Association between complement activation pathways and nonalcoholic fatty liver disease

• Project/Area Number: 18K15789
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Fukushima Medical University
• Principal Investigator: Hayashi Manabu 福島県立医科大学, 医学部, 助教 (80745787)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
• Keywords: 脂肪肝 / 補体 / MASP / MASP-1 / MASP-3 / 線維化 / 非アルコール性脂肪肝疾患 / 非アルコール性脂肪肝炎

Outline of Final Research Achievements

We investigated the role of MASP-1 and MASP-3 in complement activation pathway using MASP-1 deficient mice and MASP-3 deficient mice. We revealed that MASP-3 is an alternative pathway-specific serine protease, whereas MASP-1 is an lectin pathway-specific serine protease. Further, we investigated the role of MASP-1 and MASP-3 in nonalcoholic fatty liver disease. Our Oil Red O staining of hepatic lipids revealed that decrease of liver steatosis in MASP-3 deficient mice. MASP-3 deficient mice also showed low serum ALT and low expression of Col1a1 in the liver compared with wild type mice. These findings suggested that MASP-3 deficient play protective role for NAFLD in mice.

Academic Significance and Societal Importance of the Research Achievements

非アルコール性脂肪肝疾患(NAFLD)はメタボリックシンドロームの肝臓における病態であるが、有病率が高く、また肝不全へ進行するため、新たな治療方法が必要とされている。補体は生体の恒常性維持のために重要な自然免疫因子であり、MASP-1とMASP-3はそれぞれ異なる補体活性化経路の重要な活性化因子であることを明らかにした。また補体第二経路の活性化因子であるMASP-3の欠損がNAFLD病態に保護的に作用する結果が得られた。本研究は補体の特に第二経路を標的とした治療方法の創出に役立つものと考える。

Research Products

• [Journal Article] Cutting Edge: Role of MASP-3 in the physiological activation of factor D of the alternative complement pathway (2019)
  • Author(s): Manabu Hayashi, Takeshi Machida, Yumi Ishida, Yusuke Ogata, Tomoko Omori, Mika Takasumi, Yuichi Endo, Toshiyuki Suzuki, Masayuki Sekimata, Yoshimi Homma, Masahito Ikawa, Hiromasa Ohira, Teizo Fujita, and Hideharu Sekine
  • Journal Title: the J Immunol Volume: 203 Pages: 1411-1416
  • DOI: 10.4049/jimmunol.1900605
  • Peer Reviewed / Open Access / Int'l Joint Research