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

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K17519
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Jichi 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
• Keywords: オキシステロール / 25-hydroxycholesterol / NCEH1 / アポトーシス

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.

Free Research Field

脂質生化学

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。