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

• Published in: International journal of molecular sciences 2021-10, Vol.22 (20), p.11085
• Main Authors: Kim, Ji-Hyun, Nagappan, Arukumar, Jung, Dae Young, Suh, Nanjoo, Jung, Myeong Ho
• Format: Article
• Language: English
• Subjects: Accumulation; Acyltransferase; Adenoviruses; Animals; diacylglycerol acyltransferase 2; Diacylglycerol O-Acyltransferase - genetics; Diacylglycerol O-Acyltransferase - metabolism; Diglycerides; Epigenetics; Fatty acids; Fatty liver; Hep G2 Cells; hepatic steatosis; histone demethylase KDM7A; Histone H3; histone methylation; Histones; Histones - metabolism; Humans; Jumonji Domain-Containing Histone Demethylases - genetics; Jumonji Domain-Containing Histone Demethylases - metabolism; Liver; Liver diseases; Lysine; Lysine - metabolism; Methylation; Mice; Mice, Inbred C57BL; Mice, Obese; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; nonalcoholic fatty liver disease; Promoter Regions, Genetic; Proteins; Steatosis; triglyceride; Triglycerides; Triglycerides - metabolism
• ISSN: 1422-0067; 1661-6596; 1422-0067
• 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.