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Elucidation of the apotosis mechanism induced by 25-HC ester and analysis of its effects on cellular functions

Research Project

Project/Area Number 20K17519
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 54040:Metabolism and endocrinology-related
Research InstitutionJichi Medical University

Principal Investigator

Yamamuro Daisuke  自治医科大学, 医学部, リサーチ・レジデント (20739255)

Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2022: ¥390,000 (Direct Cost: ¥300,000、Indirect Cost: ¥90,000)
Fiscal Year 2021: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywordsオキシステロール / 25-hydroxycholesterol / NCEH1 / アポトーシス / 25-Hydroxycholesterol / 小胞体ストレス
Outline of Research at the Start

コレステロール酸化代謝物であるオキシステロール類は様々な生理活性が報告され、多くの疾患との関連について報告がなされてきたが、その詳細な分子機序は未解明な点が多い。本研究で内因性25-HC esterのアポトーシス誘導機序を解明し、マクロファージ細胞機能に対する25-HC esterの新たな生理活性を提示することは、生体内25-HC esterおよびNCEH1の動脈硬化症を始めとしたマクロファージ関連疾患における発症因子としての提示、さらには発症機序の解明へと発展することが期待できる。

Outline of Final Research Achievements

In this study, the addition of 25-HC to NCEH1-deficient macrophages resulted in the accumulation of 25-HC ester in the endoplasmic reticulum. The accumulation of 25-HC ester inducted apoptosis via the PERK/eIF2α/ATF4 pathway, and the Galectin-3 which is involved in macrophage cell function and Cathepsin D which is involved in macrophage foaming were upregulated. In order to analyze the upstream molecules of the PERK/eIF2α/ATF4 pathway, we analyzed Oxysterol binding protein (OSBPL)5/8, which plays an endoplasmic reticulum sensor for oxysterols. OSBPL5/8 was knocked down with siRNA and examined for effects on the PERK/eIF2α/ATF4 pathway activation and apoptosis, but these were not inhibited by OSBPL5/8 (endoplasmic reticulum sensors) knock down. These results suggest that 25-HC ester induces apoptosis by PERK/eIF2α/ATF4 pathway activation without mediated by the OSBPL family.

Academic Significance and Societal Importance of the Research Achievements

従来のオキシステロールに関する研究報告では、free体またはtotal量(free体とester体の総量)に着目し、その生理活性や疾患発症機序との関連が報告されてきた。生体内オキシステロール類はfree体とester体が存在しており、これらを区別して解析した研究報告はない。本研究ではマクロファージでの25-HC ester蓄積を起因とした新たなアポトーシス誘導メカニズムを明らかとした。マクロファージに対する25-HC esterの新たな生理活性を提示することは、動脈硬化症を始めとしたマクロファージ関連疾患における発症因子としての提示、さらには発症機序の解明へと発展することが期待できる。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (2 results)

All 2021

All Journal Article (1 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (1 results)

  • [Journal Article] Esterification of 4-hydroxycholesterol and other oxysterols in human plasma occurs independently of LCAT2021

    • Author(s)
      Daisuke Yamamuro , Hisataka Yamazaki , Jun-Ichi Osuga , Kenta Okada , Tetsuji Wakabayashi , Akihito Takei , Shoko Takei , Manabu Takahashi , Shuichi Nagashima , Adriaan G Holleboom , Masayuki Kuroda , Hideaki Bujo , Shun Ishibashi
    • Journal Title

      The Journal of Lipid Research

      Volume: 61 Pages: 1287-1299

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] 脂質代謝の概日リズムと摂餌刺激2021

    • Author(s)
      山室 大介
    • Organizer
      日本動脈硬化学会
    • Related Report
      2021 Research-status Report

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Published: 2020-04-28   Modified: 2024-01-30  

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