Altered Fatty Acid Oxidation in Lymphocyte Populations of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (Maya et al, 2023)

[Consul]

Abstract

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling multisystem illness in which individuals are plagued with fatigue, inflammatory symptoms, cognitive dysfunction, and the hallmark symptom, post-exertional malaise. While the cause of this disease remains unknown, there is evidence of a potential infectious component that, along with patient symptoms and common onsets of the disease, implicates immune system dysfunction. To further our understanding of the state of ME/CFS lymphocytes, we characterized the role of fatty acids in isolated Natural Killer cells, CD4+ T cells, and CD8+ T cells in circulation and after overnight stimulation, through implicit perturbations to fatty acid oxidation. We examined samples obtained from at least 8 and as many as 20 subjects for immune cell fatty acid characterization in a variety of experiments and found that all three isolated cell types increased their utilization of lipids and levels of pertinent proteins involved in this metabolic pathway in ME/CFS samples, particularly during higher energy demands and activation. In T cells, we characterized the cell populations contributing to these metabolic shifts, which included CD4+ memory cells, CD4+ effector cells, CD8+ naïve cells, and CD8+ memory cells. We also discovered that patients with ME/CFS and healthy control samples had significant correlations between measurements of CD4+ T cell fatty acid metabolism and demographic data. These findings provide support for metabolic dysfunction in ME/CFS immune cells. We further hypothesize about the consequences that these altered fuel dependencies may have on T and NK cell effector function, which may shed light on the illness’s mechanism of action.


https://www.mdpi.com/1422-0067/24/3/2010

 

[Consul]

3.2. Effects of Lipid Metabolism Abnormalities in ME/CFS NK Cells

Our study of fatty acid oxidation revealed that ME/CFS NK cells increased their use of this pathway during stress, absorbed more of the supplied fatty acid, and had higher levels of CPT1a in circulation. These metabolic differences were not overcome after stimulatory factors were added. Conversely, patients had lower levels of the cell membrane lipid transporter, CD36, in both resting and activated states. The finding that FAO is used more often within these cells while CD36 is less abundant may be attributed to CD36’s dual functions, not only as a fatty acid transporter but as a regulator of intracellular fatty acid homeostasis. The downregulation of CD36 in environments with high amounts of surrounding lipids can reduce cellular lipid overaccumulation by promoting the oxidation of fatty acids already present in the cell, according to research on CD36 in hepatocytes. This regulatory mechanism has been observed in fatty acid liver disease and metabolic syndromes [77]. Previous metabolomic findings support this theory, as they report high levels of certain fatty acids in ME/CFS plasma and hypothesize that it could be a sign of hyperlipidemia or a deficiency in liver activity [33].
High levels of fatty acids in and surrounding these cells—and the subsequent increased fatty acid oxidation—could also explain a commonly cited finding in ME/CFS literature: decreased NK cell cytotoxicity [19,20,21,22,23,24]. Lipid accumulation has been shown to suppress mTOR activity and block cytotoxic machinery necessary for NK cell functionality [55,78,79]. If excess free fatty acids block the cellular components necessary for effector functions, ME/CFS NK cells will have a lower cytotoxic response than healthy individuals. This, in turn, will lead to a lower capability of the innate immune system to defend against virally infected cells [80]. In practice, these findings suggest that targeting or rewiring fatty acid metabolism through multiple additive mechanisms could improve NK cell function in individuals with ME/CFS [55].

Is mecfs a hyperlipidemia disease where the excess lipid levels are messing up cellular functions as mentioned above and cells have to promote FAO to get rid of the lipids?

I got reminded of Jahanbani 2022s electron microscope study when i read this, here is a quote from that paper:

We also found a large increase in intracellular giant lipid droplet-like organelles in the stimulated PBMCs from the extremely severe ME/CFS patient potentially indicative of a lipid storage disorder.

 

[linusbert]

muscle biopsy showed for me increase in fatty acid deposition in muscles.

but what does this mean - besides metabolism not working properly?

 

[Consul]

muscle biopsy showed for me increase in fatty acid deposition in muscles.

but what does this mean - besides metabolism not working properly?

Well the authors propose that excessive lipids can get in the way of cellular functions such as cytotoxicity in immune cells.

IIRC the forum user Martin had loads of lipids in blood.

I myself always had loads of adrenaline going on because of a neurological issue. Adrenaline increases free fatty acids and triglycerides in blood by stimulating lypolysis in adipose tissue.

I also think mecfs is highly associated with anti phospholipid syndrome which causes lots of lipids in blood IIRC.

 

[linusbert]

i dont understand it. i mean it sounds like diabetes. in diabetes also fatty acids are increased, as are amino acids.

 

[Consul]

i dont understand it. i mean it sounds like diabetes. in diabetes also fatty acids are increased, as are amino acids.

Sure that would need to be explained somehow.

The authors also mention liver failure as a possibility though. Not the first time liver failure has been suggested.

 

[Oliver3]

Sure that would need to be explained somehow.

The authors also mention liver failure as a possibility though. Not the first time liver failure has been suggested.

Not doubting this line of research. But how are we alive?

 

[SWAlexander]

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling multisystem illness in which individuals are plagued with fatigue, inflammatory symptoms, cognitive dysfunction, and the hallmark symptom, post-exertional malaise. While the cause of this disease remains unknown, there is evidence of a potential infectious component that, along with patient symptoms and common onsets of the disease, implicates immune system dysfunction. To further our understanding of the state of ME/CFS lymphocytes, we characterized the role of fatty acids in isolated Natural Killer cells, CD4+ T cells, and CD8+ T cells in circulation and after overnight stimulation, through implicit perturbations to fatty acid oxidation. We examined samples obtained from at least 8 and as many as 20 subjects for immune cell fatty acid characterization in a variety of experiments and found that all three isolated cell types increased their utilization of lipids and levels of pertinent proteins involved in this metabolic pathway in ME/CFS samples, particularly during higher energy demands and activation. In T cells, we characterized the cell populations contributing to these metabolic shifts, which included CD4+ memory cells, CD4+ effector cells, CD8+ naïve cells, and CD8+ memory cells. We also discovered that patients with ME/CFS and healthy control samples had significant correlations between measurements of CD4+ T cell fatty acid metabolism and demographic data. These findings provide support for metabolic dysfunction in ME/CFS immune cells. We further hypothesize about the consequences that these altered fuel dependencies may have on T and NK cell effector function, which may shed light on the illness’s mechanism of action.
more: https://www.mdpi.com/1422-0067/24/3/2010#B89-ijms-24-02010

 

[Wishful]

This doesn't actually mean there's a problem with the immune cells. It could mean that they're responding correctly to abnormal signalling from the brain. There's a really small number (~1000?) of brain cells in the hypothalamus that respond to cytokines, and in return those cells send out signals to the immune system, altering its functions. So, ME could be as simple as an abnormality in a small set of brain cells; they overrespond to an immune activation event, and alter their signals to the immune system in a way that maintains this abnormal response.

 

[Forummember9922]

Noob question does this reveal any new insights regarding previous controversial or disregarded theories about fish oil and evening primrose oil? Does this paper have any therapeutic implications?