Roles of macrophage proliferation in the progression of nonalcoholic fatty liver disease.

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K09787
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Metabolomics
• Research Institution: Kumamoto University
• Principal Investigator: Senokuchi Takafumi 熊本大学, 大学院生命科学研究部(医), 助教 (00530320)
• Co-Investigator(Kenkyū-buntansha): 松村 剛 熊本大学, 大学院生命科学研究部(医), 准教授 (20398192)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: NASH/NAFLD / マクロファージ / メタボリックシンドローム

Outline of Final Research Achievements

To verify the direct evidence of involvement of local macrophage proliferation for Nonalcoholic fatty liver disease (NAFLD) and total glucose tolerance we have generated transgenic mice whose macrophage proliferation is specifically suppressed by inducing the expression of p27kip (mac-p27Tg). The High-Fat Diet-fed mac-p27Tg showed improved insulin sensitivity compared with the controls. The triglyceride content in the liver was significantly decreased in mac-p27Tg mice. Hepatic steatosis was formed less by macrophage growth inhibition.
The inhibition of local macrophage growth resulted in the marked suppression of obesity-associated liver insulin resistance by ameliorating excess inflammatory responses in these tissues. These results suggested that the local macrophage proliferation could be one of the major pathophysiological features in the dietary-induced insulin resistance, and possibly be one of the therapeutic targets for chronic inflammation diseases.

Free Research Field

糖尿病合併症、メタボリックシンドローム

Academic Significance and Societal Importance of the Research Achievements

肝臓におけるNAFLD/NASHの病態を慢性炎症性疾患としてとらえ、マクロファージ特異的増殖抑制マウスを用いた検討により肝内マクロファージ増殖のNAFLD/NASHにおける病態生理学的意義を明らかにした。これらの結果から動脈硬化、糖尿病、NAFLD/NASHのマクロファージ増殖を基盤とした共通の進展機序が示された。また、マクロファージ増殖の制御が、肝臓の炎症、繊維化のみならず、メタボリックシンドロームおよびその合併症の抑制を目指した治療の標的となり得ることを明らかにした。