P53 Protects Against Alcoholic Fatty Liver Disease Via ALDH2 Inhibition

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2023 Feb 24

PMID 36825429

Authors

Pengbo Yao

Zhenxi Zhang

Hongchao Liu

Peng Jiang

Wei Li

Wenjing Du

Affiliations

Soon will be listed here.

Abstract

The 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.

Citing Articles

Molecular mechanisms of lipid droplets-mitochondria coupling in obesity and metabolic syndrome: insights and pharmacological implications.

Zhang C, Zheng M, Bai R, Chen J, Yang H, Luo G Front Physiol. 2024; 15:1491815.

PMID: 39588271 PMC: 11586377. DOI: 10.3389/fphys.2024.1491815.

Exosome-mediated Transfer of lncRNA in Liver Associated Diseases; Uncovered Truths.

Saleh R, Hamad H, Najim M, Menon S, Kaur M, Sivaprasad G Cell Biochem Biophys. 2024; .

PMID: 39567423 DOI: 10.1007/s12013-024-01617-x.

The Binding of HSPA8 and Mitochondrial ALDH2 Mediates Oxygen-Glucose Deprivation-Induced Fibroblast Senescence.

Hui W, Song T, Yu L, Chen X Antioxidants (Basel). 2024; 13(1).

PMID: 38247467 PMC: 10812545. DOI: 10.3390/antiox13010042.

ME2 Promotes Hepatocellular Carcinoma Cell Migration through Pyruvate.

Yang Y, Zhang Z, Li W, Li L, Zhou Y, Du W Metabolites. 2023; 13(4).

PMID: 37110198 PMC: 10145348. DOI: 10.3390/metabo13040540.

p53 protects against alcoholic fatty liver disease via ALDH2 inhibition.

Yao P, Zhang Z, Liu H, Jiang P, Li W, Du W EMBO J. 2023; 42(8):e112304.

PMID: 36825429 PMC: 10106987. DOI: 10.15252/embj.2022112304.

References

Adeniji E, Olotu F, Soliman M . Alcohol Metabolic Inefficiency: Structural Characterization of Polymorphism-Induced ALDH2 Dysfunctionality and Allosteric Site Identification for Design of Potential Wildtype Reactivators. Protein J. 2018; 37(3):216-222. DOI: 10.1007/s10930-018-9768-8. View

Wang W, Wang C, Xu H, Gao Y . Aldehyde Dehydrogenase, Liver Disease and Cancer. Int J Biol Sci. 2020; 16(6):921-934. PMC: 7053332. DOI: 10.7150/ijbs.42300. View

Yao P, Sun H, Xu C, Chen T, Zou B, Jiang P . Evidence for a direct cross-talk between malic enzyme and the pentose phosphate pathway via structural interactions. J Biol Chem. 2017; 292(41):17113-17120. PMC: 5641861. DOI: 10.1074/jbc.M117.810309. View

Vousden K, Prives C . Blinded by the Light: The Growing Complexity of p53. Cell. 2009; 137(3):413-31. DOI: 10.1016/j.cell.2009.04.037. View

Guo R, Xu X, Babcock S, Zhang Y, Ren J . Aldehyde dedydrogenase-2 plays a beneficial role in ameliorating chronic alcohol-induced hepatic steatosis and inflammation through regulation of autophagy. J Hepatol. 2014; 62(3):647-56. PMC: 4336638. DOI: 10.1016/j.jhep.2014.10.009. View

Larson H, Weiner H, Hurley T . Disruption of the coenzyme binding site and dimer interface revealed in the crystal structure of mitochondrial aldehyde dehydrogenase "Asian" variant. J Biol Chem. 2005; 280(34):30550-6. PMC: 1262676. DOI: 10.1074/jbc.M502345200. View

OBrate A, Giannakakou P . The importance of p53 location: nuclear or cytoplasmic zip code?. Drug Resist Updat. 2004; 6(6):313-22. DOI: 10.1016/j.drup.2003.10.004. View

Zhao M, Yao P, Mao Y, Wu J, Wang W, Geng C . Malic enzyme 2 maintains protein stability of mutant p53 through 2-hydroxyglutarate. Nat Metab. 2022; 4(2):225-238. DOI: 10.1038/s42255-022-00532-w. View

Jones R, Plas D, Kubek S, Buzzai M, Mu J, Xu Y . AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell. 2005; 18(3):283-93. DOI: 10.1016/j.molcel.2005.03.027. View

10.

Bian X, Jiang H, Meng Y, Li Y, Fang J, Lu Z . Regulation of gene expression by glycolytic and gluconeogenic enzymes. Trends Cell Biol. 2022; 32(9):786-799. DOI: 10.1016/j.tcb.2022.02.003. View

11.

Zhong W, Zhang W, Li Q, Xie G, Sun Q, Sun X . Pharmacological activation of aldehyde dehydrogenase 2 by Alda-1 reverses alcohol-induced hepatic steatosis and cell death in mice. J Hepatol. 2014; 62(6):1375-81. PMC: 7949737. DOI: 10.1016/j.jhep.2014.12.022. View

12.

Moon S, Huang C, Houlihan S, Regunath K, Freed-Pastor W, Morris 4th J . p53 Represses the Mevalonate Pathway to Mediate Tumor Suppression. Cell. 2018; 176(3):564-580.e19. PMC: 6483089. DOI: 10.1016/j.cell.2018.11.011. View

13.

Campana L, Esser H, Huch M, Forbes S . Liver regeneration and inflammation: from fundamental science to clinical applications. Nat Rev Mol Cell Biol. 2021; 22(9):608-624. DOI: 10.1038/s41580-021-00373-7. View

14.

Jiang P, Du W, Mancuso A, Wellen K, Yang X . Reciprocal regulation of p53 and malic enzymes modulates metabolism and senescence. Nature. 2013; 493(7434):689-93. PMC: 3561500. DOI: 10.1038/nature11776. View

15.

Mews P, Egervari G, Nativio R, Sidoli S, Donahue G, Lombroso S . Alcohol metabolism contributes to brain histone acetylation. Nature. 2019; 574(7780):717-721. PMC: 6907081. DOI: 10.1038/s41586-019-1700-7. View

16.

Kleiner D, Brunt E, Van Natta M, Behling C, Contos M, Cummings O . Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005; 41(6):1313-21. DOI: 10.1002/hep.20701. View

17.

Osna N, Donohue Jr T, Kharbanda K . Alcoholic Liver Disease: Pathogenesis and Current Management. Alcohol Res. 2017; 38(2):147-161. PMC: 5513682. View

18.

Lee B, Vittinghoff E, Dodge J, Cullaro G, Terrault N . National Trends and Long-term Outcomes of Liver Transplant for Alcohol-Associated Liver Disease in the United States. JAMA Intern Med. 2019; 179(3):340-348. PMC: 6439700. DOI: 10.1001/jamainternmed.2018.6536. View

19.

Chaudhry K, Samak G, Shukla P, Mir H, Gangwar R, Manda B . ALDH2 Deficiency Promotes Ethanol-Induced Gut Barrier Dysfunction and Fatty Liver in Mice. Alcohol Clin Exp Res. 2015; 39(8):1465-75. PMC: 4515212. DOI: 10.1111/acer.12777. View

20.

Lahalle A, Lacroix M, De Blasio C, Cisse M, Linares L, Le Cam L . The p53 Pathway and Metabolism: The Tree That Hides the Forest. Cancers (Basel). 2021; 13(1). PMC: 7796211. DOI: 10.3390/cancers13010133. View