Could increased oxLDL with poor albumin buffering contribute to ME/CFS?

[TamaraRC]

I searched the forum and I can't see any discussion about the possible role of oxLDL in ME/CFS and Long Covid, so decided to make a thread.

I've been developing a hypothesis that attempts to connect several findings that repeatedly appear in the ME/CFS literature but are often discussed separately.

The central idea is that the problem may not simply be increased oxidative stress or oxidized LDL (oxLDL), but persistent oxLDL carrying excess lysophosphatidylcholine (LysoPC) because albumin buffering is insufficient.

Under normal circumstances, oxidation of phosphatidylcholine (PC) on LDL can make it susceptible to phospholipase-mediated hydrolysis, producing LysoPC. Albumin normally acts as an important carrier for LysoPC, limiting its retention on lipoproteins. If albumin concentration or albumin buffering capacity is reduced, LysoPC may remain associated with oxidized LDL for longer, potentially increasing its biological effects on the vascular endothelium and immune system.

This could potentially explain several apparently unrelated observations in ME/CFS.

1. Oxidative Stress

Studies have reported increased oxidative stress in ME/CFS.

One study demonstrated increased plasma peroxide concentrations together with a trend toward increased circulating antibodies against oxidized LDL, suggesting greater exposure to oxidatively modified lipoproteins in patients.

https://medscimonit.com/abstract/full/idArt/881699

Separately, researchers have shown that LDL isolated from ME/CFS patients appears to be more susceptible to copper-induced oxidation, suggesting that the lipoproteins themselves may have increased oxidative vulnerability rather than simply reflecting systemic oxidative stress.

https://www.sciencedirect.com/science/article/abs/pii/S0024320501010013

​

2. Albumin Binding

A severe ME/CFS patient study reported reduced serum albumin compared with controls.

https://www.mdpi.com/2227-9032/9/10...NdNZL3-juIRbPHClmWvUqfi5y8VO7Beass6wWcKoM1lhk

Albumin is a major circulating carrier for LysoPC and many non-esterified fatty acids (NEFAs).

If albumin levels fall, or if albumin binding sites become increasingly occupied, LysoPC buffering could theoretically become impaired.

3. High NEFA Subtype

Research has found a subgroup of ME/CFS patients with elevated circulating non-esterified fatty acids-

https://insight.jci.org/articles/view/149217

Because NEFAs and LysoPC both bind albumin, elevated NEFAs could potentially compete for albumin binding sites, leaving more LysoPC associated with oxidized LDL. I am not aware of direct evidence that this occurs in ME/CFS, but it seems like a biologically testable possibility.

​

4. Endothelial Dysfunction

One of the most reproducible findings in both ME/CFS and Long COVID is endothelial dysfunction.

Recent work has demonstrated significantly impaired flow-mediated dilation in both diseases, suggesting persistent vascular dysfunction rather than purely neurological abnormalities.

LysoPC-rich oxidized LDL is already well known in cardiovascular research to promote endothelial activation, reduce nitric oxide bioavailability, increase oxidative stress and impair vascular function.

This raises the possibility that the endothelial abnormalities observed in ME/CFS could arise from abnormal lipoprotein biology rather than representing an unrelated downstream phenomenon.

5. Oxidative stress becomes part of one mechanism​

Rather than oxidative stress being an isolated finding, it could become part of a self-reinforcing cycle:

• increased LDL oxidation
• greater phospholipid hydrolysis
• increased LysoPC generation
• insufficient albumin buffering
• prolonged exposure of the endothelium to LysoPC-rich oxLDL
• endothelial dysfunction
• mitochondrial oxidative stress
• further ROS generation and LDL oxidation

6. Possible link with SS-31​

Another observation that I find intriguing is SS-31 (elamipretide).

The Stanford nanoneedle work reported that SS-31 was able to normalise the abnormal electrical impedance signal observed in ME/CFS patient cells.

