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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 1

The Lxr/LPCAT3 pathway regulates SREBP-1c processing in hepatocytes.

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The Lxr/LPCAT3 pathway regulates SREBP-1c processing in hepatocytes.
(A)...
(A) Primary mouse hepatocytes from C57BL/6 mice were infected with adenovirus expressing HSV-tagged SREBP-1c for 36 hours and treated with GW3965 (GW, 1 μM) for the last 24 hours. SREBP-1c from membrane fraction (precleaved SREBP-1 [pSREBP-1]) and nuclear fraction (mature SREBP-1 [mSREBP-1]) were analyzed by immunoblotting with anti-HSV antibody. HMGB1 served as internal loading controls for nuclear fractions. (B) Primary mouse hepatocytes from Lpcat3fl/fl (F/F) and Lpcat3fl/fl albumin-Cre+ (L-Lpcat3–/–) mice were infected with adenovirus expressing HSV-tagged SREBP-1c for 36 hours and treated with GW3965 for the last 24 hours. SREBP-1c from membrane fraction (pSREBP-1) and nuclear fraction (mSREBP-1) was analyzed by immunoblotting with anti-HSV antibody. (C) Primary mouse hepatocytes from Lpcat3fl/fl (F/F) and Lpcat3fl/fl albumin-Cre+ (L-Lpcat3–/–) mice were treated with DMSO (veh) or GW3965 (1 μM) for 24 hours. Endogenous SREBP-1 from membrane and nuclear fractions was analyzed by immunoblotting (upper panel) and quantified by ImageJ. The ratio of mSREBP-1 to pSREBP-1 was shown (lower panel). HMGB1 served as an internal loading control for the nuclear fraction. (D) Gene expression in primary hepatocytes treated as in C was analyzed by real-time PCR. (E) Primary mouse hepatocytes from C57BL/6 mice were infected with adenoviral shRNA vectors targeting LPCAT3 (shLPCAT3) or control (shCtrl) for 36 hours and treated with GW3965 (1 M) for the last 24 hours. Gene expression was analyzed by real-time PCR. *P < 0.05; **P < 0.01. Values are shown as mean ± SD.

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