한빛사논문
- 조회1,021
Chad N. Brocker1,4, Donghwan Kim1,4, Tisha Melia2, Kritika Karri2, Thomas J. Velenosi1, Shogo Takahashi1,3, Daisuke Aibara1, Jessica A. Bonzo1, Moshe Levi3, David J. Waxman2 & Frank J. Gonzalez1,*
1Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20814, USA. 2Department of Biology and Bioinformatics Program, Boston University, Boston, MA 02215, USA. 3Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC 20057, USA.
4These authors contributed equally: Chad N. Brocker, Donghwan Kim.
*Corresponding author
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.
논문정보
- Research article
- 2020년 11월 (BRIC 등록일 2020-11-26)
- 국외 연구진
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