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首页> 外文期刊>Molecular and Cellular Biology >Targeted Disruption of the Idol Gene Alters Cellular Regulation of the Low-Density Lipoprotein Receptor by Sterols and Liver X Receptor Agonists
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Targeted Disruption of the Idol Gene Alters Cellular Regulation of the Low-Density Lipoprotein Receptor by Sterols and Liver X Receptor Agonists

机译：偶像基因的靶向破坏改变了低密度脂蛋白受体的甾醇和肝X受体激动剂的细胞调节。

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Previously, we identified the E3 ubiquitin ligase Idol (inducible degrader of the low-density lipoprotein [LDL] receptor [LDLR]) as a posttranscriptional regulator of the LDLR pathway. Idol stimulates LDLR degradation through ubiquitination of its C-terminal domain, thereby limiting cholesterol uptake. Here we report the generation and characterization of mouse embryonic stem cells homozygous for a null mutation in the Idol gene. Cells lacking Idol exhibit markedly elevated levels of the LDLR protein and increased rates of LDL uptake. Furthermore, despite an intact sterol responsive element-binding protein (SREBP) pathway, Idol-null cells exhibit an altered response to multiple regulators of sterol metabolism, including serum, oxysterols, and synthetic liver X receptor (LXR) agonists. The ability of oxysterols and lipoprotein-containing serum to suppress LDLR protein levels is reduced, and the time course of suppression is delayed, in cells lacking Idol. LXR ligands have no effect on LDLR levels in Idol-null cells, indicating that Idol is required for LXR-dependent inhibition of the LDLR pathway. In line with these results, the half-life of the LDLR protein is prolonged in the absence of Idol. Finally, the ability of statins and PCSK9 to alter LDLR levels is independent of, and additive with, the LXR-Idol pathway. These results demonstrate that the LXR-Idol pathway is an important contributor to feedback inhibition of the LDLR by sterols and a biological determinant of cellular LDL uptake.
机译：以前，我们将E3泛素连接酶偶像（低密度脂蛋白[LDL]受体[LDLR]的诱导型降解子）鉴定为LDLR途径的转录后调节剂。偶像通过其C末端结构域的泛素化刺激LDLR降解，从而限制了胆固醇的摄取。在这里我们报告的偶像基因的突变为纯合的小鼠胚胎干细胞的生成和表征。缺乏偶像的细胞表现出显着升高的LDLR蛋白水平和增加的LDL摄取率。此外，尽管存在完整的固醇反应性元件结合蛋白（SREBP）途径，但无偶像细胞对固醇代谢的多种调节剂（包括血清，氧固醇和合成肝X受体（LXR）激动剂）的反应也发生了改变。在缺乏偶像的细胞中，氧固醇和含脂蛋白的血清抑制LDLR蛋白水平的能力降低，并且抑制的时间过程被延迟。 LXR配体对无偶像细胞中的LDLR水平没有影响，这表明LDLR依赖性抑制LDLR途径需要偶像。与这些结果一致，在没有偶像的情况下，LDLR蛋白的半衰期延长。最后，他汀类药物和PCSK9改变LDLR水平的能力独立于LXR-Idol途径并与之相加。这些结果表明，LXR-Idol途径是固醇对LDLR反馈抑制的重要贡献，也是细胞摄取LDL的生物学决定因素。

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