Homocysteine accelerates hepatocyte autophagy by upregulating TFEB via DNMT3b-mediated DNA hypomethylation

Acta Biochim Biophys Sin (Shanghai). 2023 Apr 6;55(8):1184-1192. doi: 10.3724/abbs.2023060.

Abstract

Autophagy plays a critical role in the physiology and pathophysiology of hepatocytes. High level of homocysteine (Hcy) promotes autophagy in hepatocytes, but the underlying mechanism is still unknown. Here, we investigate the relationship between Hcy-induced autophagy level and the expression of nuclear transcription factor EB (TFEB). The results show that Hcy-induced autophagy level is mediated by upregulation of TFEB. Silencing of TFEB decreases the level of autophagy-related protein LC3BII/I and increases p62 expression level in hepatocytes after exposure to Hcy. Moreover, the effect of Hcy on the expression of TFEB is regulated by hypomethylation of the TFEB promoter catalyzed by DNA methyltransferase 3b (DNMT3b). In summary, this study shows that Hcy can activate autophagy by inhibiting DNMT3b-mediated DNA methylation and upregulating TFEB expression. These findings provide another new mechanism for Hcy-induced autophagy in hepatocytes.

Keywords: DNA methylation; DNA methyltransferase 3b; TFEB; autophagy; homocysteine.

MeSH terms

  • Autophagy* / genetics
  • DNA
  • DNA Methylation*
  • DNA Methyltransferase 3B
  • Hepatocytes*
  • Homocysteine* / metabolism
  • Homocysteine* / pharmacology
  • Humans

Substances

  • DNA
  • Homocysteine

Grants and funding

This work was supported by the grants from the National Natural Science Foundation of China (Nos. U21A20343, 82160088, 81870332, 81700404, 82260088, and 82060110), the Natural Science Foundation of Ningxia (Nos. 2022AAC05025, 2020AAC02021, 2020AAC02038 and 2021AAC03337), the Key Research and Development Projects in Ningxia (Nos. 2019BFG02004, 2020BFH02003, 2020BEG03005 and 2020BEG03008), Ningxia Project of Supporting Engineering Talents (No. TJGC2019092), a School-level Special Talent Launching Project of Ningxia Medical University (No. XT2018015), Ningxia Science and Technology Leading Talent Project (No. KJT2017007), and Basic Scientific Research Operating Expenses from the Public Welfare Research Institutes at the Central Level of the Chinese Academy of Medical Sciences (No. 2019PT330002).