Scholarlink

<p>Obesity can be classified into metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO), but the molecular mechanisms remain unclear. We identify geranylgeranyl pyrophosphate (GGPP), a metabolite of the hepatic mevalonate pathway involved in cholesterol biosynthesis, as a critical mediator that distinguishes MUO from MHO. In this study, Long-term feeding of mice with starch oleate significantly upregulated the expression of geranylgeranyl diphosphate synthase (Ggpps), resulting in elevated GGPP levels. Liver-specific deletion of <i>Ggpps</i> reduced GGPP and selectively attenuated adipocyte hypotrophy while specifically enhancing insulin sensitivity in epididymal white adipose tissue (eWAT). Mechanistic studies suggest that GGPP modulates acyl-CoA synthetase long-chain family member 1 (ACSL1) in eWAT through non-covalent binding rather than protein geranylgeranylation, thereby inhibiting its translocation from the endoplasmic reticulum to mitochondria. The retention of ACSL1 in the ER induces eWAT-specific adipose remodeling by promoting triglyceride (TG) synthesis and suppressing lipid oxidation. These findings establish a “liver-adipose” axis mediated by the hepatic metabolite GGPP via its non-covalent interaction with adipocyte ACSL1, highlighting potential therapeutic targets for metabolic dysfunction associated with metabolically unhealthy obesity.</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

Hepatic GGPP triggers visceral adipose hypertrophy via binding with adipocyte ACSL1 in metabolic unhealthy obesity

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月28日

查看全文
  • Hong-Yu Nie,
  • Ming-Jie Zou,
  • Meng-Fei Zhao,
  • Yi-Ping Tang,
  • Nan-Nan Wang,
  • Zi-Yue Zhou,
  • Jing-Zi Zhang,
  • Chao-Jun Li,
  • Lei Fang

摘要

Obesity can be classified into metabolically healthy obesity (MHO) and metabolically unhealthy obesity (MUO), but the molecular mechanisms remain unclear. We identify geranylgeranyl pyrophosphate (GGPP), a metabolite of the hepatic mevalonate pathway involved in cholesterol biosynthesis, as a critical mediator that distinguishes MUO from MHO. In this study, Long-term feeding of mice with starch oleate significantly upregulated the expression of geranylgeranyl diphosphate synthase (Ggpps), resulting in elevated GGPP levels. Liver-specific deletion of Ggpps reduced GGPP and selectively attenuated adipocyte hypotrophy while specifically enhancing insulin sensitivity in epididymal white adipose tissue (eWAT). Mechanistic studies suggest that GGPP modulates acyl-CoA synthetase long-chain family member 1 (ACSL1) in eWAT through non-covalent binding rather than protein geranylgeranylation, thereby inhibiting its translocation from the endoplasmic reticulum to mitochondria. The retention of ACSL1 in the ER induces eWAT-specific adipose remodeling by promoting triglyceride (TG) synthesis and suppressing lipid oxidation. These findings establish a “liver-adipose” axis mediated by the hepatic metabolite GGPP via its non-covalent interaction with adipocyte ACSL1, highlighting potential therapeutic targets for metabolic dysfunction associated with metabolically unhealthy obesity.