibition of the stearoyl‐CoA desaturase‐1 (SCD1) gene expression. Mechanistically, p53 directly binds to ALDH2 and prevents the formation of its active tetramer and indirectly limits the production of pyruvate that promotes the activity of ALDH2. Notably, p53‐deficient mice exhibit increased lipid accumulation, which can be reversed by ALDH2 depletion. Moreover, liver‐specific knockdown of SCD1 alleviates ethanol‐induced hepatic steatosis caused by p53 loss. By contrast, overexpression of SCD1 in liver promotes ethanol‐induced fatty liver development in wild‐type mice, while it has a mild effect on p53−/− or ALDH2−/− mice. Overall, our findings reveal a previously unrecognized function of p53 in alcohol‐induced fatty liver and uncover pyruvate as a natural regulator of ALDH2.

Funder

National Key Research and Development Program of China

Publisher

Springer Science and Business Media LLC

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,Molecular Biology,General Neuroscience

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