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

• 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
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: NASH/NAFLD / マクロファージ / メタボリックシンドローム / NASH / インスリン抵抗性 / NAFLD/NASH / NAFLD / 肝線維化 / マクロファージ増殖 / Kufppfer細胞

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.

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。

Research Products

• [Journal Article] Inhibition of local macrophage growth ameliorates focal inflammation and suppresses atherosclerosis. (2018)
  • Author(s): Yamada S, Senokuchi T, Matsumura T, Morita Y, Ishii N, Fukuda K, Murakami S, Nishida S, Kawasaki S, Motoshima H, Furukawa N, Komohara Y, Fujiwara Y, Koga T, Yamagata K, Takeya M, Araki E
  • Journal Title: Arteriosclerosis, Thrombosis, and Vascular Biology Volume: 印刷中 Issue: 5 Pages: 994-1006
  • DOI: 10.1161/atvbaha.117.310320
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of microRNA that represses IRS-1 expression in liver. (2018)
  • Author(s): Ono K, Igata M, Kondo T, Kitano S, Takaki Y, Hanatani S, Sakaguchi M, Goto R, Senokuchi T, Kawashima J, Furukawa N, Motoshima H, Araki E
  • Journal Title: PLoS One Volume: 13 Issue: 1 Pages: 0191553-0191553
  • DOI: 10.1371/journal.pone.0191553
  • Peer Reviewed / Open Access
• [Journal Article] The clinical course and pathophysiological investigation of adolescent gestational diabetes insipidus: a case report (2018)
  • Author(s): Kondo Tatsuya、Nakamura Miwa、Kitano Sayaka、Kawashima Junji、Matsumura Takeshi、Ohba Takashi、Yamaguchi Munekage、Katabuchi Hidetaka、Araki Eiichi
  • Journal Title: BMC Endocrine Disorders Volume: 18 Issue: 1 Pages: 4-4
  • DOI: 10.1186/s12902-018-0234-6
  • Peer Reviewed / Open Access
• [Journal Article] Low glucose induces mitochondrial reactive oxygen species via fatty acid oxidation in bovine aortic endothelial cells. (2017)
  • Author(s): Kajihara N, Kukidome D, Sada K, Motoshima H, Furukawa N, Matsumura T, Nishikawa T, Araki E.
  • Journal Title: J Diabetes Investig. Volume: 印刷中 Issue: 6 Pages: 750-761
  • DOI: 10.1111/jdi.12678
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Empagliflozin suppresses atherosclerotic lesion formation in apolipoprotein E deficient mice by inhibiting macrophage activation. (2018)
  • Author(s): Matsumura T, Murakami-Nishida S, Senokuchi T, Ishii N, Nishida S, Kondo T, Motoshima H, Araki E
  • Organizer: 54th EASD Annual Meeting
  • Int'l Joint Research
• [Presentation] 慢性炎症性疾患としての動脈硬化発症・進展におけるマクロファージ増殖の意義 (2018)
  • Author(s): 瀬ノ口 隆文
  • Organizer: 50回 日本動脈硬化学会
  • Invited
• [Presentation] 動脈硬化の進展，インスリン抵抗性発現における組織浸潤マクロファージ増殖の意義 (2018)
  • Author(s): 瀬ノ口隆文、山田沙梨恵、守田雄太郎、和田敏明、松村剛、本島寛之、荒木栄一
  • Organizer: 第33回日本糖尿病合併症学会
• [Presentation] 動脈硬化病変形成に対するマクロファージ増殖抑制効果の検討 (2018)
  • Author(s): 守田雄太郎、瀬ノ口隆文、山田沙梨恵、本島寛之、松村剛、荒木栄一
  • Organizer: 50回 日本動脈硬化学会
• [Presentation] 組織マクロファージ増殖の脂肪組織および肝インスリン抵抗性における役割 (2018)
  • Author(s): 守田雄太郎、瀬ノ口隆文、山田沙梨恵、本島寛之、松村 剛、荒木栄一
  • Organizer: 第5回肝臓と糖尿病・代謝研究会
• [Presentation] Empagliflozin, a sodium-glucose cotransporter 2 inhibitor, suppresses the progression of atherosclerosis in diabetic apoE-deficient mice. (2017)
  • Author(s): Murakami S, Matsumura T, Senokuchi T, Ishii N, Fukuda K, Nishida S, Kondo T, Araki E
  • Organizer: The 77th ADA scientific meeting
  • Int'l Joint Research
• [Presentation] Renal protective effect of sodium dependent glucose transporter 2 inhibitor in combination with the renin angiotensin system blockers in early stage of diabetic nephropathy. (2017)
  • Author(s): Kukidome D, Kajihara N, Hanatani S, Kawashima J, Matsumura T, Araki E
  • Organizer: 53th EASD Annual Meeting
  • Int'l Joint Research
• [Presentation] Impaired balance strongly correlated with advanced microvascular complications in younger participants with diabetes. (2017)
  • Author(s): Kukidome D, Kajihara N, Hanatani S, Kawashima J, Matsumura T, Araki E
  • Organizer: IDF congress 2017
  • Int'l Joint Research
• [Presentation] マクロファージ増殖抑制による動脈硬化プラーク安定化に対する効果 (2017)
  • Author(s): 瀬ノ口隆文, 山田沙梨恵, 守田雄太郎, 本島寛之, 松村 剛, 荒木栄一
  • Organizer: 第55回日本糖尿病学会九州地方会
• [Presentation] Inhibition of Local Macrophage Growth Ameliorates Obesity-associated Adipose Tissue Inflammation, Insulin Resistance and Hepatic Steatosis in HFD-fed mice (2016)
  • Author(s): Yutaro Morita
  • Organizer: 11th IDF-WPR & 8th AASD
  • Place of Presentation: Taipei, Taiwan
  • Year and Date: 2016-10-27
  • Int'l Joint Research
• [Presentation] 肥満に伴うインスリン抵抗性および肝脂肪蓄積に対する組織マクロファージ増殖の病態生理学的意義の検討 (2016)
  • Author(s): 瀬ノ口隆文
  • Organizer: 日本肥満学会
  • Place of Presentation: 東京
  • Year and Date: 2016-10-07
• [Presentation] 肥満に伴う耐糖能異常及び非アルコール性脂肪性肝疾患（NAFLD）に対する組織マクロファージ増殖の病態生理学的意義の検討 (2016)
  • Author(s): 山田沙梨恵
  • Organizer: 西日本肥満研究会
  • Place of Presentation: 長崎市
  • Year and Date: 2016-07-23
• [Presentation] 非アルコール性脂肪性肝疾患（NAFLD）における肝内マクロファージ増殖の意義 (2016)
  • Author(s): 瀬ノ口隆文
  • Organizer: 第3回肝臓と糖尿病・代謝研究会
  • Place of Presentation: 金沢市
  • Year and Date: 2016-07-16