Rong Xin, Wang Bo, Palladino Elisa Nd, de Aguiar Vallim Thomas Q, Ford David A, Tontonoz Peter
Department of Pathology and Laboratory Medicine, Department of Medicine, UCLA, Los Angeles, California, USA.
Department of Biochemistry and Molecular Biology, and Center for Cardiovascular Research, Saint Louis University, St. Louis, Missouri, USA.
J Clin Invest. 2017 Oct 2;127(10):3640-3651. doi: 10.1172/JCI93616. Epub 2017 Aug 28.
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.
固醇调节元件结合蛋白1c（SREBP-1c）是脂肪生成的核心调节因子，其活性受蛋白水解切割的控制。影响其加工过程的代谢因素尚未完全明确。在此，我们表明内质网（ER）磷脂酰基链组成的动态变化在生理和疾病状态下影响SREBP-1c的成熟。肝脏内质网中多不饱和磷脂酰胆碱的丰度在进食后以及在肥胖相关的胰岛素抵抗情况下会选择性增加。将多不饱和磷脂酰胆碱外源性递送至内质网可通过一种需要完整的SREBP裂解激活蛋白（SCAP）途径的机制加速SREBP-1c的加工。此外，响应肝脏X受体（LXR）激活而诱导的磷脂重塑酶LPCAT3通过驱动多不饱和脂肪酸掺入内质网促进SREBP-1c的加工。相反，LPCAT3缺乏会增加膜饱和度，降低核SREBP-1c丰度，并减弱对进食、LXR激动剂治疗或肥胖相关胰岛素抵抗的脂肪生成反应。内质网膜的去饱和作用可能作为进食状态的辅助信号，以响应营养物质的可利用性促进脂质合成。
