Sulfated oxysterol, 25HC3S, is a potent regulator of lipid metabolism in human hepatocytes
Sulfated oxysterol, 25HC3S, is a potent regulator of lipid metabolism in human hepatocytes
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DOI：
10.1016/j.bbrc.2007.06.143
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发表时间：
2007-09-07
影响因子：
3.1
通讯作者：
Pandak, William M.
中科院分区：
文献类型：
--
作者：
Ren, Shunlin;Li, Xiaobo;Pandak, William M.
最近，在原代大鼠肝细胞中发现了一种新的氧固醇，5-胆固酮-3-β，25-二醇-3-硫酸酯(25HC3S)，它是在胆固醇转运蛋白StarD1过表达后被发现的。在人的肝细胞核中也检测到这种氧合甾醇。本研究采用化学方法合成了25HC3S。在人肝细胞中加入25HC3S(6mU M)可显著抑制胆固醇的生物合成。定量RT-PCR和Western印迹分析显示，25HC3S显著降低HMG-CoA还原酶的mRNA和蛋白水平。巧合的是，25HC3S抑制了固醇调节元件结合蛋白(SREBPs)的激活，这表明抑制胆固醇的生物合成是通过阻断SREBP-1的激活，进而通过抑制HMG CoA还原酶的表达来实现的。25HC3S还可降低SREBP-1mRNA水平，抑制编码乙酰辅酶A羧基酶-1(ACC-1)和脂肪酸合成酶(Fas)的靶基因表达。相反，25-羟基胆固醇增加了原代人肝细胞中SREBP1和Fas的mRNA水平。这些结果表明，25HC3S是SREBP介导的脂代谢的有效调节因子。(C)2007 Elsevier Inc.保留所有权利。
Recently, a novel oxysterol, 5-cholesten-3 beta, 25-diol 3-sulfate (25HC3S) was identified in primary rat hepatocytes following overexpression of the cholesterol transport protein, StarD1. This oxysterol was also detected in human liver nuclei. In the present study, 25HC3S was chemically synthesized. Addition of 25HC3S (6 mu M) to human hepatocytes markedly inhibited cholesterol biosynthesis. Quantitative RT-PCR and Western blot analysis showed that 25HC3S markedly decreased HMG-CoA reductase mRNA and protein levels. Coincidently, 25HC3S inhibited the activation of sterol regulatory element binding proteins (SREBPs), suggesting that inhibition of cholesterol biosynthesis occurred via blocking SREBP-1 activation, and subsequently by inhibiting the expression of HMG CoA reductase. 25HC3S also decreased SREBP-1 mRNA levels and inhibited the expression of target genes encoding acetyl CoA carboxylase-1 (ACC-1) and fatty acid synthase (FAS). In contrast, 25-hydroxycholesterol increased SREBP1 and FAS mRNA levels in primary human hepatocytes. The results imply that 25HC3S is a potent regulator of SREBP mediated lipid metabolism. (c) 2007 Elsevier Inc. All rights reserved.