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

Research Paper

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

Fengxiao Zhang1,2✉#, Cheng Wang1#, Yuhan Jiang1,2, Kun Huang1,2, Fangmei Liu1, Meng Du1, Xi Luo1, Dan Huang1,2✉, Kai Huang2✉

1. Department of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology.
2. Clinical Center for Human Genomic Research, Union Hospital, Huazhong University of Science and Technology.
#These authors contributed equally to this work.

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Citation:
Zhang F, Wang C, Jiang Y, Huang K, Liu F, Du M, Luo X, Huang D, Huang K. Yin and Yang Regulation of Liver X Receptor α Signaling Control of Cholesterol Metabolism by Poly(ADP-ribose) polymerase 1. Int J Biol Sci 2020; 16(15):2868-2882. doi:10.7150/ijbs.50042. Available from http://www.ijbs.com/v16p2868.htm

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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.

Keywords: PARP1, LXRα, cholesterol metabolism