Long non-coding RNA Gm15441 attenuates hepatic inflammasome activation in response to metabolic stress

Abstract

Fasting paradigms elicit a wide-range of health benefits including suppressing inflammation.Exploring the molecular mechanisms that prevent inflammation during caloric restriction may yield promising new therapeutic targets. During fasting, activation of the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARA) promotes the utilization of lipids as an energy source. Herein, we show that ligand activation of PPARA directly upregulates the long non-coding RNA gene Gm15441 through binding sites within its promoter. Gm15441 expression suppresses its antisense transcript, encoding thioredoxin interacting protein (TXNIP). This, in turn, decreases TXNIP-stimulated NLRP3 inflammasome activation, caspase-1 (CASP1) cleavage, and proinflammatory interleukin 1 beta (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 metabolic and inflammatory stimuli. These findings provide evidence for a novel mechanism by which PPARA attenuates hepatic inflammasome activation in response to metabolic stress through lncRNA Gm15441 induction. 4Txnip expression in vivo. Gm15441 LSL mice were treated with a PPARA agonist or fasted to assess how loss of Gm15441 impacts hepatic inflammasome activation in response to both pharmacological and physiologically-induced metabolic stress. TXNIP protein, caspase-1 (CASP1) levels, and interleukin 1 beta (IL1B) cleavage were elevated in Gm15441 LSL mice and were further increased by PPARA activation, indicating that this lncRNA plays a major role in attenuating inflammasome activation. Thus, hepatic PPARA directly regulates the lncRNA Gm15441, which in turn suppresses Txnip expression, which attenuates NLRP3 inflammasome activation during periods of metabolic stress. These studies revealed a novel regulatory mechanism supporting the beneficial effects of fasting, namely, reduced inflammation. Results LncRNA regulation by PPARA is highly tissue-specificTo assess the regulation of lncRNAs by PPARA, RNA-seq was performed using total liver RNA isolated from Ppara +/+ mice, both with and without dietary exposure to the PPARA agonist WY-14643. A lncRNA discovery pipeline was implemented that identified 15,558 liver-expressed lncRNA genes. Of these, 13,343 were intergenic, 1,966 were antisense, and 249 were intragenic lncRNAs. 44% of the 15,558 liver-expressed lncRNAs are considered novel (Melia and Waxman, 2019). Differential gene expression analysis revealed that a total of 1,735 RefSeq genes and 442 liver-expressed lncRNA genes responded to treatment with WY-14643 at an expression foldchange >2 at FDR<0.05, with 968 RefSeq genes and 245 lncRNA genes upregulated, and 767

Inflammasome activation and regulation: toward a better understanding of complex mechanisms

“…Among these, antisense noncoding RNA in the INK4 locus (ANRIL) can sponge miR-122-5p to enhance NLRP3 inflammasome activation in uric acid nephropathy 143 , and MALAT1 has been implicated to sponge miR-133 in ischemia-reperfusion injured myocardium 144 . Other lncRNAs were reported to either promote or attenuate inflammasome signaling, including nuclear enriched abundant transcript 1 (Neat1) 145 and Gm15441 146 . These promising data provide potential for miRNA-and lncRNA-targeted therapies of diseases Fig.…”

The Long Non-coding RNAs: Paramount Regulators of the NLRP3 Inflammasome

“…The introduction of PPARA agonist to the Gm15441 knockout mouse model resulted in elevated expression of TXNIP, active caspase-1 as well as active IL-1β. This indicated that lncRNA Gm15441 is a significant negative regulator of the NLRP3 inflammasome by suppressing TXNIP (93).…”

“…Brocker et al unraveled the molecular events that inhibited inflammation during restricted calorie intake. The PPARA plays a significant role during fasting by enhancing the consumption of lipids as an alternative energy source (93). The process of fasting activates PPARA which directly enhances the expression of lncRNA Gm15441.…”

“…Recently, their involvement in NLRP3 inflammasome regulation has also been reported. Brocker et al demonstrated that the induction of lncRNA Gm15441 attenuated the activation of hepatic NLRP3 inflammasome during metabolic stress through nuclear receptor peroxisome proliferator-activated receptor alpha (PPARA) ( 93 ). The process of fasting improves immunity by suppressing inflammation ( 93 ).…”

“…Brocker et al demonstrated that the induction of lncRNA Gm15441 attenuated the activation of hepatic NLRP3 inflammasome during metabolic stress through nuclear receptor peroxisome proliferator-activated receptor alpha (PPARA) ( 93 ). The process of fasting improves immunity by suppressing inflammation ( 93 ). Brocker et al unraveled the molecular events that inhibited inflammation during restricted calorie intake.…”