mTORC1 抑制脂肪细胞脂解以防止全身高血脂症。
mTORC1 restrains adipocyte lipolysis to prevent systemic hyperlipidemia.
机构信息
Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA; Biochemistry and Molecular Biophysics Graduate Group, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perlman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA; Institute for Diabetes, Obesity, and Metabolism, Perlman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
出版信息
Mol Metab. 2020 Feb;32:136-147. doi: 10.1016/j.molmet.2019.12.003. Epub 2019 Dec 13.
OBJECTIVE
Pharmacological agents targeting the mTOR complexes are used clinically as immunosuppressants and anticancer agents and can extend the lifespan of model organisms. An undesirable side effect of these drugs is hyperlipidemia. Although multiple roles have been described for mTOR complex 1 (mTORC1) in lipid metabolism, the etiology of hyperlipidemia remains incompletely understood. The objective of this study was to determine the influence of adipocyte mTORC1 signaling in systemic lipid homeostasis in vivo.
METHODS
We characterized systemic lipid metabolism in mice lacking the mTORC1 subunit Raptor (Raptor), the key lipolytic enzyme ATGL (ATGL), or both (ATGL-Raptor) in their adipocytes.
RESULTS
Mice lacking mTORC1 activity in their adipocytes failed to completely suppress lipolysis in the fed state and displayed prominent hypertriglyceridemia and hypercholesterolemia. Blocking lipolysis in their adipose tissue restored normal levels of triglycerides and cholesterol in the fed state as well as the ability to clear triglycerides in an oral fat tolerance test.
CONCLUSIONS
Unsuppressed adipose lipolysis in the fed state interferes with triglyceride clearance and contributes to hyperlipidemia. Adipose tissue mTORC1 activity is necessary for appropriate suppression of lipolysis and for the maintenance of systemic lipid homeostasis.
目的
靶向 mTOR 复合物的药物已在临床上用作免疫抑制剂和抗癌药物，可延长模式生物的寿命。这些药物的一个不良副作用是高血脂。尽管 mTOR 复合物 1（mTORC1）在脂质代谢中具有多种作用，但高血脂的病因仍不完全清楚。本研究的目的是确定脂肪细胞中 mTORC1 信号对体内全身脂质稳态的影响。
方法
我们在脂肪细胞中缺乏 mTORC1 亚基 Raptor（Raptor）、关键的脂肪酶 ATGL（ATGL）或两者（ATGL-Raptor）的小鼠中，对全身脂质代谢进行了表征。
结果
脂肪细胞中缺乏 mTORC1 活性的小鼠在进食状态下无法完全抑制脂肪分解，表现出明显的高甘油三酯血症和高胆固醇血症。阻断其脂肪组织中的脂肪分解在进食状态下恢复了甘油三酯和胆固醇的正常水平，以及在口服脂肪耐量试验中清除甘油三酯的能力。
结论
进食状态下未被抑制的脂肪分解会干扰甘油三酯的清除，并导致高血脂。脂肪组织中 mTORC1 的活性对于适当抑制脂肪分解和维持全身脂质稳态是必要的。
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