Scholarlink

<p>Maintenance of glucose and lipid homeostasis is essential for metabolic health, and its dysregulation, driven by complex gene-environment interactions-underlies various metabolic disorders. Free fatty acid receptor 4 (FFAR4) has been proposed to link dietary signals with genetic metabolic predisposition, yet the precise mechanisms underlying the pathophysiological function of FFAR4 remain elusive and lack of the highly selective FFAR4 agonists. Our study shed light on the pivotal role of FFAR4 in metabolic homeostasis within metabolic organs. Hepatic <i>FFAR4</i> deficiency in mice exacerbates lipid accumulation and promoted severe steatosis, whereas its overexpression ameliorates diet-induced metabolic dysfunction. Mechanistically, suppression of hepatic FFAR4 promotes lipogenesis by enhancing co-activation of the nuclear receptor Nr1h3 and PPARγ. Furthermore, we identify bavachalcone, a non-carboxylated compound isolated from the traditional Chinese medicine <i>Psoralea corylifolia L</i>., as a functionally effective FFAR4 agonist, which could robustly attenuate metabolic dysfunction. Structural analysis using cryo-electron microscopy reveals the binding mode of bavachalcone within the FFAR4-Gα<sub>iq</sub> complex and illuminated the underlying mechanisms. In conclusion, our findings highlight an indispensable role of hepatic FFAR4 in counteracting metabolic dysregulation and identify bavachalcone as a selective and translatable FFAR4 agonist worthy of further clinical evaluation.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Gαq activation of free fatty acid receptor 4 suppresses metabolic dysfunction by disrupting Nr1h3-PPARγ axis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月15日

查看全文
  • Yulin Kong,
  • Jixia Wang,
  • Zhen Wang,
  • Shuting Yang,
  • Xianlong Ye,
  • Wei Wang,
  • Hui Wang,
  • Wanjun Deng,
  • Yanfang Liu,
  • Fangfang Xu,
  • Tao Hou,
  • Yaopeng Zhao,
  • Binyu Zhang,
  • Xuekui Yu,
  • Yongquan Chen,
  • Xinmiao Liang,
  • Shenglong Zhu

摘要

Maintenance of glucose and lipid homeostasis is essential for metabolic health, and its dysregulation, driven by complex gene-environment interactions-underlies various metabolic disorders. Free fatty acid receptor 4 (FFAR4) has been proposed to link dietary signals with genetic metabolic predisposition, yet the precise mechanisms underlying the pathophysiological function of FFAR4 remain elusive and lack of the highly selective FFAR4 agonists. Our study shed light on the pivotal role of FFAR4 in metabolic homeostasis within metabolic organs. Hepatic FFAR4 deficiency in mice exacerbates lipid accumulation and promoted severe steatosis, whereas its overexpression ameliorates diet-induced metabolic dysfunction. Mechanistically, suppression of hepatic FFAR4 promotes lipogenesis by enhancing co-activation of the nuclear receptor Nr1h3 and PPARγ. Furthermore, we identify bavachalcone, a non-carboxylated compound isolated from the traditional Chinese medicine Psoralea corylifolia L., as a functionally effective FFAR4 agonist, which could robustly attenuate metabolic dysfunction. Structural analysis using cryo-electron microscopy reveals the binding mode of bavachalcone within the FFAR4-Gαiq complex and illuminated the underlying mechanisms. In conclusion, our findings highlight an indispensable role of hepatic FFAR4 in counteracting metabolic dysregulation and identify bavachalcone as a selective and translatable FFAR4 agonist worthy of further clinical evaluation.