内毒素通过核因子 κB 介导的 Sptlc2 上调激活从头鞘脂生物合成。
Endotoxin activates de novo sphingolipid biosynthesis via nuclear factor kappa B-mediated upregulation of Sptlc2.
机构信息
Lee Gil Ya Cancer and Diabetes Institute, Department of Molecular Medicine, Gachon University of Medicine and Science, Inchon, South Korea.
出版信息
Prostaglandins Other Lipid Mediat. 2011 Feb;94(1-2):44-52. doi: 10.1016/j.prostaglandins.2010.12.003. Epub 2010 Dec 15.
Sphingolipids are membrane components and are involved in cell proliferation, apoptosis and metabolic regulation. In this study we investigated whether de novo sphingolipid biosynthesis in macrophages is regulated by inflammatory stimuli. Lipopolysaccharide (LPS) treatment upregulated Sptlc2, a subunit of serine palmitoyltransferase (SPT), mRNA and protein in Raw264.7 and mouse peritoneal macrophages, but Sptlc1, another subunit of SPT, was not altered. SPT activation by LPS elevated cellular levels of ceramides and sphingomyelin (SM). Pharmacological inhibition of nuclear factor kappa B (NFκB) prevented LPS-induced upregulation of Sptlc2 while transfection of p65 subunit of NFκB upregulated Sptlc2 and increased cellular ceramide levels. In contrast, MAP kinases were not involved in regulation of sphingolipid biosynthesis. Analysis of Sptlc2 promoter and chromatin immunoprecipitation (ChIP) assay showed that NFκB binding sites are located in Sptlc2 promoter region. Our results demonstrate that inflammatory stimuli activate de novo sphingolipid biosynthesis via NFκB and may play a critical role in lipid metabolism in macrophages.
鞘脂是细胞膜的组成部分，参与细胞增殖、凋亡和代谢调节。在本研究中，我们研究了炎症刺激是否调节巨噬细胞中鞘脂的从头生物合成。脂多糖 (LPS) 处理上调了 Raw264.7 和小鼠腹腔巨噬细胞中丝氨酸棕榈酰转移酶 (SPT) 的亚基 Sptlc2 的 mRNA 和蛋白，但 SPT 的另一个亚基 Sptlc1 没有改变。LPS 通过 SPT 激活增加了细胞内神经酰胺和鞘磷脂 (SM) 的水平。核因子 kappa B (NFκB) 的药理学抑制阻止了 LPS 诱导的 Sptlc2 上调，而 NFκB 的 p65 亚基的转染上调了 Sptlc2 并增加了细胞内神经酰胺水平。相比之下，MAP 激酶不参与鞘脂生物合成的调节。Sptlc2 启动子分析和染色质免疫沉淀 (ChIP) 实验表明，NFκB 结合位点位于 Sptlc2 启动子区域。我们的结果表明，炎症刺激通过 NFκB 激活鞘脂的从头生物合成，可能在巨噬细胞中的脂质代谢中起关键作用。
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