Postprandial triglyceride-rich lipoproteins promote the adipogenic differentiation of adipose-derived mesenchymal stem cells via the LRP1/caveolin-1/AKT1 pathway |
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| Affiliation: | 1. Department of Cardiovascular Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, PR China;2. Research Institute of Blood Lipid and Atherosclerosis, Central South University, Changsha, Hunan 410011, PR China;3. Modern Cardiovascular Disease Clinical Technology Research Center of Hunan Province, Changsha, Hunan 410011, PR China;4. Cardiovascular Disease Research Center of Hunan Province, Changsha, Hunan 410011, PR China;5. Department of Geriatrics, The Second Xiangya Hospital, Central South University, Changsha 410011, Hunan, PR China;6. Department of Geriatric Cardiovascular Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, PR China;7. Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, PR China;8. Department of Emergency Medicine, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, PR China;9. Emergency Medicine and Difficult Diseases Institute, The Second Xiangya Hospital, Central South University, Hunan 410011, PR China;1. Research Unit for Molecular Medicine, Department of Clinical Medicine, Aarhus University and Aarhus University Hospital, Palle Juel-Jensens Boulevard 99, 8200 Aarhus, Denmark;2. School of Pharmacy, Liverpool John Moore University, Byrom Street, Liverpool L3 3AF, United Kingdom;1. Graduate School of Technology, Industrial and Social Sciences, Tokushima University, Tokushima 770-8502, Japan;2. Graduate School of Biomedical Sciences, Tokushima University, Tokushima 770-8505, Japan;3. Diabetic Neuropathy Project, Department of Diseases and Infection, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan;1. Department of Cardiovascular Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China;2. Department of Cardiothoracic Surgery, Shenshan Medical Center, Memorial Hospital of Sun Yat-sen University, Shanwei, China;3. Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China;1. ECOMARE – Laboratory for Innovation and Sustainability of Marine Biological Resources, CESAM – Centre for Environmental and Marine Studies, Department of Chemistry, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal;2. Mass Spectrometry Centre & LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, Campus Universitário de Santiago, 3810-193 Aveiro, Portugal;3. ECOMARE - Laboratory for Innovation and Sustainability of Marine Biological Resources, CESAM – Centre for Environmental and Marine Studies, Department of Biology, Campus Universitário de Santiago, University of Aveiro, 3810-193 Aveiro, Portugal;4. GreenCoLab – Associação Oceano Verde, University of Algarve, Campus de Gambelas, 8005-139 Faro, Portugal;5. Department of Economics and Business, Universitat Pompeu Fabra, Barcelona School of Management, Barcelona, Spain |
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| Abstract: | Diet-induced obesity (OB) is usually accompanied by hypertriglyceridemia, which is characterized by the accumulation of triglyceride (TG)-rich lipoprotein (TRL) particles in the circulation. We previously found that postprandial TRL combined with insulin induced the adipogenic differentiation of 3T3-L1 preadipocytes, which may represent a key mechanism underlying obesity. However, the specific mechanism and signaling pathway involved in this process remain to be fully elucidated. In this study, we found that, in the postprandial state, patients with obesity had significantly higher levels of TG and remnant cholesterol (RC) than normal-weight controls. In vitro, we found that postprandial TRL, together with insulin, promoted the adipogenic differentiation of adipose-derived mesenchymal stem cells (AMSCs), as evidenced by the increased expression of lipogenesis-related genes and their protein products, including low-density lipoprotein related protein 1 (LRP1). Besides, caveolin-1 (Cav-1) expression was also significantly upregulated under this condition. Cav-1 and LRP1 were observed to interact, and then led to the activation of the PI3K/AKT1 signaling pathway. Meanwhile, the inhibition of LRP1 or Cav-1 significantly attenuated the adipogenic differentiation of AMSCs and downregulated AKT1 phosphorylation levels. Moreover, treatment with a selective AKT1 inhibitor significantly suppressed postprandial TRL and insulin-induced adipogenesis in AMSCs. Combined, our results demonstrated that, in association with insulin, postprandial TRL can promote the adipogenic differentiation of AMSCs in a manner that is dependent on the LRP1/Cav-1-mediated activation of the PI3K/AKT1 signaling pathway. Our findings indicated that a postprandial increase in TRL content is a critical factor in the pathogenesis of hypertriglyceridemia and diet-induced obesity. |
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