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  3. Hepatic ASPG-mediated lysophosphatidylinositol catabolism impairs insulin signal transduction

Hepatic ASPG-mediated lysophosphatidylinositol catabolism impairs insulin signal transduction

  • EMBO J. 2025 Aug 4. doi: 10.1038/s44318-025-00525-x.
Feiyan Li 1,  Hua-Sheng Huang 2,  Qingwen Zhao 3,  Wei Zhang 1,  Ting Shi 1,  Wenjing Lv 1,  Qi Zhu 1,  Haojie Liu 1,  Yingjiang Xu 4,  Haiyan Huang 1,  Qi-Qun Tang 1,  Yue Gao 3,  Tao Peng 2,  Dongning Pan 5 6
Affiliations

Affiliations

  • 1 Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences; Fudan University, 200032, Shanghai, China.
  • 2 Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, 530021, Nanning, China.
  • 3 Zhejiang Key Laboratory of Traditional Chinese Medicine for the Prevention and Treatment of Senile Chronic Diseases, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, 310006, Hangzhou, China.
  • 4 Department of Interventional Vascular Surgery, Binzhou Medical University Hospital, Binzhou, Shandong, China.
  • 5 Key Laboratory of Metabolism and Molecular Medicine of the Ministry of Education; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences; Fudan University, 200032, Shanghai, China. dongning.pan@fudan.edu.cn.
  • 6 Department of Endocrinology and Metabolism, Qingpu Branch of Zhongshan Hospital, Fudan University, 200032, Shanghai, China. dongning.pan@fudan.edu.cn.
PMID: 40760121 DOI: 10.1038/s44318-025-00525-x
Abstract

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.

Keywords

ASPG; Insulin Signaling; Lysophosphatidylinositol; Lysophospholipase; PTP1B.

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