Liver X receptor α (LXRα) controls a set of key genes involved in cholesterol metabolism. However, the molecular mechanism of this regulation remains unknown. The regulatory role of poly(ADP-ribose) polymerase 1 (PARP1) in cholesterol metabolism in the liver was examined. Activation of PARP1 in the liver suppressed LXRα sensing and prevented upregulation of genes involved in HCD-induced cholesterol disposal. Mechanistically, LXRα was poly(ADP-ribosyl)ated by activated PARP1, which decreased DNA binding capacity of LXRα, thus preventing its recruitment to the target promoter. Intriguingly, we found that unactivated PARP1 was indispensable for LXRα transactivation and target expression. Further exploration identified unactivated PARP1 as an essential component of the LXRα-promoter complex. Taken together, the results indicate that activated PARP1 suppresses LXRα activation through poly(ADP-ribosyl)ation, while unactivated PARP1 promotes LXRα activation through physical interaction. PARP1 is a pivotal regulator of LXRα signaling and cholesterol metabolism in the liver.

中文翻译：

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多聚（ADP-核糖）聚合酶 1 对肝脏 X 受体 α 信号传导控制胆固醇代谢的阴阳调节

肝脏 X 受体 α (LXRα) 控制一组参与胆固醇代谢的关键基因。然而，这种调节的分子机制仍然未知。检查了聚 (ADP-核糖) 聚合酶 1 (PARP1) 在肝脏胆固醇代谢中的调节作用。肝脏中 PARP1 的激活抑制了 LXRα 感应并阻止了参与 HCD 诱导的胆固醇处理的基因的上调。从机制上讲，LXRα 被活化的 PARP1 聚（ADP-核糖基）化，这降低了 LXRα 的 DNA 结合能力，从而阻止其募集到靶启动子。有趣的是，我们发现未激活的 PARP1 对于 LXRα 反式激活和目标表达是必不可少的。进一步的探索发现未激活的 PARP1 是 LXRα-启动子复合物的重要组成部分。综合起来，结果表明，活化的PARP1通过聚（ADP-核糖基）化抑制LXRα的活化，而未活化的PARP1通过物理相互作用促进LXRα的活化。PARP1 是肝脏中 LXRα 信号传导和胆固醇代谢的关键调节因子。