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.

中文翻译：

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ER磷脂成分在进食和肥胖中调节脂肪生成

甾醇调节元件结合蛋白1c（SREBP-1c）是脂肪形成的中央调节剂，其活性受蛋白水解切割控制。影响其加工的代谢因素尚不完全清楚。在这里，我们表明，ER磷脂的酰基链组成的动态变化会影响SREBP-1c在生理和疾病中的成熟。响应于进食和与肥胖相关的胰岛素抵抗的情况，选择性地增加了肝脏ER中多不饱和磷脂酰胆碱的丰度。通过需要完整的SREBP裂解活化蛋白（SCAP）途径的机制，将多不饱和磷脂酰胆碱外源递送至ER可以加速SREBP-1c的加工。此外，响应肝X受体（LXR）活化的磷脂重塑酶LPCAT3的诱导通过驱动多不饱和脂肪酸掺入ER促进了SREBP-1c加工。相反，LPCAT3缺乏症增加了膜的饱和度，降低了核SREBP-1c的丰度，并且减弱了对进食，LXR激动剂治疗或肥胖相关的胰岛素抵抗的生脂反应。ER膜的去饱和可以用作进食状态的辅助信号，其响应于养分的可利用性而促进脂质合成。