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肝 X 受体 α 信号的阴阳调节 通过聚（ADP-核糖）聚合酶 1 控制胆固醇代谢。

Yin and Yang Regulation of Liver X Receptor α Signaling Control of Cholesterol Metabolism by Poly(ADP-ribose) polymerase 1.

机构信息

Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology.

Clinical Center for Human Genomic Research, Union Hospital, Huazhong University of Science and Technology.

出版信息

Int J Biol Sci. 2020 Sep 1;16(15):2868-2882. doi: 10.7150/ijbs.50042. eCollection 2020.

DOI:10.7150/ijbs.50042
PMID:33061802
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7545717/
Abstract

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.

摘要

肝 X 受体 α（LXRα）调控一组参与胆固醇代谢的关键基因。然而，这种调控的分子机制尚不清楚。本研究考察了多聚（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的感应作用，并阻止了 HCD 诱导的胆固醇清除相关基因的上调。在机制上，激活的 PARP1 使 LXRα发生多聚（ADP-核糖）化，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的转录激活和靶基因表达是必不可少的。进一步的探索确定了未激活的 PARP1 是 LXRα-启动子复合物的必需组成部分。总之，这些结果表明，激活的 PARP1 通过多聚（ADP-核糖）化抑制 LXRα的激活，而未激活的 PARP1 通过物理相互作用促进 LXRα的激活。PARP1 是肝脏中 LXRα信号和胆固醇代谢的关键调节因子。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/469a/7545717/013e51bb0d1a/ijbsv16p2868g007.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/469a/7545717/792abed2d89e/ijbsv16p2868g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/469a/7545717/65a7038e034b/ijbsv16p2868g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/469a/7545717/d5e5790940d7/ijbsv16p2868g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/469a/7545717/013e51bb0d1a/ijbsv16p2868g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/469a/7545717/0f0af6839285/ijbsv16p2868g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/469a/7545717/afdb0bff1865/ijbsv16p2868g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/469a/7545717/2e806ff88612/ijbsv16p2868g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/469a/7545717/792abed2d89e/ijbsv16p2868g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/469a/7545717/65a7038e034b/ijbsv16p2868g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/469a/7545717/d5e5790940d7/ijbsv16p2868g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/469a/7545717/013e51bb0d1a/ijbsv16p2868g007.jpg

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本文引用的文献

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J Hepatol. 2017 May;66(5):962-977. doi: 10.1016/j.jhep.2016.11.020. Epub 2016 Dec 12.
2
Cholesterol is a significant risk factor for non-alcoholic steatohepatitis.胆固醇是非酒精性脂肪性肝炎的一个重要风险因素。
Expert Rev Gastroenterol Hepatol. 2015;9(11):1343-6. doi: 10.1586/17474124.2015.1092382. Epub 2015 Sep 22.
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Poly(ADP-ribose) polymerase 1 promotes oxidative-stress-induced liver cell death via suppressing farnesoid X receptor α.
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Mol Cell Biol. 2013 Nov;33(22):4492-503. doi: 10.1128/MCB.00160-13. Epub 2013 Sep 16.
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