Liver-specific suppression of ANGPTL4 improves obesity-associated diabetes and mitigates atherosclerosis in mice
Liver-specific suppression of ANGPTL4 improves obesity-associated diabetes and mitigates atherosclerosis in mice
ABSTRACT Angiopoietin-like 4 (ANGPTL4) is a major regulator of lipoprotein lipase (LPL) activity, which is responsible for maintaining optimal levels of circulating triacylglycerol (TAG) for distribution to different tissues including the adipose tissues (ATs), heart, muscle and liver. Dysregulation of trafficking and portioning of fatty acids (FA) can promote ectopic lipid accumulation in metabolic tissues such as the liver, ultimately leading to systemic metabolic dysfunction. To investigate how ANGPTL4 regulates hepatic lipid and glucose metabolism, we generated liver-specific ANGPTL4 knockout mice (LKO). Using metabolic turnover studies, we demonstrate that hepatic ANGPTL4 deficiency facilitates catabolism of TAG-rich lipoprotein (TRL) remnants in the liver via increased hepatic lipase (HL) activity, which results in a significant reduction in circulating TAG and cholesterol levels. Deletion of hepatocyte ANGPTL4 protects against diet-induce obesity, glucose intolerance, liver steatosis, and atherogenesis. Mechanistically, we demonstrate that absence of ANGPTL4 in hepatocytes promotes FA uptake which results in increased FA oxidation, ROS production, and AMPK activation. Finally, we demonstrate the utility of a targeted pharmacologic therapy that specifically inhibits ANGPTL4 in the liver and protects against diet-induced obesity, dyslipidemia, glucose intolerance, and liver damage without causing any of the deleterious effects previously observed with neutralizing antibodies.
Chaube Balkrishna、Canfr¨￠n-Duque Alberto、Sun Jonathan、Rotllan Noemi、Lee Richard G.、Su¨￠rez Yajaira、Aryal Binod、Fern¨￠ndez-Hernando Carlos、Price Nathan L.、Zhang Xinbo、Citrin Kathryn M、Singh Abhishek K.
Vascular Biology and Therapeutics Program, Yale University School of Medicine||Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine, Yale University School of MedicineVascular Biology and Therapeutics Program, Yale University School of Medicine||Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine, Yale University School of MedicineVascular Biology and Therapeutics Program, Yale University School of MedicineVascular Biology and Therapeutics Program, Yale University School of Medicine||Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine, Yale University School of MedicineCardiovascular Group, Antisense Drug DiscoveryVascular Biology and Therapeutics Program, Yale University School of Medicine||Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine, Yale University School of MedicineVascular Biology and Therapeutics Program, Yale University School of Medicine||Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine, Yale University School of MedicineVascular Biology and Therapeutics Program, Yale University School of Medicine||Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine, Yale University School of MedicineVascular Biology and Therapeutics Program, Yale University School of Medicine||Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine, Yale University School of MedicineVascular Biology and Therapeutics Program, Yale University School of Medicine||Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine, Yale University School of MedicineVascular Biology and Therapeutics Program, Yale University School of Medicine||Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine, Yale University School of MedicineVascular Biology and Therapeutics Program, Yale University School of Medicine||Integrative Cell Signaling and Neurobiology of Metabolism Program, Department of Comparative Medicine, Yale University School of Medicine
基础医学生物化学生理学
ANGPTL4LPLDiabetesAtherosclerosis
Chaube Balkrishna,Canfr¨￠n-Duque Alberto,Sun Jonathan,Rotllan Noemi,Lee Richard G.,Su¨￠rez Yajaira,Aryal Binod,Fern¨￠ndez-Hernando Carlos,Price Nathan L.,Zhang Xinbo,Citrin Kathryn M,Singh Abhishek K..Liver-specific suppression of ANGPTL4 improves obesity-associated diabetes and mitigates atherosclerosis in mice[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/2020.06.02.130922.点此复制
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