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<p>Bioactive glycerolysophospholipids (GLPs) are implicated in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) and obesity; however, the mechanisms underlying glycerolysophospholipid-mediated changes in insulin signaling remain poorly understood. Here, we identify the amino acid-metabolism enzyme asparaginase (ASPG) as a critical regulator of systemic fatty acid handling and insulin signal transduction. Hepatic ASPG expression levels negatively correlate with insulin sensitivity in humans. Loss of <i>Aspg</i> in MASLD mice modifies the liver hepatokine secretome, enhancing systemic insulin sensitivity. Notably, ASPG bears lysophospholipase activity towards the bioactive lipid lysophosphatidylinositol (LPI) in vitro and in vivo. Mechanistically, <i>Aspg</i> deficiency results in accumulation of intracellular LPIs and consequently in suppression of tyrosine phosphatase PTP1B activity. This in turn decreases FOXO1-dependent expression of the hepatokine <i>Sepp1</i>, leading to reduced SEPP1 secretion and extrahepatic insulin-sensitization. In summary, this study uncovers a novel biological mechanism whereby ASPG-controlled bioactive lipid levels modulate insulin resistance and insulin secretion, suggesting complementary therapeutic strategies for the improvement of systemic glucose homeostasis.</p>

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Hepatic ASPG-mediated lysophosphatidylinositol catabolism impairs insulin signal transduction

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月4日

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  • Feiyan Li,
  • Hua-Sheng Huang,
  • Qingwen Zhao,
  • Wei Zhang,
  • Ting Shi,
  • Wenjing Lv,
  • Qi Zhu,
  • Haojie Liu,
  • Yingjiang Xu,
  • Haiyan Huang,
  • Qi-Qun Tang,
  • Yue Gao,
  • Tao Peng,
  • Dongning Pan

摘要

Bioactive glycerolysophospholipids (GLPs) are implicated in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) and obesity; however, the mechanisms underlying glycerolysophospholipid-mediated changes in insulin signaling remain poorly understood. Here, we identify the amino acid-metabolism enzyme asparaginase (ASPG) as a critical regulator of systemic fatty acid handling and insulin signal transduction. Hepatic ASPG expression levels negatively correlate with insulin sensitivity in humans. Loss of Aspg in MASLD mice modifies the liver hepatokine secretome, enhancing systemic insulin sensitivity. Notably, ASPG bears lysophospholipase activity towards the bioactive lipid lysophosphatidylinositol (LPI) in vitro and in vivo. Mechanistically, Aspg deficiency results in accumulation of intracellular LPIs and consequently in suppression of tyrosine phosphatase PTP1B activity. This in turn decreases FOXO1-dependent expression of the hepatokine Sepp1, leading to reduced SEPP1 secretion and extrahepatic insulin-sensitization. In summary, this study uncovers a novel biological mechanism whereby ASPG-controlled bioactive lipid levels modulate insulin resistance and insulin secretion, suggesting complementary therapeutic strategies for the improvement of systemic glucose homeostasis.