生物能状态通过转录共阻遏物CtBP调节先天性炎症反应。,Nature Communications

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生物能状态通过转录共阻遏物CtBP调节先天性炎症反应。
Nature Communications ( IF 16.6 ) Pub Date : 2017-09-22 , DOI: 10.1038/s41467-017-00707-0
Yiguo Shen _{1,

2,

3} , David Kapfhamer _{1,

2} , Angela M Minnella _{1,

2} , Ji-Eun Kim _{1,

2} , Seok Joon Won _{1,

2} , Yanting Chen _{1,

2,

4} , Yong Huang ₁ , Ley Hian Low _{1,

2} , Stephen M Massa _{1,

2} , Raymond A Swanson _{1,

2,

3}

Affiliation

先天性炎症反应导致脑外伤和其他疾病的继发性损伤。热量限制，生酮饮食和高血糖等代谢因素会影响炎症反应，但目前尚不清楚如何发生。在这里，我们显示葡萄糖代谢通过对细胞质NADH：NAD +比率和NAD（H）敏感的转录共抑制子CtBP的影响来调节促炎性NF-κB转录活性。减少的葡萄糖可利用性会降低巨噬细胞和小胶质细胞中的NADH：NAD +比，NF-κB转录活性以及促炎基因表达。这些作用可通过强制升高NADH，降低CtBP的表达或用NAD（H）不敏感的CtBP转染来抑制，并通过抑制CtBP二聚化的合成肽复制。NADH的变化：NAD +比调节CtBP与乙酰转移酶p300的结合，并调节p300和转录因子NF-κB与促炎基因启动子的结合。这些发现确定了细胞葡萄糖代谢改变可影响细胞炎症反应的机制。几种代谢因子影响细胞葡萄糖代谢以及先天炎症反应。在这里，作者表明，葡萄糖代谢通过影响细胞质中的NADH：NAD +比值和NAD（H）敏感的转录共抑制因子CtBP来调节促炎反应。这些发现确定了细胞葡萄糖代谢改变可影响细胞炎症反应的机制。几种代谢因子影响细胞葡萄糖代谢以及先天炎症反应。在这里，作者表明，葡萄糖代谢通过影响细胞质中的NADH：NAD +比值和NAD（H）敏感的转录共抑制因子CtBP来调节促炎反应。这些发现确定了细胞葡萄糖代谢改变可影响细胞炎症反应的机制。几种代谢因子影响细胞葡萄糖代谢以及先天炎症反应。在这里，作者表明，葡萄糖代谢通过影响细胞质中的NADH：NAD +比值和NAD（H）敏感的转录共抑制因子CtBP来调节促炎反应。

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Bioenergetic state regulates innate inflammatory responses through the transcriptional co-repressor CtBP.

The innate inflammatory response contributes to secondary injury in brain trauma and other disorders. Metabolic factors such as caloric restriction, ketogenic diet, and hyperglycemia influence the inflammatory response, but how this occurs is unclear. Here, we show that glucose metabolism regulates pro-inflammatory NF-κB transcriptional activity through effects on the cytosolic NADH:NAD+ ratio and the NAD(H) sensitive transcriptional co-repressor CtBP. Reduced glucose availability reduces the NADH:NAD+ ratio, NF-κB transcriptional activity, and pro-inflammatory gene expression in macrophages and microglia. These effects are inhibited by forced elevation of NADH, reduced expression of CtBP, or transfection with an NAD(H) insensitive CtBP, and are replicated by a synthetic peptide that inhibits CtBP dimerization. Changes in the NADH:NAD+ ratio regulate CtBP binding to the acetyltransferase p300, and regulate binding of p300 and the transcription factor NF-κB to pro-inflammatory gene promoters. These findings identify a mechanism by which alterations in cellular glucose metabolism can influence cellular inflammatory responses.Several metabolic factors affect cellular glucose metabolism as well as the innate inflammatory response. Here, the authors show that glucose metabolism regulates pro-inflammatory responses through effects on the cytosolic NADH:NAD+ ratio and the NAD(H)-sensitive transcription co-repressor CtBP.

更新日期：2017-09-21

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