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

Chad N. Brocker; Donghwan Kim; Tisha Melia; Kritika Karri; Thomas J. Velenosi; Shogo Takahashi; Jessica A. Bonzo; David J. Waxman; Frank J. Gonzalez

The physiological alterations that accompany fasting impart several health benefits, including anti-inflammatory effects (Goodpaster and Sparks, 2017; Montagner et al., 2016) . As such, the underlying molecular pathways modulated by caloric restriction may present promising new therapeutic targets. PPARA activation during fasting is a key regulatory event of lipid and glucose metabolism. A growing body of evidence indicates that PPARA activation also potently suppresses inflammation in several disease models and tissues (Abcouwer, 2013; Krysiak et al., 2011; Lee et al., 2007; Tomizawa et al., 2011; Zhao et al., 2017) . However, the mechanism by which PPARA modulates metabolic stress-induced inflammation is not known. PPARA is activated by endogenous fatty acid metabolite ligands in response to fasting and promotes the uptake, utilization, and catabolism of fatty acids by regulating a wide range of genes that reprogram metabolic pathways to facilitate the use of lipids as an energy source. The direct regulation of protein-coding genes by PPARA is well characterized, but it was not known whether lncRNAswhich may influence gene expression through a variety of mechanisms (Li et al., 2017b; Militello et al., 2018; Zhao et al., 2016) -also serve as direct targets contributing to physiological changes induced by PPARA activation. This possibility was suggested by the finding that several hundred liver-expressed lncRNAs are dysregulated in livers exposed to xenobiotic agonist ligands of the nuclear receptors CAR and PXR (Lodato et al., 2017) , which contribute to the regulation of lipid metabolism and whose gene targets overlap with those of PPARA (Cui and Klaassen, 2016; Wada et al., 2009) . The present study identified several hundred PPARA-responsive liver-expressed lncRNA genes, including anti-sense lncRNAs, which often contribute to the regulation of genes on the opposing strand (Guil and Esteller, 2012; Qu et al., 2019; Zhang et al., 2017a) . Further, a novel PPARA-dependent regulatory axis involving one such anti-sense lncRNA, Gm15441, was characterized. Gm15441 was shown to be transcribed in a liver-specific, PPARA-dependent manner to yield an anti-sense lncRNA that protects against metabolic stress by suppressing PPARA induction of the opposing, sense transcript, TXNIP, and thereby suppresses TXNIPmediated NLRP3 inflammasome activation.