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

Nature Communications
Chad N BrockerFrank J Gonzalez

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.

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Datasets Mentioned

BETA
GSE132385
GSE132386

Methods Mentioned

BETA
RNA-seq
ChIP-seq
ChIP
gene
transgenic
genotyping
Illumina sequencing
transfection
ELISA
Protein Assay

Software Mentioned

TopHat2
Galaxy
CuffMerge
Primer
featureCounts
Aperio ImageScope
ImageJ
Prism
GraphPad
EdgeR

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