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

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.

Global analysis of expression, maturation and subcellular localization of mouse liver transcriptome identifies novel sex-biased and TCPOBOP-responsive long non-coding RNAs

“…Alternatively, lnc13509 could serve as a hepatoprotective miRNA sponge [ 101 ] that depletes miR802 . These and other putative regulatory lncRNAs may be investigated using a variety of experimental and computational approaches [ 102 , 103 ], including innovative knockout technologies [ 36 ] that may uncover their biological functions and gene targets in the liver.…”

“…Furthermore, sex and strain-dependent genetic regulation was characterized in livers of Diversity Outbred mice [ 35 ], where co-expression network analysis identified sex-biased lncRNAs likely to control sex-biased PCG expression through negative regulatory mechanisms [ 26 ]. Furthermore, liver lncRNAs that respond to xenobiotic exposure and may impact xenobiotic toxicity have been identified [ 22 , 36 – 39 ] and were closely linked to xenobiotic dysregulation of pathways involving fatty acid metabolism, cell division and immune responses [ 27 ]. However, key information regarding subcellular localization is lacking for the vast majority of liver-expressed lncRNAs, which complicates efforts to determine whether they have regulatory or other cellular functions in the cytoplasm, nucleoplasm or when bound to chromatin.…”

Global analysis of expression, maturation and subcellular localization of mouse liver transcriptome identifies novel sex-biased and TCPOBOP-responsive long non-coding RNAs

“…In contrast, the very strong induction by TCPOBOP of lnc13509 may stimulate the divergent transcription of miR802, whose expression is elevated in type-II diabetes [64] and in livers of high fat diet-fed mice, where it impairs glucose metabolism and increases oxidative stress [65][66][67]. Alternatively, lnc13509 could serve as hepatoprotective miRNA sponge [90] that depletes miR802, which may be investigated using a variety of experimental and computational approaches [91,92], including innovative knockout technologies [30] that may uncover its biological functions and gene targets in the liver.…”

“…We previously identified 15,558 lncRNAs expressed in mouse liver under a variety of biological conditions [29], a subset of which were characterized with regard to their tissues-specific expression patterns, epigenetic states, and regulatory elements, including nearby regions of chromatin accessibility and liver-specific transcription factor binding [22]. These liver-expressed lncRNAs include lncRNA genes that are responsive to xenobiotic exposure [21,30] or to pituitary growth hormone secretory patterns [22], a key factor regulating sex-biased gene expression in the liver [31,32]. Co-expression network analysis in Diversity Outbred mice identified sex-biased lncRNAs whose expression is inversely correlated with that of oppositely sex-biased PCGs, suggesting they have important negative regulatory actions in mouse liver [29].…”

Global Analysis of Expression, Maturation and Subcellular Localization of Mouse Liver Transcriptome Identifies Novel Sex-biased and TCPOBOP-responsive Long Non-coding RNAs

“…We previously identi ed 15,558 lncRNAs expressed in mouse liver under a variety of biological conditions [29], a subset of which were characterized with regard to their tissues-speci c expression patterns, epigenetic states, and regulatory elements, including nearby regions of chromatin accessibility and liverspeci c transcription factor binding [22]. These liver-expressed lncRNAs include lncRNA genes that are responsive to xenobiotic exposure [21,30] or to pituitary growth hormone secretory patterns [22], a key factor regulating sex-biased gene expression in the liver [31,32]. Co-expression network analysis in Diversity Outbred mice identi ed sex-biased lncRNAs whose expression is inversely correlated with that of oppositely sex-biased PCGs, suggesting they have important negative regulatory actions in mouse liver [29].…”