Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20814, USA.
Department of Biology and Bioinformatics Program, Boston University, Boston, MA, 02215, USA.
Nat Commun. 2020 Nov 17;11(1):5847. doi: 10.1038/s41467-020-19554-7.
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.
探索热量限制期间防止炎症的分子机制可能会产生有前途的治疗靶点。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。本文中，我们表明，配体激活 PPARα 通过其启动子内的 PPARα 结合位点直接上调长非编码 RNA 基因 Gm15441。Gm15441 的表达抑制了其反义转录本，编码硫氧还蛋白相互作用蛋白（TXNIP）。反过来，这会降低 TXNIP 刺激的 NOD、LRR 和富含亮氨酸重复序列家族 pyrin 结构域包含 3（NLRP3）炎性小体的激活、半胱天冬酶-1（CASP1）的切割以及促炎性白细胞介素 1β（IL1B）的成熟。开发了 Gm15441 基因敲除小鼠，并表明它们对 NLRP3 炎性小体激活更为敏感，并且在对 PPARα 激动剂和禁食的反应中表现出 CASP1 和 IL1B 切割的升高。这些发现为 PPARα 通过诱导 lncRNA Gm15441 减轻代谢应激时肝炎性小体激活的机制提供了证据。
