A Systems Hypothesis: Reverse Cholesterol Transport Dysfunction, Arachidonic Acid Accumulation, and Noradrenergic Imbalance in ME/CFS ,2025 Carnac

Tamara Carnac

This version is not peer-reviewed.


Abstract
Myalgic Encephalomyelitis (ME), sometimes known as Chronic Fatigue Syndrome (CFS), is a complex illness marked by fatigue, post-exertional malaise, cognitive dysfunction, autonomic instability, and immune abnormalities. This paper proposes a unifying hypothesis centred on dysfunction of lecithin–cholesterol acyltransferase (LCAT) and deficiency of phosphatidylcholine (PC), leading to altered membrane lipid composition, excess arachidonic acid release, and chronic inflammation. These changes may promote dysregulated production of prostaglandins and leukotrienes, imbalance in PPAR-γ activity, and disruptions in sex hormone metabolism, potentially contributing to conditions like polycystic ovary syndrome (PCOS), endometriosis and mast cell activation syndrome (MCAS). We propose that different combinations of LCAT dysfunction and PC deficiency result in distinct physiological subtypes. These include a neuronal insulin-hypersensitive subtype with reduced norepinephrine transporter (NET) expression and high extracellular norepinephrine; a high membrane arachidonic acid subtype with preserved PC but increased NET expression and neuronal insulin resistance; and a third group characterised by both elevated norepinephrine and downregulated β₂-adrenergic receptors. Each subtype presents with a different pattern of autonomic, metabolic, and immune dysregulation. Additional variation may arise from differences in acetylcholine synthesis, norepinephrine production capacity, and feedback mechanisms within the adrenergic system. This framework helps explain the heterogeneity of ME and offers a biologically coherent basis for further investigation into its pathophysiology.

A Systems Hypothesis: Reverse Cholesterol Transport Dysfunction, Arachidonic Acid Accumulation, and Noradrenergic Imbalance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)[v3] | Preprints.org

 

Ctrl+f for «PEM» didn’t give me any immediate answers for how they believe that PEM works. That’s the part I’m most interested in.

 

Did you search on the webpage or click on the pdf and download it? There is a mention of PEM on page 9.

 

I downloaded it. There is nothing on page 9 that explains how the mechanisms cause the symptoms, or how the delay works.

I think any explanation of ME/CFS has to clearly show a timeline for how PEM is caused and why it’s delayed. Based on the headers, that isn’t included in this paper.

 

PEM could be a downstream effect of ME, rather than a necessary component of it, so a theory that explains other aspects of ME could be valid even if it doesn't explain PEM.

 

I don’t understand the distinction you are trying to make here.

 

This work should be further investigated in my opinion and see whether ME patients have LCAT dysfunction. From the paper, observe the mentions on PGC-1a , ABCA1 and LXR :
The author also mentions "Reverse Cholesterol Transport" and Choline deficiency (Phosphatidylcholine) :



Here is the -now hopefully well known- Network Analysis generated in 2017. Nodes Choline deficiency, LXR, PGC1 and Peroxisome proliferators appear in the analysis :







Regarding reverse cholesterol transport (RCT) and ABCA1, we have also agreement (meaning that different research efforts, identify the same elements) which can be found in the following thread : https://www.s4me.info/threads/presentation-at-euromene-london-uk.5760/

Back then, I collected concepts related to cholesterol transport because the analysis of my personal data suggested that I felt better when consuming cholesterol-rich foods. @TamaraRC does this make sense?

 

I looked at the thread and it's interesting that you were suggesting all of these things several years ago. It is a shame there isn't much research by ME scientists into cell membrane dysfunction, as I don't think it would be the hardest thing to research- I am sure there are ways to study the cholesterol/phospholipid balance in cell membranes of immune cells and RBCs.

Ron Davis and his team found ME patient RBCs to be less deformable, which suggests cell membrane dysfunction and increased rigidity. It is plausible that this could be caused by a phosphatidylcholine and cholesterol imbalance in the cell membrane. Then when you consider this same membrane dysregulation happening in other cells in the body, (immune, endothelial etc) affecting the functioning of membrane proteins like receptors and transporters, it is quite a plausible explanation for the pathophysiology of ME.

However, it doesn't really fit with your experience of feeling better after high cholesterol. High dietary cholesterol can activate Liver X Receptor, which upregulates CYP7A1. So if you have suppression of CYP7A1, maybe due to PPARα dysregulation, the high cholesterol could be helping upregulate CYP7A1?

I think that there could be multiple pathways leading to cholesterol build up in the membrane and these might constitute subtypes.

 

Same here, I tend to have the most energy and endurance after eating a high fat meal. I related this to a couple findings showing increased reliance on fatty acid oxidation in ME/CFS, I'll see if I have those on hand.

 

My response was that it's not proven that PEM is an essential outcome of ME's mechanism, therefore PEM's mechanism isn't absolutely required for a theory of ME. PEM's mechanism could be many steps removed from ME's core mechanism, and may not show up in all victims. Yes, yes, the official definition of ME includes PEM, but maybe there are a fairly large number of people suffering from ME's mechanism without PEM, and they weren't included when the definition of ME was decided upon.

I had PEM for many years, and now I don't, but all the other aspects of my ME seem unchanged, so I don't consider myself to no longer have ME. If they studied me enough to figure out the mechanism of ME, that mechanism would not have to clearly show how PEM is caused and why it's delayed.

 

@TamaraRC keep an eye out for my next experimental manuscript that I have just sent to co-authors for final review , perhaps we should have a chat some time

PS: have thought about it some more and we can probably test your ideas directly, easily enough? I couldn't find an email address so I dmed you on twitter with details

 

What are the other aspects?

 

You have definitely piqued my interest! Very interested in testing the hypothesis. I've emailed you

 

Other symptoms such as lethargy, brainfog, aches, and double-vision, and I would include "general malaise". Also food intolerances that affect severity of my ME symptoms. The only other significant change at that time was that my need to take iodine or T2 every 21 days stopped.

So, from my perspective, my ME remained unchanged except for the general symptoms not increasing in severity 24 hrs after exertion.

Some of my food intolerances were indistinguishable from PEM. Is the rise in ME symptom severity caused by a "PEM mechanism" that is triggered by multiple inputs, and I'm just missing the physical and cognitive exertion triggering? Triggering on physical exertion certainly doesn't seem to be required to have other ME symptoms.