- Pathophysiology
- Deficiency of ASGR1 Alleviates Diet-Induced Systemic Insulin Resistance via Improved Hepatic Insulin Sensitivity
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Xiaorui Yu, Jiawang Tao, Yuhang Wu, Yan Chen, Penghui Li, Fan Yang, Miaoxiu Tang, Abdul Sammad, Yu Tao, Yingying Xu, Yin-Xiong Li
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Diabetes Metab J. 2024;48(4):802-815. Published online February 1, 2024
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DOI: https://doi.org/10.4093/dmj.2023.0124
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 Abstract
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- Background
Insulin resistance (IR) is the key pathological basis of many metabolic disorders. Lack of asialoglycoprotein receptor 1 (ASGR1) decreased the serum lipid levels and reduced the risk of coronary artery disease. However, whether ASGR1 also participates in the regulatory network of insulin sensitivity and glucose metabolism remains unknown.
Methods
The constructed ASGR1 knockout mice and ASGR1-/- HepG2 cell lines were used to establish the animal model of metabolic syndrome and the IR cell model by high-fat diet (HFD) or drug induction, respectively. Then we evaluated the glucose metabolism and insulin signaling in vivo and in vitro.
Results
ASGR1 deficiency ameliorated systemic IR in mice fed with HFD, evidenced by improved insulin intolerance, serum insulin, and homeostasis model assessment of IR index, mainly contributed from increased insulin signaling in the liver, but not in muscle or adipose tissues. Meanwhile, the insulin signal transduction was significantly enhanced in ASGR1-/- HepG2 cells. By transcriptome analyses and comparison, those differentially expressed genes between ASGR1 null and wild type were enriched in the insulin signal pathway, particularly in phosphoinositide 3-kinase-AKT signaling. Notably, ASGR1 deficiency significantly reduced hepatic gluconeogenesis and glycogenolysis.
Conclusion
The ASGR1 deficiency was consequentially linked with improved hepatic insulin sensitivity under metabolic stress, hepatic IR was the core factor of systemic IR, and overcoming hepatic IR significantly relieved the systemic IR. It suggests that ASGR1 is a potential intervention target for improving systemic IR in metabolic disorders.
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Citations
Citations to this article as recorded by  - Association Analysis of the Circulating Proteome With Sarcopenia‐Related Traits Reveals Potential Drug Targets for Sarcopenia
Simin Wen, Siqi Xu, Xizeng Zong, Shifeng Wen, Wende Xiao, Weipeng Zheng, Han Cen, Zhaohua Zhu, Jingyu Xie, Yan Zhang, Changhai Ding, Guangfeng Ruan
Journal of Cachexia, Sarcopenia and Muscle.2025;[Epub] CrossRef - Serum Soluble Asialoglycoprotein Receptor 1: A Potential Predictor Marker Linked to Type 2 Diabetes Mellitus, Demonstrating Positive Correlation With High Sensitive C-Reactive Protein
Haifeng Zhu, Ziyi Zhong, Gaonian Zhao, Yuan Cao, Wei Liu, Yawen Guo, Jing Jin
Diabetes, Metabolic Syndrome and Obesity.2025; Volume 18: 663. CrossRef - Experimental cell models of insulin resistance: overview and appraisal
Ying Yang, Ting-ting Wang, Hu-ai Xie, Ping Ping Hu, Pan Li
Frontiers in Endocrinology.2024;[Epub] CrossRef
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