Elucidation of the molecular mechanism of lipid-sensing by the novel SREBP-1 protease R4

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K11713
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 59040:Nutrition science and health science-related
• Research Institution: University of Tsukuba
• Principal Investigator: Han Song-iee 筑波大学, 国際統合睡眠医科学研究機構, 研究員 (80729541)
• Co-Investigator(Kenkyū-buntansha): 中川 嘉 富山大学, 学術研究部薬学・和漢系, 教授 (80361351)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: SREBP-1 / protease / 脂肪酸

Outline of Final Research Achievements

SREBPs are the master regulators of fatty acid and cholesterol synthesis, and their dysregulation of activity leads to dyslipidemia pathology. SREBPs on the endoplasmic reticulum membrane are cleaved and activated by nutrient sensing. The activated SREBPs translocate to the nucleus and regulate the expression of target genes. In this study, we identified a novel protease R4 that cleaves and activates SREBP-1 and elucidated its molecular mechanism. The R4-SREBP-1 pathway promotes lipid synthesis, polyunsaturated fatty acid synthesis, and lipoprotein secretion by sensing fatty acids, and plays an important role in lipid accumulation and homeostasis in the body.

Free Research Field

分子生物学

Academic Significance and Societal Importance of the Research Achievements

脂質代謝異常の病態におけるSREBP-1活性化の分子機構は不明な点が多く残されており、既存の経路では説明できない新たなメカニズムの解明が必要とされていた。本研究により、新規プロテアーゼR4によるSREBP-1活性化制御機構を明らかにしたこと、また脂肪酸によるsensing機構を明らかにしたことから、R4-SREBP-1経路が新たな脂質異常症治療戦略に繋がることが期待される。