Separately, experimental research outside the ME/CFS field has shown that SS-31 can protect mitochondria from damage induced by oxidized LDL, reduce mitochondrial ROS and improve mitochondrial bioenergetics.

https://pmc.ncbi.nlm.nih.gov/articles/PMC6332157/
https://www.researchgate.net/figure...mulation-in-peritoneal-derived_fig6_320122235
https://www.researchgate.net/figure...mulation-in-peritoneal-derived_fig6_320122235

7. Connection to Reverse Cholesterol Transport

Studies have consistently shown lower HDL cholesterol in ME/CFS patients.

http://pmc.ncbi.nlm.nih.gov/articles/PMC11599898/

LCAT is a blood plasma enzyme which converts free cholesterol into cholesteryl esters, helping mature HDL. Research has show oxLDL can inhibit the activity of LCAT enzyme, which could explain lower HDL and also contribute to the reduced RBC deformability seen in ME/CFS patients (genetic LCAT deficiency has reduced RBC deformability).

https://academic.oup.com/bbb/article-abstract/60/4/580/5949235?redirectedFrom=fulltext

8. Reduced LysoPC transport back to liver

If LysoPC remains on oxLDL, this can reduce albumin mediated recycling of lysoPC back to the liver. In most people this might not matter but in a subtype who already have reduced PC synthesis due to PEMT gene variants, this could contribute to low liver PC which can cause NAFLD.


I put some slides in a video giving a simple overview of the concept if anyone is interested-

@Jonathan Edwards @DMissa @mariovitali

 

[Jonathan Edwards]

Low albumin in severe cases is likely to be due to recumbency, which reproducibly lowers albumin. So it seems to be likely an effect rather than a cause of problems.

I think the lipid aspects are more likley to be relevant without invoking albumin.
Has anyone measured LysoPC in ME/CFS?

I am not sure how all these various metabolic and vacular issues are supposed to translate to symptoms though? Especially with the dynamics of PEM?

 

[TamaraRC]

Low albumin in severe cases is likely to be due to recumbency, which reproducibly lowers albumin. So it seems to be likely an effect rather than a cause of problems.

I think the lipid aspects are more likley to be relevant without invoking albumin.
Has anyone measured LysoPC in ME/CFS?

I am not sure how all these various metabolic and vacular issues are supposed to translate to symptoms though? Especially with the dynamics of PEM?

Can we be completely sure that PEM is the same thing in every patient. I recovered over the course of a few years and as I improved I realised PEM had actually been 3 things-

1. A poisoned feeling which was worsened by activity and stress, which improved after taking ketotifen, fexofenadine and other histamine related supplements, so I think this was mast cell related.

2. I was still left with a physical and mental PEM. The physical PEM would involve my whole body losing it's strength very suddenly, sometimes this could be after 20 minutes of exertion, other days it would be after a few hours. This went away quite suddenly after 10 weeks of taking medication to prevent frequent hypoglycaemia. Most people with ME do not get the hypoglycaemia that I experienced, so I don't think this type of PEM is happening in everyone with ME, possibly just a subtype.

3. Despite correcting mast cell/histamine issues and also completely getting rid of physical PEM, I still had a cognitive PEM - if I tried to read for a few hours, I would feel brain foggy for a few days afterwards and wouldn't be able to read. This eventually improved and I think that L-Tyrosine and supplements that reduce oxidative stress helped. I think this may have been related to low norepinephrine, potentially BH4 related.

A patient experiencing 1 and 3 would say they have PEM but then a patient experiencing just 2 would also say they have PEM.

I think low norepinephrine is the more common type of PEM, and the recent study connecting the norepinephrine pathway to PEM fits with that-

https://academic.oup.com/braincomms/article/8/3/fcag173/8677724

As BH4 is used during norepinephrine synthesis, low BH4 could contribute to low norepinephrine.

So the most obvious connection between lysoPC-laden oxLDL and PEM would be-

• oxLDL activates LOX-1, NADPH oxidase (especially NOX2/NOX4), mitochondrial ROS production, and inflammatory signalling
• This increases superoxide production in endothelial cells and vascular smooth muscle
• Superoxide reacts rapidly with nitric oxide to form peroxynitrite
• Peroxynitrite is particularly effective at oxidizing tetrahydrobiopterin (BH4) to BH2
• Lower BH4 for norepinephrine synthesis

However it's not clear if lower vascular BH4 would lower BH4 available for neuronal norepinephrine synthesis, although I think it's plausible.

The presence of lysoPC on oxLDL also increases LOX-1 uptake which means that excess lysoPC on oxLDL would likely cause more vascular superoxide production than oxLDL alone-

https://www.sciencedirect.com/science/article/pii/S0014579300011546

I don't think oxLDL levels, particularly how much lysoPC burden is on oxLDL, has been measured in ME/CFS patients.

