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<p>Obesity and related metabolic disorders, including metabolic dysfunction-associated steatohepatitis (MASLD), have reached epidemic proportions worldwide. We unveil a previously unknown moonlighting role for arginase 1 (Arg1) in facilitating hepatic lipogenesis. Male mice lacking hepatic Arg1 exhibit diminished lipid accumulation in both liver and adipocytes, an effect mirrored in genetically- or diet-induced obesity models following Arg1 inhibitor treatment. Mechanistically, Arg1 competes with RSK2 and Elk1 for binding to the substrate-binding pocket of extracellular signal-regulated kinase 2 (ERK2) via its S-shaped motif, thereby enhancing ERK2 ubiquitination and degradation and upregulating the AKT/mTOR/PPARγ and Elk1/c-Fos/PPARγ cascades, ultimately augmenting lipogenesis. Peptides designed to mimic the ERK2 substrate-binding pocket disrupt the Arg1-ERK2 interaction and improve metabolic profiles in obesity and MASLD models. Our findings implicate Arg1 regulates hepatic lipid metabolism via its physical interaction with ERK2, highlighting the Arg1-ERK2 interaction as a promising therapeutic target for obesity and related metabolic disorders in male mice.</p>

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Arginase 1 promotes hepatic lipogenesis by regulating ERK2/PPARγ signaling in a non-canonical manner

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年2月18日

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  • Mingyang Shao,
  • Xiaoyue Cao,
  • Yuwei Chen,
  • Ziqi Zhu,
  • Yuke Shu,
  • Qing Tao,
  • Qing Xu,
  • Tingting Ma,
  • Zhenru Wu,
  • Menglin Chen,
  • Yongjie Zhou,
  • Rong Yao,
  • Junhua Gong,
  • Jiayin Yang,
  • Yujun Shi

摘要

Obesity and related metabolic disorders, including metabolic dysfunction-associated steatohepatitis (MASLD), have reached epidemic proportions worldwide. We unveil a previously unknown moonlighting role for arginase 1 (Arg1) in facilitating hepatic lipogenesis. Male mice lacking hepatic Arg1 exhibit diminished lipid accumulation in both liver and adipocytes, an effect mirrored in genetically- or diet-induced obesity models following Arg1 inhibitor treatment. Mechanistically, Arg1 competes with RSK2 and Elk1 for binding to the substrate-binding pocket of extracellular signal-regulated kinase 2 (ERK2) via its S-shaped motif, thereby enhancing ERK2 ubiquitination and degradation and upregulating the AKT/mTOR/PPARγ and Elk1/c-Fos/PPARγ cascades, ultimately augmenting lipogenesis. Peptides designed to mimic the ERK2 substrate-binding pocket disrupt the Arg1-ERK2 interaction and improve metabolic profiles in obesity and MASLD models. Our findings implicate Arg1 regulates hepatic lipid metabolism via its physical interaction with ERK2, highlighting the Arg1-ERK2 interaction as a promising therapeutic target for obesity and related metabolic disorders in male mice.