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ER phospholipid composition modulates lipogenesis during feeding and in obesity
Xin Rong, … , David A. Ford, Peter Tontonoz
Xin Rong, … , David A. Ford, Peter Tontonoz
Published August 28, 2017
Citation Information: J Clin Invest. 2017;127(10):3640-3651. https://doi.org/10.1172/JCI93616.
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Research Article Cell biology Metabolism

ER phospholipid composition modulates lipogenesis during feeding and in obesity

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Abstract

Sterol regulatory element–binding protein 1c (SREBP-1c) is a central regulator of lipogenesis whose activity is controlled by proteolytic cleavage. The metabolic factors that affect its processing are incompletely understood. Here, we show that dynamic changes in the acyl chain composition of ER phospholipids affect SREBP-1c maturation in physiology and disease. The abundance of polyunsaturated phosphatidylcholine in liver ER is selectively increased in response to feeding and in the setting of obesity-linked insulin resistance. Exogenous delivery of polyunsaturated phosphatidylcholine to ER accelerated SREBP-1c processing through a mechanism that required an intact SREBP cleavage–activating protein (SCAP) pathway. Furthermore, induction of the phospholipid-remodeling enzyme LPCAT3 in response to liver X receptor (LXR) activation promoted SREBP-1c processing by driving the incorporation of polyunsaturated fatty acids into ER. Conversely, LPCAT3 deficiency increased membrane saturation, reduced nuclear SREBP-1c abundance, and blunted the lipogenic response to feeding, LXR agonist treatment, or obesity-linked insulin resistance. Desaturation of the ER membrane may serve as an auxiliary signal of the fed state that promotes lipid synthesis in response to nutrient availability.

Authors

Xin Rong, Bo Wang, Elisa N.D. Palladino, Thomas Q. de Aguiar Vallim, David A. Ford, Peter Tontonoz

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Figure 4

Liver ER membrane composition is dynamically regulated during feeding.

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Liver ER membrane composition is dynamically regulated during feeding.
(...
(A) Validation of ER fractionation of mouse liver extracts by immunoblot analysis of subcellular markers. (B) ESI-MS/MS analysis of PC species in the ER fraction from livers of C57BL/6 mice fasted 12 hours or fasted 12 hours and refed 12 hours with a high-carbohydrate diet (21). Indicated (sn-1/sn-2) molecular species were confirmed by product ion scanning for aliphatic composition. n = 6 per group. Statistical analysis was by Student’s t test with correction for multiple comparisons using the Holm-Šidák method. *P < 0.05. Values are shown as mean ± SEM. (C) ESI-MS/MS analysis of PC species in the ER fraction from livers of C57BL/6 mice fasted 12 hours or fasted 12 hours and refed 12 hours with a high-fat diet (60% fat). Indicated (sn-1/sn-2) molecular species were confirmed by product ion scanning for aliphatic composition. n = 6 per group. Statistical analysis was by Student’s t test with correction for multiple comparisons using the Holm-Šidák method. *P < 0.05. Values are shown as mean ± SEM.

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