25-Hydroxycholesterol-3-sulfate regulates macrophage lipid metabolism via the LXR/SREBP-1 signaling pathway
25-Hydroxycholesterol-3-sulfate regulates macrophage lipid metabolism via the LXR/SREBP-1 signaling pathway
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DOI：
10.1152/ajpendo.90555.2008
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发表时间：
2008-12-01
影响因子：
5.1
通讯作者：
Ren, Shunlin
中科院分区：
文献类型：
--
作者：
Ma, Yongjie;Xu, Leyuan;Ren, Shunlin
Ma Y，Xu L，Rodriguez-Agudo D，Li X，Heuman DM，Hylemon PB，潘达克WM，Ren S. 25-羟基胆固醇-3-硫酸盐通过LXR/SREBP-1信号通路调节巨噬细胞脂质代谢。美国生理学杂志内分泌代谢295：E1369-E1379，2008年。首次发表于2008年10月14日; doi：10.1152/ajpendo.90555.2008。- 氧固醇受体LXR是脂质代谢的关键转录调节因子。LXR增加SREBP-1的表达，SREBP-1反过来调节至少32个参与脂质合成和转运的基因。我们最近发现25-羟基胆固醇-3-硫酸酯（25 HC 3S）作为一个重要的调节分子在肝脏。我们现在已经研究了25 HC 3S及其前体25-羟基胆固醇（25 HC）对巨噬细胞中LXR/SREBP-1信号转导介导的脂质代谢的影响。向人THP-1衍生的巨噬细胞中添加25 HC 3S显著降低核LXR蛋白水平。25 HC 3S给药后，SREBP-1成熟蛋白和mRNA水平呈剂量和时间依赖性降低。25 HC 3S降低了SREBP-1响应基因、乙酰辅酶A羧化酶-1和脂肪酸合成酶（FAS）以及HMGR和LDLR的表达，这些基因是参与脂质代谢的关键蛋白。随后，25 HC 3S降低细胞内脂质并增加细胞增殖。与25 HC 3S相反，25 HC作为LXR配体，增加ABCA 1、ABCG 1、SREBP-1和FAS mRNA水平。在25 HC 3S、25 HC和LXR激动剂T0901317的存在下，抑制了对LXR靶向基因表达的刺激。我们的结论是，25 HC 3S在巨噬细胞中作为胆固醇饱腹信号，通过抑制LXR/SREBP信号转导下调胆固醇和脂肪酸合成途径。提出了氧化甾醇硫酸化的可能作用。
Ma Y, Xu L, Rodriguez-Agudo D, Li X, Heuman DM, Hylemon PB, Pandak WM, Ren S. 25-Hydroxycholesterol-3-sulfate regulates macrophage lipid metabolism via the LXR/SREBP-1 signaling pathway. Am J Physiol Endocrinol Metab 295: E1369-E1379, 2008. First published October 14, 2008; doi: 10.1152/ajpendo.90555.2008. - The oxysterol receptor LXR is a key transcriptional regulator of lipid metabolism. LXR increases expression of SREBP-1, which in turn regulates at least 32 genes involved in lipid synthesis and transport. We recently identified 25-hydroxycholesterol-3-sulfate (25HC3S) as an important regulatory molecule in the liver. We have now studied the effects of 25HC3S and its precursor, 25-hydroxycholesterol (25HC), on lipid metabolism as mediated by the LXR/SREBP-1 signaling in macrophages. Addition of 25HC3S to human THP-1-derived macrophages markedly decreased nuclear LXR protein levels. 25HC3S administration was followed by dose-and time-dependent decreases in SREBP-1 mature protein and mRNA levels. 25HC3S decreased the expression of SREBP-1-responsive genes, acetyl-CoA carboxylase-1, and fatty acid synthase (FAS) as well as HMGR and LDLR, which are key proteins involved in lipid metabolism. Subsequently, 25HC3S decreased intracellular lipids and increased cell proliferation. In contrast to 25HC3S, 25HC acted as an LXR ligand, increasing ABCA1, ABCG1, SREBP-1, and FAS mRNA levels. In the presence of 25HC3S, 25HC, and LXR agonist T0901317, stimulation of LXR targeting gene expression was repressed. We conclude that 25HC3S acts in macrophages as a cholesterol satiety signal, downregulating cholesterol and fatty acid synthetic pathways via inhibition of LXR/SREBP signaling. A possible role of oxysterol sulfation is proposed.