Long non-coding RNA Gm15441 attenuates hepatic inflammasome activation in response to PPARA agonism and fasting
| Autor: | Donghwan Kim, Shogo Takahashi, Jessica A. Bonzo, Kritika Karri, Chad Brocker, Moshe Levi, Tisha Melia, Thomas J. Velenosi, Daisuke Aibara, Frank J. Gonzalez, David J. Waxman |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Thioredoxin-Interacting Protein Inflammasomes Science General Physics and Astronomy Mice Transgenic Biochemistry Pyrin domain Article General Biochemistry Genetics and Molecular Biology Proinflammatory cytokine 03 medical and health sciences Thioredoxins 0302 clinical medicine medicine Animals Humans PPAR alpha Promoter Regions Genetic lcsh:Science Cells Cultured Mice Knockout Regulation of gene expression Multidisciplinary Chemistry Inflammasome Fasting General Chemistry Cell biology Mice Inbred C57BL HEK293 Cells Pyrimidines 030104 developmental biology Gene Expression Regulation Liver Nuclear receptor 030220 oncology & carcinogenesis Long non-coding RNAs Peroxisome Proliferators RNA Long Noncoding lcsh:Q Carrier Proteins Energy source TXNIP medicine.drug |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-16 (2020) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. PPAR-alpha is a ligand responsive transcription factor that mediates energy metabolism during fasting in the liver. Here the authors show that Gm15441 is a PPAR-alpha dependent lncRNA that prevents the expression of its antisense transcript, thioredoxin interacting protein (TXNIP), and attenuates inflammasome activation. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|