Analysis of the epigenetic modification of ATGL gene in idiopathic TGCV pathogenesis

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K11555
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 59040:Nutrition science and health science-related
• Research Institution: Osaka University
• Principal Investigator: Hara Yasuhiro 大阪大学, 大学院医学系研究科, 特任研究員(常勤) (70568617)
• Co-Investigator(Kenkyū-buntansha): 平野 賢一 大阪大学, 大学院医学系研究科, 特任教授(常勤) (30332737)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: ATGL / TGCV

Outline of Final Research Achievements

The original aim of the study was to find the epigenetic mechanism by which ATGL gene is regulated in idiopathic TGCV (I-TGCV) that has no pathogenic ATGL mutations. However, the ATGL protein mass in I-TGCV patients was found not to be decreased, rather up-regulated, compared to healthy controls. Therefore, the goal of the study needed to be reconsidered.
To find new targets for the elucidation of I-TGCV pathogenesis, the followings were performed in this study. (1) A long chain fatty acid (LCFA) metabolism assay using white blood cells from patient’s peripheral blood based on ex vivo detection of a fluorescent LCFA probe export, which our laboratory previously developed. (2) Analysis of ATGL coding exons of 24 samples from I-TGCV patients to identify SNPs and to elucidate their relationship with the pathogenesis. (3) More detailed re-analyses of proteome data from fibroblast cells derived from TGCV patients and the hearts of ATGL-knockout mice using our published results.

Free Research Field

病態分子生物学

Academic Significance and Societal Importance of the Research Achievements

(1)蛍光標識長鎖脂肪酸アナログAlexa680-BMPPがTGCV患者白血球を用いて長鎖脂肪酸代謝を見るプローブとして有効であると判断できた。(2)特発性TGCVの24検体のATGLエキソンにおいてトータル7個のSNPsが見つかったが、これらはいずれも日本人のATGLのSNPとして既知のCommon SNPでありタンパク質機能に影響を与える可能性は低いと考えた。 (3)TGCV患者由来線維芽細胞、およびATGL-KOマウス心臓のプロテオーム解析の再解析を行い、TGCV発症とATGL欠損の心臓において重要と思われる候補分子を同定した。これらは今後のTGCV研究の重要な手掛かりと考えられる。