Mechanism and prevention strategy of inflammation and fibrosis caused by quantitative and qualitative transformation of organ lipids in inflammation cellular society

2021 Fiscal Year Final Research Report

• Project Area: Preventive medicine through inflammation cellular sociology
• Project/Area Number: 17H06395
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Complex systems
• Research Institution: University of Tsukuba
• Principal Investigator: Hitoshi Shimano 筑波大学, 医学医療系, 教授 (20251241)
• Co-Investigator(Kenkyū-buntansha): 松坂 賢 筑波大学, 医学医療系, 教授 (70400679) ; 中川 嘉 筑波大学, 国際統合睡眠医科学研究機構, 准教授 (80361351)
• Project Period (FY): 2017-06-30 – 2022-03-31
• Keywords: scRNA-seq / 糖尿病 / 脂質異常症 / 動脈硬化

Outline of Final Research Achievements

This study aimed to investigate the significance of quantity and quality aspects of organ lipids in the pathophysiology of chronic inflammation, fibrosis and organopathy. We observed that 1) we performed scRNA-seq of pancreatic islets from diabetic mice and identified a new prediabetic marker gene and several beta-cell transdifferentiation pathways; 2) CREB3L3 has multi-potent protective effects against atherosclerosis owing to new mechanistic interaction between CREB3L3 and SREBPs under atherogenic conditions; 3) RHBDL4/RHBDD1, a rhomboid family protease, directly cleaves SREBP-1 at ER and the RHBDL4-SREBP-1c pathway reveals a regulatory system for monitoring fatty acid composition and maintaining cellular lipid homeostasis. Our findings provided evidence supporting the important role of quantity and quality control of organ lipids as a therapeutic target for inflammatory diseases.

Free Research Field

代謝・内分泌学

Academic Significance and Societal Importance of the Research Achievements

本研究により、前糖尿病から2型糖尿病発症における膵島の細胞社会の変遷を解明し、新規糖尿病未病マーカーを発見することが出来た。さらに、脂質異常症および動脈硬化の治療標的としてのCREBH、RHBDL4の重要性を明らかにした。今後、これらの知見、分子に着目した研究をさらに進めることにより、炎症関連疾患の発症機序の解明や新しい予防法と治療法の開発が期待される。