Molecular mechanism of metabolic regulation through protein acylations

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K22639
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 54:Internal medicine of the bio-information integration and related fields
• Research Institution: Kumamoto University
• Principal Investigator: Yamagata Kazuya 熊本大学, 大学院生命科学研究部(医), 教授 (70324770)
• Co-Investigator(Kenkyū-buntansha): 吉澤 達也 熊本大学, 大学院生命科学研究部(医), 准教授 (40313530)
• Project Period (FY): 2019-06-28 – 2021-03-31
• Keywords: PPARγ / 脂肪細胞 / サーチュイン / SIRT7

Outline of Final Research Achievements

Peroxisome proliferator-activated receptor (PPARγ2) is a transcription factor crucial for regulating adipogenesis and glucose/lipid metabolism. Sirtuin 7 (SIRT7), a nicotinamide adenine dinucleotide-dependent deacetylase, also controls metabolism. However, it is not known whether SIRT7 regulates the function of PPARγ2 by its deacetylation. We demonstrated that SIRT7 binds to PPARγ2 and deacetylates PPARγ2 at K382. C3H10T1/2-derived adipocytes expressing PPARγ2K382Q (a mimic of acetylated K) accumulated much less fat than adipocytes expressing wild-type PPARγ2 or PPARγ2K382R (a mimic of nonacetylated K). Global gene expression analysis of adipocytes expressing PPARγ2K382Q revealed that K382Q caused the dysregulation of a set of genes involved in lipogenesis, including Srebp1c, Acaca, Fasn, and Scd1. Our findings indicate that SIRT7-dependent PPARγ2 deacetylation at K382 controls lipogenesis in adipocytes.

Free Research Field

代謝学

Academic Significance and Societal Importance of the Research Achievements

PPARγの合成リガンドは糖尿病の治療薬として広く臨床で使用されているが、近年、PPARγの翻訳後修飾を制御する新たなタイプのPPARγモジュレーターの開発が進んでいる。今回の我々の研究結果はPPARγ382番目のアセチル化修飾が脂質代謝の制御に重要であることを意味しており、今後、同部位のアセチル化修飾変容薬が新たな脂質代謝・代謝異常症の治療標的となる可能性が示された