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<p>The enzymatic role of ABHD6 in insulin secretion and resistance is well documented. However, its non-enzymatic function, especially its effects on metabolic health, including selective hepatic insulin resistance and metabolic dysfunction-associated steatotic liver disease (MASLD), is poorly understood. To define the role of ABHD6 in liver physiology, we generated liver-specific ABHD6 knockout mice, as well as liver-specific native and enzymatically inactive mutant ABHD6 overexpression&#xa0;mouse models. We demonstrate that non-enzymatic ABHD6 contributes to the regulation of selective hepatic insulin resistance and MASLD progression. Mechanistically, we show that ABHD6 localizes to the nucleus and interacts with Akt/FoxO1 axis to regulate insulin signaling. Our findings identify a mechanism underlying selective hepatic insulin resistance and highlight a role for the non-enzymatic function of ABHD6 in this process. This study suggests that&#xa0;modulation of this non-enzymatic activity may represent a potential therapeutic strategy for improving metabolic health.</p>

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Non-enzymatic hepatic ABHD6 interacts with Akt-FoxO1 axis to regulate metabolic health

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月3日

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  • Guannan Li,
  • Laurence T. Maeyens,
  • Jiyuan Yin,
  • Jan-Bernd Funcke,
  • Chanmin Joung,
  • Ruizhen Li,
  • Ziying Xu,
  • Ting Wu,
  • Xin Li,
  • Nisi Jiang,
  • Mbolle Ekane,
  • Maria Paula Lopez,
  • Pengju Cao,
  • Sijia He,
  • Adam B. Salmon,
  • S. R. Murthy Madiraju,
  • Marc Prentki,
  • Juli Bai,
  • James F. Nelson,
  • Xianlin Han,
  • Yi Zhu,
  • Shangang Zhao

摘要

The enzymatic role of ABHD6 in insulin secretion and resistance is well documented. However, its non-enzymatic function, especially its effects on metabolic health, including selective hepatic insulin resistance and metabolic dysfunction-associated steatotic liver disease (MASLD), is poorly understood. To define the role of ABHD6 in liver physiology, we generated liver-specific ABHD6 knockout mice, as well as liver-specific native and enzymatically inactive mutant ABHD6 overexpression mouse models. We demonstrate that non-enzymatic ABHD6 contributes to the regulation of selective hepatic insulin resistance and MASLD progression. Mechanistically, we show that ABHD6 localizes to the nucleus and interacts with Akt/FoxO1 axis to regulate insulin signaling. Our findings identify a mechanism underlying selective hepatic insulin resistance and highlight a role for the non-enzymatic function of ABHD6 in this process. This study suggests that modulation of this non-enzymatic activity may represent a potential therapeutic strategy for improving metabolic health.