| Project/Area Number |
17K19648
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| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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| Allocation Type | Multi-year Fund |
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| Research Field |
General internal medicine and related fields
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| Research Institution | Niigata University |
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Principal Investigator |
Shimizu Ippei 新潟大学, 医歯学総合研究科, 特任准教授 (60444056)
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| Research Collaborator |
Minamino Tohru
Yoshida Yohko
Okuda Shujiro
Sakimura Kenji
Terai Shuji
Sasaoka Toshikuni
Nakagami Hironori
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| Project Period (FY) |
2017-06-30 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2017: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
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| Keywords | 非アルコール性脂肪性肝炎 / NASH / 線維化促進分泌型タンパク質 / 肥満疾患 / 非アルコール生脂肪性肝炎 |
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| Outline of Final Research Achievements |
Non-alcoholic fatty liver disease (NAFLD) develops with obesity. Non-alcoholic steatohepatitis (NASH) is the extreme form of NAFLD characterized with sterile inflammation and fibrosis in the liver. NASH patients are increasing in many societies, however, the molecular mechanisms of fibrosis in the liver are largely unknown. We found a significant increase in obesity associated pro-fibrotic protein (OAFP) level in the serum from NASH patients compared to control groups. Obese-NASH model developed significant liver fibrosis associated with high circulating OAFP level. Injection of a plasmid encoding OAFP into skeletal muscle promoted fibrosis in the liver. In contrast, genetic suppression of OAFP inhibited liver fibrosis. Our studies from humans and rodents suggest the pathological role of OAFP in promoting fibrotic responses in liver upon metabolic stress. Suppression of OAFP would become next generation therapy for NASH.
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| Academic Significance and Societal Importance of the Research Achievements |
肥満NASHモデルマウスとNASH患者の血液中で、線維化促進分泌タンパクOAFPが２倍程度増加することがわかり、肥満ストレス下で唯一褐色脂肪組織でのみ発現が増加することがわかった。OAFPは肥満時に褐色脂肪組織で発現レベルが上昇し、肝臓の線維化を促進する可能性が高い。バイオマーカーとしての有用性に加え、治療標的として重要である可能性が高い。NASHには未だ満たされない医療ニーズが存在し、疾患特異的治療法の開発は急務である。本研究をさらに発展させ、中和抗体による治療法や小分子による阻害剤を開発し、NASHの新たな治療法を創出したいと考えている。
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