Regulation of acute hepatic injury in mice by leptin

2022 Fiscal Year Final Research Report

• Project/Area Number: 19K07487
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: Kitasato University
• Principal Investigator: Kawamura Toshihiko 北里大学, 医療衛生学部, 教授 (70301182)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Keywords: NKT細胞 / 肝臓 / 肝炎 / α-galactosylceramide / レプチン / レプチンレセプター

Outline of Final Research Achievements

In a mouse model of NKT cell-dependent liver injury which is induced by alpha-galactosylceramide administration, serum levels of leptin were found to be significantly elevated. Using leptin deficient (ob/ob) or leptin receptor deficient (db/db) mice and anti-leptin Ab or anti-leptin receptor Ab, it was demonstrated that leptin contributed to the aggravation of liver injury. NKT cells expressed high levels of leptin receptor and produced TNF-alpha which aggravates liver injury in response to leptin. Hepatocytes also expressed leptin receptors and apoptosis was induced in these cells in response to leptin. These results suggest that leptin directly or indirectly contributed to aggravation of NKT cell-dependent liver injury.

Free Research Field

実験病理学

Academic Significance and Societal Importance of the Research Achievements

レプチンが、直接あるいは間接的に NKT 細胞を活性化し、あるいは、肝細胞の細胞死感受性を調節し、肝炎の悪化に働くことが明らかになった。この急性肝炎モデルの治療法として抗レプチン抗体や抗レプチンレセプター抗体が候補となりうる。マウスのみならず、ヒトにおいても、免疫機序による急性肝炎が存在し、肝細胞破壊が大規模に起こると、劇症肝炎につながる場合もある。本研究は、臨床医学の観点からも、これらヒト急性肝炎の病態解明・治療法開発にもつながる。さらに、ホルモンによる急性炎症の制御など、ホルモンの新たな機能を探る契機にもなり、内分泌学・免疫学・炎症学・病理学の観点からも、学術的波及効果が大きいと考える。