| Project/Area Number |
17K16154
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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 |
Metabolomics
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| Research Institution | Jichi Medical University |
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Principal Investigator |
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| Project Period (FY) |
2017-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | 脂肪肝 / チアゾリジン誘導体 / マウス / ラット / PPARγ |
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| Outline of Final Research Achievements |
While TZDs improve fatty liver in human, TZDs aggravate it in mice. To explore the mechanism for this species difference, we analyzed leptin deficient obese models, ob/ob mice and Lepmkyo/Lepmkyo rats and generalized lipodystrophy models, A-ZIP/F-1 mice and seipin KO (SKO) rats. All four animal models showed severe fatty liver. However, hepatic PPARγ mRNA expression was upregulated only in mouse models. We treated with TZDs for 4 weeks. Fatty liver in ob/ob and A-ZIP/F-1 was aggravated while it was improved in Lepmkyo/Lepmkyo. Surprisingly, fatty liver in SKO was unchanged. At this time, TZDs increased a PPARγ target gene in the liver in mouse models but not in rat models. In WAT, TZDs increased Fsp27 expression in both ob/ob and Lepmkyo/Lepmkyo. Furthermore, TZDs improved insulin sensitivity in ob/ob, A-ZIP/F-1 and Lepmkyo/Lepmkyo but not in SKO. These results clearly revealed that effects of TZDs on fatty liver and insulin sensitivity require WAT in rats and might be in humans.
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| Academic Significance and Societal Importance of the Research Achievements |
わが国の脂肪肝患者数は1千万人とも言われ、肝癌対策における非アルコール性脂肪肝疾患（NAFLD）の重要性が増している。メタボリックシンドロームや肥満、糖尿病などがNAFLDのリスクファクターであり、食事療法や運動療法がNAFLDの主な治療法である一方、現在確立した薬物療法は存在しない。近年、チアゾリジン誘導体（TZD）のNAFLDに対する治療効果が報告されている（N Engl J Med. 355:2297-307,2006）。しかしながら、TZDによる脂肪肝改善メカニズムは不明であった。本研究によりTZDによる脂肪肝改善メカニズムが解明され、TZDの脂肪肝治療薬としての意義が明らかとなった。
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