Therapeutic strategy for pancreatic beta-cell lipotoxicity by activating lipid metabolism

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08531
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Kagawa University
• Principal Investigator: Murao Koji 香川大学, 医学部, 教授 (20291982)
• Co-Investigator(Kenkyū-buntansha): 福長 健作 香川大学, 医学部, 助教 (70746932) ; 井町 仁美 香川大学, 医学部, 准教授 (80380187)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: ABCA1 / HDL / インスリン / OxLDL / 2-Methoxyestradiol / promoter / LXR / FoxO1

Outline of Final Research Achievements

The reduced function of ABCA1 leads to lipid accumulation in pancreatic β-cells, which ultimately leads to reduced insulin secretion. Lipotoxicity is thought to be the cause of impaired glucose tolerance due to reduced glucose-responsive insulin secretion. Since female hormones promote ABCA1 expression, we comprehensively investigated the metabolites of female hormones. Among the metabolites, we found that 2-Methoxyestradiol (2-ME) promoted ABCA1 expression. 2-ME enhanced ABCA1 promoter activity, but this effect was reduced after inhibition of the PI3K pathway.Furthermore, 2-ME stimulated rapid phosphorylation of Akt and FoxO1 and reduced nuclear accumulation of FoxO1. Mutation of the FoxO1-binding site in the ABCA1 promoter or treatment with FoxO1-specific siRNA abolished the effect of 2-ME2 on ABCA1 expression, and OxLDL conversely downregulated ABCA1 gene expression and inhibited insulin secretion in pancreatic β-cells.

Free Research Field

代謝

Academic Significance and Societal Importance of the Research Achievements

本研究の目的は、膵β細胞のコレステロール含量を調節するABCA1の発現調節メカニズムを解明し、コレステロール蓄積によるインスリン分泌不全のメカニズムを網羅的に解析し、最終的にはHDL代謝, ABCA1代謝を賦活することによる膵β細胞の脂肪毒性解除を目指した新たな治療ストラテージを確立することにある。