TY - JOUR
T1 - ER phospholipid composition modulates lipogenesis during feeding and in obesity
AU - Rong, Xin
AU - Wang, Bo
AU - Palladino, Elisa N.D.
AU - De Aguiar Vallim, Thomas Q.
AU - Ford, David A.
AU - Tontonoz, Peter
N1 - Funding Information:
We thank T. Osborne for SREBP antibodies, J. Gao for imaging support, and E. Tarling for the nuclear SREBP-1c plasmid. This work was supported by NIH grants HL030568 and DK063491.
PY - 2017/10/2
Y1 - 2017/10/2
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI93616
DO - 10.1172/JCI93616
M3 - Article
C2 - 28846071
AN - SCOPUS:85030558042
VL - 127
SP - 3640
EP - 3651
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
SN - 0021-9738
IS - 10
ER -