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

• Published in: Nature communications Vol. 11; no. 1; pp. 5847 - 16
• Main 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.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17-11-2020; Nature Publishing Group; Nature Portfolio
• Subjects: 38; 38/1; 38/109; 38/15; 38/77; 38/88; 38/91; 631/337/384/2568; 631/45; 64/60; 96/106; Animals; Antisense RNA; Attenuation; Binding sites; Carrier Proteins - genetics; Carrier Proteins - metabolism; Caspase-1; Cells, Cultured; Cleavage; Dietary restrictions; Energy metabolism; Energy sources; Fasting; Gene Expression Regulation; HEK293 Cells; Humanities and Social Sciences; Humans; Inflammasomes; Inflammasomes - genetics; Inflammasomes - metabolism; Inflammation; Interleukin 1; Ligands; Lipids; Liver; Liver - drug effects; Liver - metabolism; Liver - pathology; Male; Metabolic rate; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Molecular modelling; multidisciplinary; Non-coding RNA; Peroxisome proliferator-activated receptors; Peroxisome Proliferators - pharmacology; PPAR alpha - agonists; PPAR alpha - genetics; PPAR alpha - metabolism; Promoter Regions, Genetic; Proteins; Pyrimidines - pharmacology; Pyrin protein; Receptors; Ribonucleic acid; RNA; RNA, Long Noncoding - genetics; RNA, Long Noncoding - metabolism; Science; Science (multidisciplinary); Thioredoxin; Thioredoxins - genetics; Thioredoxins - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-19554-7

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
.
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.