Long non-coding RNA Gm15441 attenuates hepatic inflammasome activation in response to metabolic stress

Chad N. Brocker; Donghwan Kim; Tisha Melia; Kritika Karri; Thomas J. Velenosi; Shogo Takahashi; Jessica A. Bonzo; David J. Waxman; Frank J. Gonzalez

In summary, the present study focused on the role of lncRNA as a potential metabolic regulator. Pharmacological and physiological activation of PPARA promoted induction of large numbers of hepatic lncRNAs, a subset of which are also targeted by the nuclear receptors CAR and PXR. Gm15441 was identified as a liver-specific, PPARA-dependent lncRNA positioned antisense to the pro-inflammatory gene Txnip. Gm15441 expression was shown to suppress TXNIP protein by a mechanism involving the blocking of IRES sites within its 5'UTR. By suppressing TXNIP translation, Gm15441 inhibits TXNIP-mediated activation of the NLRP3 inflammasome as well as subsequent CASP1 cleavage and IL1B maturation. Taken together, these . CC-BY-NC-ND 4.0 International license is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the author/funder. It . https://doi.org/10.1101/675785 doi: bioRxiv preprint results indicate that lncRNA Gm15441 directly prevents metabolic stress-induced inflammation and represents a novel therapeutic target for the treatment of inflammatory disorders.