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2023 Fiscal Year Final Research Report

Understanding the pathogenesis of obesity-related tubulopathy from the perspective of lysosomal dysfunction

Research Project

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Project/Area Number 20K17279
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 53040:Nephrology-related
Research InstitutionOsaka University

Principal Investigator

Minami Satoshi  大阪大学, 大学院医学系研究科, 特任助教(常勤) (00791592)

Project Period (FY) 2020-04-01 – 2024-03-31
Keywords肥満関連尿細管症 / リソソーム / オートファジー / 飽和脂肪酸 / TFEB / FGF21
Outline of Final Research Achievements

This study examined the pathogenesis of obesity-related tubulopathy (ORT; obesity-related tubulopathy) in detail. The results revealed that 1) TFEB is the most activated transcription factor under saturated fatty acid load, 2) its activation is due to the suppression of the mTORC1 non-classical pathway, and 3) TFEB activated during ORT suppresses the progression of kidney disease through the release of undigested material accumulated inside lysosomes into the tubular lumen by promoting lysosomal exocytosis. In addition, this study identified a mechanism by which the production of FGF21 is enhanced during ORT and this FGF21 counteracts the progression of kidney disease through improving autophagy stagnation and promoting mitochondrial biosynthesis.

Free Research Field

腎臓内科学

Academic Significance and Societal Importance of the Research Achievements

本研究により①ORTの病態では尿細管でTFEBが活性化しリソソーマルエクソサイトーシスを亢進することによりリソソーム恒常性を維持しORTに対抗していること、②ORTの病態では尿細管でFGF21の産生が亢進しミトコンドリア生合成促進ならびにオートファジー停滞改善を介してORTに対抗していること、が明らかとなり、これまで大部分が未解明であったORTの病態メカニズムの一端を解明することができた。以上から今後は肥満関連腎症や糖尿病関連腎臓病に対して、TFEB-リソソーマルエクソサイトーシス経路の活性化やFGF21産生の促進を標的としたORTの病態に即した治療法の開発が期待される。

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Published: 2025-01-30  

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