The hypocholesterolemic agent LY295427 reverses suppression of sterol regulatory element-binding protein processing mediated by oxysterols
The hypocholesterolemic agent LY295427 reverses suppression of sterol regulatory element-binding protein processing mediated by oxysterols
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DOI：
10.1074/jbc.m108348200
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发表时间：
2001-11-30
影响因子：
4.8
通讯作者：
Russell, DW
中科院分区：
文献类型：
--
作者：
Janowski, BA;Shan, B;Russell, DW
甾醇LY 295427通过增加肝脏低密度脂蛋白（LDL）受体的表达来降低动物的血浆胆固醇水平。在这里，我们追踪LY 295427的降胆固醇活性，以逆转氧化固醇介导的抑制固醇调节元件结合蛋白（SREBP）加工的能力。微摩尔浓度的LY 295427诱导氧化固醇处理的培养细胞中LDL的代谢，并抑制氧化固醇介导的胆固醇酯合成的刺激。cDNA微阵列和RNA印迹实验显示，LY 295427增加LDL受体mRNA和其他SREBP靶基因的水平。该化合物在添加到培养基中的4-6小时内刺激在氧固醇存在下生长的细胞的细胞核中SREBP的积累。诱导需要正常SREBP加工途径的组分，包括SREBP切割激活蛋白和位点1蛋白酶。LY 295427克服了几种氧化固醇介导的SREBP加工的抑制，但不是LDL衍生的胆固醇。我们得出结论，LY 295427通过独特的作用机制实现了治疗上理想的终点。
The sterol LY295427 reduces plasma cholesterol levels in animals by increasing the expression of hepatic low density lipoprotein (LDL) receptors. Here we trace the hypocholesterolemic activity of LY295427 to an ability to reverse oxysterol-mediated suppression of sterol regulatory element-binding protein (SREBP) processing. Micromolar concentrations of LY295427 induced the metabolism of LDL in oxysterol-treated cultured cells and inhibited the stimulation of cholesteryl ester synthesis mediated by oxysterols. cDNA microarray and RNA blotting experiments revealed that LY295427 increased levels of the LDL receptor mRNA and those of other SREBP target genes. The compound stimulated the accumulation of SREBPs in the nuclei of cells grown in the presence of oxysterols within 4-6 h of addition to the medium. Induction required components of the normal SREBP-processing pathway, including the SREBP cleavage-activating protein and the Site 1 protease. LY295427 overcame the suppression of SREBP processing mediated by several oxysterols but not by LDL-derived cholesterol. We conclude that LY295427 achieves a therapeutically desirable end point by an unique mechanism of action.