| Project/Area Number |
15K19313
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Gastroenterology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
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| Project Period (FY) |
2015-04-01 – 2018-03-31
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| Project Status |
Completed (Fiscal Year 2017)
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| Budget Amount *help |
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | NASH / 肝細胞癌 / メタボリックリプログラミング / CPT2 / アシルカルニチン / 脂質代謝リプログラミング / 肝癌 / 脂肪酸合成 / メタボローム |
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| Outline of Final Research Achievements |
We conducted untargeted metabolomics profiling using obesity-driven HCC mouse models, and found suppression of fatty acid β-oxidation (FAO) and subsequent extensive accumulation of acylcarnitine species in HCC tissues, which was caused by downregulation of CPT2, a key enzyme of FAO. CPT2 downregulation enabled HCC cells to escape lipotoxicity by inhibiting Src-mediated JNK activation, and accumulated acylcarnitine, specifically oleoylcarnitine, enhanced carcinogenesis by conferring stem cell properties to HCC through STAT3 activation. A high-fat diet and carnitine supplementation synergistically promoted HCC development with acylcarnitine accumulation in mice. Intriguingly, in obesity-driven HCC, glucose was utilized for oxidative phosphorylation to compensate suppressed FAO, unlike the Warburg effect. NASH-HCC patients also revealed CPT2-mediated metabolic reprogramming. Increased serum acylcarnitine was a potential biomarker of NASH-HCC.
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