Mechanisms of Metabolic Disease Exacerbation through Regulation of Biological Membrane Lipid Composition by Oxidized Cholesterol

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K17680
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 59040:Nutrition science and health science-related
• Research Institution: Tohoku University
• Principal Investigator: Arisawa Kotoko 東北大学, 薬学研究科, 助教 (00813122)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 酸化コレステロール / フェロトーシス / 酸化ストレス / 飽和脂肪酸

Outline of Final Research Achievements

In recent years, there has been an increase in the consumption of animal-based and processed foods globally, and hydroxycholesterol contained in these foods has been suggested to be associated with diseases such as type 2 diabetes and non-alcoholic steatohepatitis (NASH). However, the details of the cytotoxicity caused by oxidized cholesterol remain unclear. In this study, we investigated the involvement of oxidized cholesterol in ferroptosis, an iron-dependent form of cell death that has recently been suggested to be related to NASH and other diseases. It was revealed that 7α-hydroxycholesterol specifically increases during ferroptosis induced by erastin, and gene suppression of its producing enzyme, CYP7A1, confers resistance to ferroptosis.

Free Research Field

脂質生物学

Academic Significance and Societal Importance of the Research Achievements

鉄は生体の様々な生理機能に不可欠な必須微量ミネラルである一方、鉄代謝異常は多様な疾患と密接に関係する。鉄の異常な蓄積はフェントン反応によりフリーラジカルを生成し、脂質過酸化を伴う鉄依存的な細胞死である「フェロトーシス」を引き起こすことも近年明らかになってきた。細胞膜構成脂質であるコレステロールも酸化されるが、フェロトーシス誘導時の酸化コレステロール動態はあまり解明されていなかった。本研究において、フェロトーシス誘導初期にはコレステロールの酸化酵素CYP7A1が増加し、この酵素の抑制がフェロトーシス耐性につながることが示された。本知見は、フェロトーシスを標的とした創薬などへの展開が期待できる。