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

Chad N Brocker,David J Waxman,Thomas J Velenosi,Tisha Melia,Frank J Gonzalez,Daisuke Aibara,Donghwan Kim,Kritika Karri,Shogo Takahashi,Moshe Levi,Jessica A Bonzo

doi:10.1038/s41467-020-19554-7

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.

Highlights

Exploring the molecular mechanisms that prevent inflammation during caloric restriction may yield promising therapeutic targets
Reasonable to consider that Long non-coding RNAs (lncRNAs) may play important roles in the metabolic remodeling and antiinflammatory actions that occur after peroxisome proliferator-activated receptor α (PPARα) activation
To assess the regulation of lncRNAs by PPARα, RNA-seq was performed using total liver RNA isolated from Ppara+/+ and Ppara−/− mice, both with and without dietary exposure to the PPARα agonist WY-14643

Summary

Introduction

Exploring the molecular mechanisms that prevent inflammation during caloric restriction may yield promising therapeutic targets. 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. Thioredoxin interacting protein (TXNIP) acts as a critical relay linking oxidative and endoplasmic reticulum (ER) stress to inflammation through NLR family pyrin domain containing 3 (NLRP3) inflammasome activation[21].

Methods

Results

Conclusion