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

Yiguo Shen, David Kapfhamer, Angela M. Minnella, Ji-Eun Kim, Seok Joon Won, Yanting Chen, Yong Huang, Ley Hian Low, Stephen M. Massa and Raymond A. Swanson ()
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Yiguo Shen: University of California
David Kapfhamer: University of California
Angela M. Minnella: University of California
Ji-Eun Kim: University of California
Seok Joon Won: University of California
Yanting Chen: University of California
Yong Huang: University of California
Ley Hian Low: University of California
Stephen M. Massa: University of California
Raymond A. Swanson: University of California

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/s41467-017-00707-0

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