 

[Violeta]

Lipid and protein oxidation in female patients with chronic fatigue syndrome - PMC

Chronic fatigue syndrome (CFS) is a widely recognized problem, characterized by prolonged, debilitating fatigue and a characteristic group of accompanying symptoms, that occurs four times more frequently in women than in men. The aim of the study ...

pmc.ncbi.nlm.nih.gov

"To date, only a few studies have been conducted that have implicated an increased risk of cardiovascular events in CFS patients with no comorbidities. Kennedy et al. used 8-Iso-prostaglandin F2α as a lipid peroxidation marker with a potential potent biological activity [19]. They found significantly elevated levels of F2-isoprostanes and oxidized LDL and decreased HDL in nonobese, normotensive patients. Isoprostane levels were even greater in CFS patients who had additional cardiovascular risk factors. Similarly to our study, they concluded that CFS patients have a lipid profile and oxidant biology that is consistent with cardiovascular risk.

Three years later, the same group observed a relationship between inflammation and oxidative stress and augmentation index, a measure of arterial stiffness [51]. They have shown that patients with CFS have higher serum CRP levels, elevated levels of isoprostanes and oxLDL, and significantly increased AIx@75, which indicates a significantly increased risk of a future cardiovascular event in these patients."

 

[DMissa]

Has anyone measured LysoPC in ME/CFS?

there have been lipidomic studies of plasma. I don't think LPC stood out in these from memory

 

[neophyte32]

I am severely ill and have been bedridden for nearly 17 months now. During a very severe crash that lasted three months before I started taking LDA, I rapidly lost 8 kg (despite eating), developed hyperthyroidism, and had high ferritin levels...

My thyroid function eventually normalized, but my LDL became very high and my HDL dropped below the normal range, something that had never happened to me before. My liver markers specifically ALT were also slightly elevated. Could this be due to being bedridden?
I eat well, my wife cooks using high-quality ingredients.

By the way, I am making the results of the RNA analysis I had done at Amatica available to everyone; I think there are some interesting findings. The main issues are with the endoplasmic reticulum and a "low immunity" profile, with no inflammation present.

 

[Violeta]

I am severely ill and have been bedridden for nearly 17 months now. During a very severe crash that lasted three months before I started taking LDA, I rapidly lost 8 kg (despite eating), developed hyperthyroidism, and had high ferritin levels...

My thyroid function eventually normalized, but my LDL became very high and my HDL dropped below the normal range, something that had never happened to me before. My liver markers specifically ALT were also slightly elevated. Could this be due to being bedridden?
I eat well, my wife cooks using high-quality ingredients.

By the way, I am making the results of the RNA analysis I had done at Amatica available to everyone; I think there are some interesting findings. The main issues are with the endoplasmic reticulum and a "low immunity" profile, with no inflammation present.

What gene/genes related to endoplasmic reticulum do you have?

 

[Violeta]

https://www.alzdiscovery.org/uploads/cognitive_vitality_media/Lysophosphatidylcholine-Omega3_(supplement).pdf

"Lysophosphatidylcholine-bound omega-3 polyunsaturated fatty acids (PUFAs), includingdocosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), are forms of PUFAs that are thought tohave preferential access to the brain [1]."

"LPC-DHA/EPA forms may have preferential access tocertain tissues, such as the liver..."

Does oxidized Lysophosphatidylcholine also have preferential access to the brain?

 

[TamaraRC]

there have been lipidomic studies of plasma. I don't think LPC stood out in these from memory

As far as I know lipidomic studies would probably measure plasma lysoPC including from both albumin and oxLDL so I am not sure if they would pick up on if there is more LysoPC on oxLDL. Maybe level of lysoPC on oxLDL has been researched and the results not published.

 

[TamaraRC]

I am severely ill and have been bedridden for nearly 17 months now. During a very severe crash that lasted three months before I started taking LDA, I rapidly lost 8 kg (despite eating), developed hyperthyroidism, and had high ferritin levels...

My thyroid function eventually normalized, but my LDL became very high and my HDL dropped below the normal range, something that had never happened to me before. My liver markers specifically ALT were also slightly elevated. Could this be due to being bedridden?
I eat well, my wife cooks using high-quality ingredients.

By the way, I am making the results of the RNA analysis I had done at Amatica available to everyone; I think there are some interesting findings. The main issues are with the endoplasmic reticulum and a "low immunity" profile, with no inflammation present.

That's interesting. There is research that shows hyperthyroidism increases LDL oxidation.. oxLDL does not get taken up by liver LDL receptors as well as non oxidised LDL, leading to higher LDL levels.

https://pubmed.ncbi.nlm.nih.gov/9598831/

Will be interesting to see the results of your RNA analysis.