Role of histone methylation modifications in the pathogenesis of nonalcoholic fatty liver disease.

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K15989
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Nakatsuka Takuma 東京大学, 医学部附属病院, 助教 (50772042)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Keywords: 非アルコール性脂肪性肝疾患 / 脂肪肝 / エピゲノム異常 / ヒストン修飾 / ヒストンメチル化 / G9a

Outline of Final Research Achievements

Numerous epigenomic modifications have been established to contribute to the development of hepatic steatosis. Our study employed mice harboring a liver-specific knock out (KO) of the histone methyltransferase G9a, and our findings indicate a decrease in the formation of fatty liver in G9a-KO hepatic tissues upon exposure to a high-fat diet (HFD). Furthermore, these G9a-KO mice exhibited enhanced weight gain and improved insulin sensitivity. Through an comprehensive gene expression analysis of mouse liver samples, we observed alterations in a subset of genes regulated by transcription factors associated with lipid metabolism, PPAR, LXR, and RXR, within the G9a-KO livers during HFD intake. Notably, the expression of Cd36, a pivotal mediator of fatty acid uptake into hepatocytes, was found to be reduced in G9a-KO livers, thereby suggesting its potential involvement in the amelioration of hepatic steatosis.

Free Research Field

消化器内科　肝臓病学

Academic Significance and Societal Importance of the Research Achievements

非アルコール性脂肪性肝疾患は世界中で増加しており健康保健上の大きな問題となっているが、未だ有効な薬物療法が存在しない。生活習慣病を含む様々な病態にエピゲノム異常が関与することが知られているが、本研究の成果によりエピゲノム修飾因子のひとつであるヒストンメチル化酵素G9aが脂肪肝形成やインスリン抵抗性に重要な役割を担うことが明らかとなった。G9a阻害剤により脂肪肝の病態進展を抑制できる可能性があり、脂肪肝に対する新規創薬のたーでっととなることが期待される。