Role of membrane lipid-modulated signal transductions in endotoxin hyperresponse of fatty livers

2023 Fiscal Year Final Research Report

• Project/Area Number: 20K07349
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Qin Xian-Yang 国立研究開発法人理化学研究所, 生命医科学研究センター, 研究員 (60756815)
• Project Period (FY): 2020-04-01 – 2024-03-31
• Keywords: 非アルコール性脂肪性肝炎 / 脂肪肝 / トランスグルタミナーゼ / エンドトキシン / 微小環境 / マルチオミクス解析 / 酸化ストレス / コーンオリゴペプチド

Outline of Final Research Achievements

Nonalcoholic steatohepatitis (NASH), characterized by accumulation of lipids and oxidative stress in the hepatocytes and continual liver damage, is believed will soon be the leading etiology of liver fibrosis and HCC. Hyperresponsivity to lipopolysaccharide (LPS) in fatty liver indicated to contribute to the progression of NASH, including hepatic inflammation and fibrosis, was observed in high-fat diet (HFD) mice compared with chow-fed mice. Transglutaminase (TG2) is a crosslinking enzyme that forms a covalent bond between lysine and glutamine. In this study, enhanced TG2 activation was selectively observed in liver macrophages in LPS-induced liver injury mouse models. By integrating lipidome, proteome and transcriptome analyses, a hepatic phosphatidylethanolamine-related membrane signaling network was established in NASH mouse models. Finally, liver protective functions were observed with TG2 activity inhibitors in sepsis-related liver injury and obesity and NASH mouse models.

Free Research Field

病態医化学

Academic Significance and Societal Importance of the Research Achievements

正常肝組織では、TG2の発現が観察されたが、顕著なTG2の活性化は見られなかった。それに対して、敗血症関連肝障害やNASHマウスにおいて、肝マクロファージに特異的にTG2の活性化が観察された。TG2は特定の組織環境において異なる機能を持つことが示唆された。TG2活性化を指標としたマクロファージの追跡は、敗血症性や脂肪性肝炎の発症機序の解明並びに新規治療法の開発に繋がると期待される。