Histone Demethylase KDM7A Contributes to the Development of Hepatic Steatosis by Targeting Diacylglycerol Acyltransferase 2

Int J Mol Sci. 2021 Oct 14;22(20):11085. doi: 10.3390/ijms222011085.


Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. While the development of NAFLD is correlated with aberrant histone methylation, modifiers of histone methylation involved in this event remain poorly understood. Here, we studied the functional role of the histone demethylase KDM7A in the development of hepatic steatosis. KDM7A overexpression in AML12 cells upregulated diacylglycerol acyltransferase 2 (DGAT2) expression and resulted in increased intracellular triglyceride (TG) accumulation. Conversely, KDM7A knockdown reduced DGAT2 expression and TG accumulation, and significantly reversed free fatty acids-induced TG accumulation. Additionally, adenovirus-mediated overexpression of KDM7A in mice resulted in hepatic steatosis, which was accompanied by increased expression of hepatic DGAT2. Furthermore, KDM7A overexpression decreased the enrichment of di-methylation of histone H3 lysine 9 (H3K9me2) and H3 lysine 27 (H3K27me2) on the promoter of DGAT2. Taken together, these results indicate that KDM7A overexpression induces hepatic steatosis through upregulation of DGAT2 by erasing H3K9me2 and H3K27me2 on the promoter.

Keywords: diacylglycerol acyltransferase 2; hepatic steatosis; histone demethylase KDM7A; histone methylation; nonalcoholic fatty liver disease; triglyceride.

MeSH terms

  • Animals
  • Diacylglycerol O-Acyltransferase / genetics
  • Diacylglycerol O-Acyltransferase / metabolism*
  • Hep G2 Cells
  • Histones / metabolism
  • Humans
  • Jumonji Domain-Containing Histone Demethylases / genetics
  • Jumonji Domain-Containing Histone Demethylases / metabolism*
  • Lysine / metabolism
  • Mice, Inbred C57BL
  • Mice, Obese
  • Non-alcoholic Fatty Liver Disease / genetics*
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Non-alcoholic Fatty Liver Disease / pathology
  • Promoter Regions, Genetic
  • Triglycerides / metabolism


  • Histones
  • Triglycerides
  • Jumonji Domain-Containing Histone Demethylases
  • KDM7 protein, mouse
  • KDM7A protein, human
  • DGAT2 protein, human
  • DGAT2 protein, mouse
  • Diacylglycerol O-Acyltransferase
  • Lysine