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 October 2, 2017; First 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

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 2

The LXR/LPCAT3 pathway regulates SREBP-1c processing in mouse liver.

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The LXR/LPCAT3 pathway regulates SREBP-1c processing in mouse liver. (A)...
(A) Lpcat3fl/fl (F/F) and Lpcat3fl/fl albumin-Cre+ (L-Lpcat3–/–) mice were gavaged with GW3965 at 40 mg/kg body weight once per day for 3 days. Liver gene expression was analyzed by real-time PCR. n = 5 per group. (B) Lpcat3fl/fl (F/F) and Lpcat3fl/fl albumin-Cre+ (L-Lpcat3–/–) mice were gavaged with GW3965 at 40 mg/kg body weight once per day for 3 days. Liver protein was analyzed by immunoblotting. n = 3 per group. (C) C57BL/6 mice were transduced with adenoviral shLPCAT3 or shCtrl vectors for 8 days and gavaged with GW3965 at 40 mg/kg body weight once per day on days 6, 7, and 8. Liver gene expression was analyzed by real-time PCR. n = 5 per group. Statistical analysis was by 2-way ANOVA with Bonferroni’s post hoc tests. The post hoc test results between shCtrl and shLPCAT3 in GW3965-treated groups are shown in the figure. (D) 293T cells were transfected with plasmids expressing GFP control or truncated nuclear form of SREBP-1c and treated with GW3965 at 1 μM as described in Methods. Total cell lysate was analyzed by immunoblotting with anti–SREBP-1 antibody. (E) Immunoblotting results of transfected truncated nuclear SREBP-1c from D were quantified from 4 independent experiments by ImageJ. Statistical analysis was by Student’s t test. *P < 0.05; **P < 0.01. Values are shown as mean ± SEM.