Bioenergetic state regulates innate inflammatory responses through the transcriptional co-repressor CtBP.
Bioenergetic state regulates innate inflammatory responses through the transcriptional co-repressor CtBP.
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DOI：
10.1038/s41467-017-00707-0
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发表时间：
2017-09-22
影响因子：
16.6
通讯作者：
Swanson RA
中科院分区：
文献类型：
--
作者：
Shen Y;Kapfhamer D;Minnella AM;Kim JE;Won SJ;Chen Y;Huang Y;Low LH;Massa SM;Swanson RA
先天性炎症反应会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，但其如何发生尚不清楚。在这里，我们发现葡萄糖代谢通过影响胞质 NADH:NAD+ 比率和 NAD(H) 敏感转录共阻遏物 CtBP 来调节促炎 NF-κB 转录活性。葡萄糖利用率降低会降低巨噬细胞和小胶质细胞中 NADH:NAD+ 比率、NF-κB 转录活性以及促炎基因表达。这些效应可通过强制升高 NADH、降低 CtBP 表达或用 NAD(H) 不敏感的 CtBP 转染来抑制，并通过抑制 CtBP 二聚化的合成肽来复制。 NADH:NAD+ 比例的变化调节 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的改变可以影响细胞炎症反应的机制。几种代谢因素影响细胞葡萄糖代谢以及先天炎症反应。在此，作者表明，葡萄糖代谢通过影响胞质 NADH:NAD+ 比率和 NAD(H) 敏感转录共阻遏物 CtBP 来调节促炎反应。
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.
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影响因子：
8.4
作者：
Birts CN;Nijjar SK;Mardle CA;Hoakwie F;Duriez PJ;Blaydes JP;Tavassoli A
通讯作者：
Tavassoli A
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通讯作者：
Swanson RA
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作者：
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通讯作者：
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通讯作者：
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