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Reduced methylation of PP2Ac promotes ethanol-induced lipid accumulation through FOXO1 phosphorylation in vitro and in vivo.

Authors
  • Zhang, Yali1
  • Yuan, Tianli2
  • Su, Zhangyao2
  • Wang, Xi2
  • Wang, Yilun2
  • Ni, Yao2
  • Zuo, Yue2
  • Gu, Haohao2
  • 1 Department of Biochemistry and Molecular Biology, School of Medicine, Nantong University, Nantong, Jiangsu 226001, China. Electronic address: [email protected] , (China)
  • 2 Department of Biochemistry and Molecular Biology, School of Medicine, Nantong University, Nantong, Jiangsu 226001, China. , (China)
Type
Published Article
Journal
Toxicology letters
Publication Date
May 31, 2020
Volume
331
Pages
65–74
Identifiers
DOI: 10.1016/j.toxlet.2020.05.035
PMID: 32492475
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Although disturbance of the methionine cycle and sequent decrease in hepatic methylation capacity are known to be important factors in the development of alcoholic liver injury, the underlying mechanisms are not fully understood. Here, we investigated the importance of the methylation of protein phosphatase 2A (PP2A) in alcoholic liver disease (ALD). We found that the severity of ethanol-induced liver injury and the extent of demethylation of PP2A catalytic C subunit (PP2Ac) were reduced after treatment with betaine, a methyl donor involved in the methionine-homocysteine cycle. These results suggest that PP2Ac methylation is decreased due to a broad decrease in hepatic methylation capacity after exposure to ethanol. Moreover, we found that the reduction in PP2Ac methylation led to increased degradation of the regulatory Bα subunit, thus promoting the phosphorylation and nuclear exclusion of Forkhead box O1 (FOXO1) and reducing FOXO1 transcriptional activity. Ultimately, the reduced activity of FOXO1 led to increased expression of TXNIP, which caused hepatic lipid accumulation. Our findings suggest that the reduction of PP2A methylation, a result of decrease hepatic methylation capacity, played an important role in ethanol-induced lipid accumulation via down-regulation of PP2A/Bα and FOXO1 phosphorylation. Copyright © 2020 Elsevier B.V. All rights reserved.

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