PDF(Pubmed)
Abstract：
Macrophages are critical to maintaining and restoring tissue homeostasis during inflammation. The lipid metabolic state of macrophages influences their function, but a deeper understanding of how lipid metabolism is regulated in pro-resolving macrophage responses is needed. Lipin-1 is a phosphatidic acid phosphatase with a transcriptional coregulatory activity (TC) that regulates lipid metabolism. We previously demonstrated that lipin-1 supports pro-resolving macrophage responses, and here, myeloid-associated lipin-1 is required for inflammation resolution, yet how lipin-1-regulated cellular mechanisms promote macrophage pro-resolution responses is unknown. We demonstrated that the loss of lipin-1 in macrophages led to increased free fatty acid, neutral lipid, and ceramide content and increased phosphorylation of acetyl-CoA carboxylase. The inhibition of the first step of lipid synthesis and transport of citrate from the mitochondria in macrophages reduced lipid content and restored efferocytosis and inflammation resolution in lipin-1mKO macrophages and mice. Our findings suggest macrophage-associated lipin-1 restrains lipid synthesis, promoting pro-resolving macrophage function in response to pro-resolving stimuli.
摘要：
巨噬细胞对于在炎症期间维持和恢复组织稳态至关重要。巨噬细胞的脂质代谢状态影响其功能，但需要更深入地了解脂质代谢如何在促解决巨噬细胞反应中受到调节.Lipin-1是一种磷脂酸磷酸酶，具有调节脂质代谢的转录共调节活性（TC）。我们之前证明了lipin-1支持促分辨巨噬细胞反应，在这里,骨髓相关的lipin-1是炎症消退所必需的，然而,lipin-1调节的细胞机制如何促进巨噬细胞促溶解反应尚不清楚.我们证明巨噬细胞中lipin-1的丢失导致游离脂肪酸增加，中性脂质，和神经酰胺含量和乙酰辅酶A羧化酶的磷酸化增加。在lipin-1mKO巨噬细胞和小鼠中，抑制脂质合成和从线粒体转运柠檬酸盐的第一步降低了脂质含量，并恢复了有效的细胞作用和炎症消退。我们的发现表明巨噬细胞相关的lipin-1抑制脂质合成，促进促分解巨噬细胞功能以响应促分解刺激。
■Lipin1阻断脂质生物合成诱导线粒体柠檬酸盐输出可促进红细胞增多和炎症消退。
■Lipin1阻断脂质生物合成诱导线粒体柠檬酸盐输出可促进红细胞增多和炎症消退。
