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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 Article has an altmetric score of 3

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 5

LPCAT3 modulates the lipogenic response to feeding.

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LPCAT3 modulates the lipogenic response to feeding.
(A) Lpcat3fl/fl (F/F...
(A) Lpcat3fl/fl (F/F) and Lpcat3fl/fl albumin-Cre+ (L-Lpcat3–/–) mice were fasted 12 hours or fasted 12 hours and refed 12 hours with a high-carbohydrate diet. Gene expression was analyzed by real-time PCR. n = 6 per group. Statistical analysis was by 2-way ANOVA with Bonferroni’s post hoc tests. (B) Membrane and nuclear fractions were prepared from fresh livers from mice treated as in A. Samples of 4 mice from each condition were pooled for measurement of endogenous SREBP-1 and SREBP-2 protein. (C) Lpcat3fl/fl mice were transduced with adenoviral vector control or adenoviral-Cre for 7 days and then administered vehicle or 0.75 unit/kg body weight insulin as indicated. Liver gene expression was analyzed by real-time PCR after 3 hours. n = 4 per group. *P < 0.05; **P < 0.01. Values are shown as mean ± SEM.

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