Shen Yiguo, Kapfhamer David, Minnella Angela M, Kim Ji-Eun, Won Seok Joon, Chen Yanting, Huang Yong, Low Ley Hian, Massa Stephen M, Swanson Raymond A
Department of Neurology, University of California, San Francisco, CA, 94143, USA.
Neurology Service, San Francisco Veteran Affairs Medical Center, 4150 Clement St., San Francisco, CA, 94121, USA.
Nat Commun. 2017 Sep 22;8(1):624. doi: 10.1038/s41467-017-00707-0.
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.
先天性炎症反应会导致脑外伤和其他疾病中的继发性损伤。热量限制、生酮饮食和高血糖等代谢因素会影响炎症反应，但具体机制尚不清楚。在此，我们表明葡萄糖代谢通过影响胞质NADH:NAD比值和NAD(H)敏感的转录共抑制因子CtBP来调节促炎NF-κB转录活性。葡萄糖可用性降低会降低巨噬细胞和小胶质细胞中的NADH:NAD比值、NF-κB转录活性和促炎基因表达。这些作用可通过强制升高NADH、降低CtBP表达或用NAD(H)不敏感的CtBP转染来抑制，并且可通过抑制CtBP二聚化的合成肽来复制。NADH:NAD比值的变化调节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。这些发现确定了一种细胞葡萄糖代谢改变可影响细胞炎症反应的机制。几种代谢因素会影响细胞葡萄糖代谢以及先天性炎症反应。在此，作者表明葡萄糖代谢通过影响胞质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。
