2019 Fiscal Year Final Research Report
Mechanism of insulin resistance by fatty acids via selenoprotein P
| Project/Area Number |
16K09739
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Metabolomics
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| Research Institution | Kanazawa University |
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Principal Investigator |
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| Project Period (FY) |
2016-04-01 – 2020-03-31
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| Keywords | ヘパトカイン / インスリン抵抗性 / 脂肪酸 |
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| Outline of Final Research Achievements |
Selenoprotein P (encoded by SELENOP in humans, Selenop in rat), a liver-derived secretory protein, induces resistance to insulin and VEGF in type 2 diabetes. The present findings demonstrate that EPA suppresses SELENOP expression by inactivating SREBP-1c in H4IIEC3 hepatocytes. Treatment with EPA caused concentration- and time-dependent reduction in SELENOP promoter activity. EPA activated AMPK; however, the inhibitory effect of EPA on SELENOP promoter activity was not canceled with an AMPK inhibitor compound C and dominant-negative AMPK transfection. Deletion mutant promoter assays and computational analysis of transcription factor-binding sites conserved among the species resulted in identification of a SRE-like site in the SELENOP promoter. A ChIP assay revealed that EPA decreases binding of SREBP-1c to the SELENOP promoter. Knockdown of Srebf1 resulted in a significant down-regulation of Selenop expression. SREBP-1c overexpression inhibited the suppressive effect of EPA.
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| Free Research Field |
ヘパトカイン
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| Academic Significance and Societal Importance of the Research Achievements |
我々はこれまでに、セレノプロテインP (SeP) がインスリン抵抗性を誘導する”ヘパトカイン”であることを報告してきた。H4IIEC肝細胞において、パルミチン酸 (PA)はSREBP-1c経路非依存的にSeP発現を誘導すること、エイコサペンタエン酸 (EPA)はSREBP-1cの核移行を抑制し、不活化を介して肝臓でのSeP発現を抑制することを示唆した。よって、EPAによるSeP発現抑制は全身インスリン抵抗性を改善する可能性がある。今後、マウスおよび臨床サンプルを利用したさらなる研究が、EPAの全身のインスリン抵抗性改善薬としての新たな臨床的有用性を明らかにすることが期待される。
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