mTORC1 stimulates phosphatidylcholine synthesis to promote triglyceride secretion
William J. Quinn III, … , Morris J. Birnbaum, Paul M. Titchenell
William J. Quinn III, … , Morris J. Birnbaum, Paul M. Titchenell
Published October 16, 2017
Citation Information: J Clin Invest. 2017;127(11):4207-4215. https://doi.org/10.1172/JCI96036.
View: Text | PDF
Research Article Metabolism

mTORC1 stimulates phosphatidylcholine synthesis to promote triglyceride secretion

Abstract

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.

Authors

William J. Quinn III, Min Wan, Swapnil V. Shewale, Rebecca Gelfer, Daniel J. Rader, Morris J. Birnbaum, Paul M. Titchenell

×

Figure 5

CCTα is regulated posttranscriptionally by mTORC1 activity.

Options: View larger image (or click on image) Download as PowerPoint
CCTα is regulated posttranscriptionally by mTORC1 activity. Six- to ten-...
Six- to ten-week-old Raptorfl/fl animals were injected with either AAV-GFP (control, black) or AAV-CRE (L-Raptor–KO, white) for 2 weeks prior to sacrifice. (A) Schematic of the Kennedy pathway. (B) Generation of CDP-choline was measured following incubation with 14C-choline chloride for 4 hours. n = 4. (C) CCTα activity was measured in hepatocyte lysates in the presence of excess CTP and 14C-phosphocholine. n = 12–13. (D) CCTα mRNA was interrogated by quantitative RT-PCR. n = 5–6. (E) CCTα protein was measured by Western blot. Data are representative of 6 animals. *P < 0.05; ***P < 0.001 vs. control using Student’s t test.