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mTORC1 stimulates phosphatidylcholine synthesis to promote triglyceride secretion
The Journal of Clinical Investigation ( IF 15.9 ) Pub Date : 2017-10-16 , DOI: 10.1172/jci96036
William J. Quinn , Min Wan , Swapnil V. Shewale , Rebecca Gelfer , Daniel J. Rader , Morris J. Birnbaum , Paul M. Titchenell

Liver triacylglycerol (TAG) synthesis and secretion are closely linked to nutrient availability. After a meal, hepatic TAG formation from fatty acids is decreased, largely due to a reduction in circulating free fatty acids (FFA). Despite the postprandial decrease in FFA-driven esterification and oxidation, VLDL-TAG secretion is maintained to support peripheral lipid delivery and metabolism. The regulatory mechanisms underlying the postprandial control of VLDL-TAG secretion remain unclear. Here, we demonstrated that the mTOR complex 1 (mTORC1) is essential for this sustained VLDL-TAG secretion and lipid homeostasis. In murine models, the absence of hepatic mTORC1 reduced circulating TAG, despite hepatosteatosis, while activation of mTORC1 depleted liver TAG stores. Additionally, mTORC1 promoted TAG secretion by regulating phosphocholine cytidylyltransferase α (CCTα), the rate-limiting enzyme involved in the synthesis of phosphatidylcholine (PC). Increasing PC synthesis in mice lacking mTORC1 rescued hepatosteatosis and restored TAG secretion. These data identify mTORC1 as a major regulator of phospholipid biosynthesis and subsequent VLDL-TAG secretion, leading to increased postprandial TAG secretion.

中文翻译:

mTORC1刺激磷脂酰胆碱合成,促进甘油三酸酯分泌

肝脏三酰基甘油(TAG)的合成和分泌与营养物质的利用密切相关。进餐后,由脂肪酸形成的肝TAG减少,这主要是由于循环中游离脂肪酸(FFA)的减少。尽管餐后FFA驱动的酯化和氧化减少,但VLDL-TAG的分泌得以维持,以支持外周脂质的输送和代谢。餐后控制VLDL-TAG分泌的基础调控机制仍不清楚。在这里,我们证明了mTOR复合物1(mTORC1)对于这种持续的VLDL-TAG分泌和脂质稳态是必不可少的。在鼠模型中,尽管存在肝脂肪变性,但肝mTORC1的缺乏会降低循环TAG,而mTORC1的激活会耗尽肝TAG的储存。此外,mTORC1通过调节磷脂酰胆碱(PC)合成中的限速酶磷酸胆碱胞嘧啶转移酶α(CCTα)来促进TAG分泌。在缺乏mTORC1的小鼠中增加PC合成可以挽救肝脂肪变性并恢复TAG分泌。这些数据确定mTORC1是磷脂生物合成和随后的VLDL-TAG分泌的主要调节剂,从而导致餐后TAG分泌增加。
更新日期:2017-11-02
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