| Project/Area Number |
18H04023
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Medium-sized Section 48:Biomedical structure and function and related fields
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| Research Institution | Juntendo University (2019-2020)
Nagoya University (2018) |
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Principal Investigator |
Fujimoto Toyoshi 順天堂大学, 医学(系)研究科(研究院), 特任教授 (50115929)
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| Co-Investigator(Kenkyū-buntansha) |
大崎 雄樹 名古屋大学, 医学系研究科, 准教授 (00378027)
辻 琢磨 順天堂大学, 医学(系)研究科(研究院), 特任助教 (40725628)
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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 |
¥44,330,000 (Direct Cost: ¥34,100,000、Indirect Cost: ¥10,230,000)
Fiscal Year 2020: ¥14,560,000 (Direct Cost: ¥11,200,000、Indirect Cost: ¥3,360,000)
Fiscal Year 2019: ¥14,560,000 (Direct Cost: ¥11,200,000、Indirect Cost: ¥3,360,000)
Fiscal Year 2018: ¥15,210,000 (Direct Cost: ¥11,700,000、Indirect Cost: ¥3,510,000)
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| Keywords | 脂肪滴 / ホスファチジルコリン / 肝細胞 / オートファジー / 核膜 / 小胞体ストレス / CCT / 電子顕微鏡 / 燐脂質 / リン脂質 |
|---|
| Outline of Final Research Achievements |
The surface of lipid droplets (LDs) has properties different from other biological membranes and recruit unique proteins. In hepatocytes exposed to the endoplasmic reticulum stress, we discovered that lipids, which are normally secreted as lipoproteins, enter the nucleus and generate nuclear LDs. These nuclear LDs recruit and activate CCTα, an isoform of the enzyme critical for phosphatidylcholine synthesis, thereby contributing to mitigation of the endoplasmic reticulum stress. In cells under starvation, free fatty acids derived from digested self materials generate cytoplasmic LDs. On those LDs, CCTβ3, a different isoform of CCT, is activated, and this helps cells to maintain autophagy and survive for a prolonged time in starvation.
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| Academic Significance and Societal Importance of the Research Achievements |
これまで不明であった肝細胞における核内脂肪滴の形成機構が解明され、CCTα活性化を通じてストレス緩和に寄与することが明らかになった。肝細胞のストレス増悪は脂肪肝などの疾病要因であり、今後、核内脂肪滴を標的とした予防・治療法への展開が期待できる。一方、飢餓時に形成される細胞質脂肪滴はCCTβ3活性化を通じてオートファジーの維持に重要な役割を果たすことが分かった。低栄養状態下の癌細胞生存にはこの機序が関与していると推測され、CCTβ3を標的とした制癌治療の可能性が示された。
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