Title: Long non-coding RNA Gm15441 attenuates hepatic inflammasome activation in response to PPARA agonism and fasting.
Authors: Brocker, Chad N; Kim, Donghwan; Melia, Tisha; Karri, Kritika; Velenosi, Thomas J; Takahashi, Shogo; Aibara, Daisuke; Bonzo, Jessica A; Levi, Moshe; Waxman, David J; Gonzalez, Frank J
Published In Nat Commun, (2020 11 17)
Abstract: 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 α (PPARα) promotes the utilization of lipids as an energy source. Herein, we show that ligand activation of PPARα directly upregulates the long non-coding RNA gene Gm15441 through PPARα 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 1β (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 PPARα agonism and fasting. These findings provide evidence for a mechanism by which PPARα attenuates hepatic inflammasome activation in response to metabolic stress through induction of lncRNA Gm15441.
PubMed ID: 33203882
MeSH Terms: Animals; Carrier Proteins/genetics; Carrier Proteins/metabolism; Cells, Cultured; Fasting; Gene Expression Regulation; HEK293 Cells; Humans; Inflammasomes/genetics*; Inflammasomes/metabolism; Liver/drug effects; Liver/metabolism; Liver/pathology*; Male; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; PPAR alpha/agonists*; PPAR alpha/genetics; PPAR alpha/metabolism; Peroxisome Proliferators/pharmacology; Promoter Regions, Genetic; Pyrimidines/pharmacology; RNA, Long Noncoding/genetics; RNA, Long Noncoding/metabolism*; Thioredoxins/genetics; Thioredoxins/metabolism