Long non-coding RNA Gm15441 attenuates hepatic inflammasome activation in response to PPARA agonism and fasting.
Long non-coding RNA Gm15441 attenuates hepatic inflammasome activation in response to PPARA agonism and fasting.
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长链非编码RNA Gm15441减弱响应于PPARA激动和禁食的肝脏炎性小体活化
DOI：
10.1038/s41467-020-19554-7
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发表时间：
2020-11-17
影响因子：
16.6
通讯作者：
Gonzalez FJ
中科院分区：
文献类型：
--
作者：
Brocker CN;Kim D;Melia T;Karri K;Velenosi TJ;Takahashi S;Aibara D;Bonzo JA;Levi M;Waxman DJ;Gonzalez FJ
探索在热量限制期间预防炎症的分子机制可能会产生有希望的治疗靶点。在禁食期间，核受体过氧化物酶体增殖物激活受体α (PPARα)的激活促进了脂质作为能量来源的利用。本研究表明，PPARα的配体激活通过启动子内的PPARα结合位点直接上调长链非编码RNA基因Gm15441。Gm15441的表达抑制其反义转录物，编码硫氧还蛋白相互作用蛋白（TXNIP）。这反过来又降低了txnip刺激的NLR家族pyrin结构域包含3 （NLRP3）炎性体激活、caspase-1 （CASP1）裂解和促炎白细胞介素1β (IL1B)成熟。gm15441缺失的小鼠更容易受到NLRP3炎性体激活的影响，并且在PPARα激动作用和禁食的情况下，CASP1和IL1B的切割水平升高。这些发现为PPARα通过诱导lncRNA Gm15441减轻代谢应激下肝炎性体激活的机制提供了证据。ppar - α是一种配体响应转录因子，在肝脏禁食期间介导能量代谢。在这里，作者表明Gm15441是ppar - α依赖的lncRNA，可以阻止其反义转录物硫氧还蛋白相互作用蛋白（TXNIP）的表达，并减弱炎症小体的激活。
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.
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影响因子：
4.3
作者：
Gonzalez FJ;Fang ZZ;Ma X
通讯作者：
Ma X
影响因子：
4.8
作者：
Connerney, Jeannette;Lau-Corona, Dana;Waxman, David J.
通讯作者：
Waxman, David J.
DOI：
10.1016/j.bbagrm.2016.04.010
发表时间：
2016-09
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Cui JY;Klaassen CD
通讯作者：
Klaassen CD
影响因子：
5.5
作者：
Iwakiri J;Terai G;Hamada M
通讯作者：
Hamada M
影响因子：
13.5
作者：
Kim, Jung-Hwan;Qu, Aijuan;Reddy, Janardan K.;Gao, Bin;Gonzalez, Frank J.
通讯作者：
Gonzalez, Frank J.