Oscillating lncRNA Platr4 regulates NLRP3 inflammasome to ameliorate nonalcoholic steatohepatitis in mice

• Published in: Theranostics Vol. 11; no. 1; pp. 426 - 444
• Main Authors: Lin, Yanke, Wang, Shuai, Gao, Lu, Zhou, Ziyue, Yang, Zemin, Lin, Jingpan, Ren, Shujing, Xing, Huijie, Wu, Baojian
• Format: Journal Article
• Language: English
• Published: Australia Ivyspring International Publisher Pty Ltd 01.01.2021; Ivyspring International Publisher
• Subjects: Alzheimer's disease; Circadian rhythm; Cytokines; Diabetes; Feedback; Gene expression; Inflammation; Ligands; Liver; Mammals; Metabolism; Pathogenesis; Pathogens; Physiology; Proteins; Research Paper; Stem cells; NF-κB; Platr4; NLRP3 inflammasome; RXR; Steatohepatitis
• ISSN: 1838-7640; 1838-7640
• DOI: 10.7150/thno.50281

Understanding the molecular events and mechanisms underlying development and progression of nonalcoholic steatohepatitis is essential in an attempt to formulating a specific treatment. Here, we uncover Platr4 as an oscillating and NF-κB driven lncRNA that is critical to the pathological conditions in experimental steatohepatitis RNA-sequencing of liver samples was used to identify differentially expressed lncRNAs. RNA levels were analyzed by qPCR and FISH assays. Proteins were detected by immunoblotting and ELISA. Luciferase reporter, ChIP-sequencing and ChIP assays were used to investigate transcriptional gene regulation. Protein interactions were evaluated by Co-IP experiments. The protein-RNA interactions were studied using FISH, RNA pull-down and RNA immunoprecipitation analyses Cyclic expression of Platr4 is generated by the core clock component Rev-erbα via two RevRE elements (i.e., -1354/-1345 and -462/-453 bp). NF-κB transcriptionally drives Platr4 through direct binding to two κB sites (i.e., -1066/-1056 and -526/-516 bp), potentially accounting for up-regulation of Platr4 in experimental steatohepatitis. Intriguingly, serves as a circadian repressor of inflammasome pathway by inhibiting NF-κB-dependent transcription of the inflammasome components Nlrp3 and Asc. Loss of Platr4 down-regulates inflammasome activity in the liver, blunts its diurnal rhythm, and sensitizes mice to experimental steatohepatitis, whereas overexpression of ameliorates the pathological conditions in an -dependent manner. Mechanistically, prevents binding of the NF-κB/Rxrα complex to the κB sites via a physical interaction, thereby inhibiting the transactivation of Nlrp3 and Asc by NF-κB. functions to inactivate inflammasome via intercepting NF-κB signaling. This lncRNA might be an attractive target that can be modulated to ameliorate the pathological conditions of steatohepatitis.