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

Jan 4, 2021Theranostics

Rhythmic lncRNA Platr4 controls inflammation complex to improve fatty liver disease in mice

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Abstract

Platr4 is identified as a critical lncRNA involved in the progression of experimental steatohepatitis.

Cyclic expression of Platr4 is regulated by the core clock component Rev-erbα through specific binding sites.
NF-κB directly drives Platr4 expression, which is associated with increased levels of this lncRNA in steatohepatitis.
Platr4 inhibits the inflammasome pathway by reducing NF-κB-dependent transcription of inflammasome components Nlrp3 and Asc.
Loss of Platr4 leads to decreased inflammasome activity and increased sensitivity to steatohepatitis in experimental models.
Overexpression of Platr4 has been shown to alleviate pathological conditions associated with steatohepatitis.

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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 steatohepatitisRNA-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 analysesCyclic 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 ofinflammasome pathway by inhibiting NF-κB-dependent transcription of the inflammasome components Nlrp3 and Asc. Loss of Platr4 down-regulatesinflammasome activity in the liver, blunts its diurnal rhythm, and sensitizes mice to experimental steatohepatitis, whereas overexpression ofameliorates 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 inactivateinflammasome via intercepting NF-κB signaling. This lncRNA might be an attractive target that can be modulated to ameliorate the pathological conditions of steatohepatitis. Background: Methods: Results: Conclusions: Platr4Nlrp3Nlrp3Platr4Nlrp3Platr4Platr4Nlrp3

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

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