Long non-coding RNA Gm15441 attenuates hepatic inflammasome activation in response to PPARA agonism and fasting

Exploring the molecular mechanisms that prevent inflammation during caloric restriction may yield promising therapeutic targets. During fasting, activation of the nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR alpha) promotes the utilization of lipids as an energy source. Herein, we show that ligand activation of PPAR alpha directly upregulates the long non-coding RNA gene Gm15441 through PPAR alpha binding sites within its promoter. Gm15441 expression suppresses its antisense transcript, encoding thioredoxin interacting protein (TXNIP). This, in turn, decreases TXNIP-stimulated NLR family pyrin domain containing 3 (NLRP3) inflammasome activation, caspase-1 (CASP1) cleavage, and proinflammatory interleukin 1 beta (IL1B) maturation. Gm15441-null mice were developed and shown to be more susceptible to NLRP3 inflammasome activation and to exhibit elevated CASP1 and IL1B cleavage in response to PPAR alpha agonism and fasting. These findings provide evidence for a mechanism by which PPAR alpha attenuates hepatic inflammasome activation in response to metabolic stress through induction of lncRNA Gm15441. PPAR-alpha is a ligand responsive transcription factor that mediates energy metabolism during fasting in the liver. Here the authors show that Gm15441 is a PPAR-alpha dependent lncRNA that prevents the expression of its antisense transcript, thioredoxin interacting protein (TXNIP), and attenuates inflammasome activation.