Molecular mechanisms and translational research in NASH and obesity-related liver cancer focusing on lipid metabolic reprograming
| Project/Area Number |
18H02789
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 53010:Gastroenterology-related
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| Research Institution | The University of Tokyo |
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Principal Investigator |
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥16,510,000 (Direct Cost: ¥12,700,000、Indirect Cost: ¥3,810,000)
Fiscal Year 2020: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2019: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2018: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
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| Keywords | 非アルコール性脂肪肝炎 / 肝細胞癌 / アシルカルニチン / SREBP / 脂質代謝 / ビタミンD / 脂質生合成経路 / metabolic reprogramming / NASH |
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| Outline of Final Research Achievements |
We analzyed molecular mechanisms of NASH-related HCC development focusing on lipid metabolsim and explored biomarkers. In addition, we conducted preclinical studies using new compounds. We obtained the following results. 1) Altered serum acylcarnitine profile is a potential biomarker for NASH, 2) We developed VDR-silent vitamin D derivative that impairs SREBP in vivo, 3) Strong inhibition of SCAP-SREBP pawathy rather exacerbates liver injury in NASH, 4), Myeloid cell-specific KO of ASK1 prevents NASH-related HCC.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究結果によって、NASHの病態を反映する血清バイオマーカーを同定することができ、さらにNASHの治療につながり得る脂肪酸合成を標的とした新規化合物の導出に成功した。しかしながらマウスモデルにおける検討では、強力すぎる脂質生合成の阻害はかえってNASHの病態を悪化させる可能性を示唆する結果が得られた。このことは今後のNASHの治療戦略を考えるうえで、重要な示唆を与えるものである。
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Report
(4 results)
Research Products
(19 results)
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[Journal Article] Discovery of a VDR-Silent Vitamin D Derivative That Impairs SREBP in Vivo.2021
Author(s)
1.Kawagoe F, Mendoza A, Hayata Y, Asano L, Kotate K, Mototani S, Kawamura S, Kurosaki S, Akagi Y, Takemoto Y, Nagasawa K, Nakagawa H, Uesugi M, Kittaka A.
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Journal Title
J Med Chem.
Volume: in press
Related Report
Peer Reviewed
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