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mTORC1 stimulates phosphatidylcholine synthesis to promote triglyceride secretion.

Authors
  • Quinn, William J 3rd1
  • Wan, Min1
  • Shewale, Swapnil V2
  • Gelfer, Rebecca1
  • Rader, Daniel J2
  • Birnbaum, Morris J1, 3
  • Titchenell, Paul M1, 4
  • 1 Institute for Diabetes, Obesity, and Metabolism, and.
  • 2 Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
  • 3 Internal Medicine, Pfizer Inc., Cambridge, Massachusetts, USA.
  • 4 Department of Physiology Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Type
Published Article
Journal
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Publication Date
Nov 01, 2017
Volume
127
Issue
11
Pages
4207–4215
Identifiers
DOI: 10.1172/JCI96036
PMID: 29035283
Source
Medline
License
Unknown

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.

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