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

[AndyPR]

Might, or might not, be of interest.

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.

Full open access at https://www.nature.com/articles/s41467-017-00707-0

Mainstream article on the paper at http://neurosciencenews.com/ketonic-diet-inflammation-7553/

Ketogenic diets — extreme low-carbohydrate, high-fat regimens that have long been known to benefit epilepsy and other neurological illnesses — may work by lowering inflammation in the brain, according to new research by UC San Francisco scientists. The UCSF team has discovered a molecular key to the diet’s apparent effects, opening the door for new therapies that could reduce harmful brain inflammation following stroke and brain trauma by mimicking the beneficial effects of an extreme low-carb diet

“It’s a key issue in the field — how to suppress inflammation in brain after injury,” said Raymond Swanson, MD, a professor of neurology at UC San Francisco, chief of the neurology service at the San Francisco Veterans Affairs Medical Center, and senior author of the new study.

In the paper, published online September 22, 2017 in the journal Nature Communications, Swanson and his colleagues found the previously undiscovered mechanism by which a low carbohydrate diet reduces inflammation in the brain. Importantly, the team identified a pivotal protein that links the diet to inflammatory genes, which, if blocked, could mirror the anti-inflammatory effects of ketogenic diets.

“The ketogenic diet is very difficult to follow in everyday life, and particularly when the patient is very sick,” Swanson said. “The idea that we can achieve some of the benefits of a ketogenic diet by this approach is the really exciting thing here.”

 

[adreno]

Interesting, I think. Especially because of how difficult it is for many PwME to tolerate low carb diets.

 

[jpcv]

Maybe that´s the reason many patients with ME have reported benefits with low carb diets, myself included.

 

[Tunguska]

It's nice to know the protein. But this is largely in context of hypoxia and you could already use methylene blue for this (search methylene blue TBI), and it will probably have broader effect than targeting the protein alone. You could do both I guess.