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Jun 21

Lipoprotein Power – LDL and the Immune System

If one were to hear the words “lipoprotein” or “cholesterol” in a sentence, it might be expected that the next words would be “heart disease”, or “diabetes” or “metabolic syndrome”. However, while working alongside Dave and digging deeper into research on the lipid system, I found that surprisingly the next words were sometimes “infection” or “immune system” or even “protective”. 

Immunological Velcro

The one who first pointed me towards the connection between lipoproteins and the immune system was Dave, back in 2017. He described how LDL could, in a sense, velcro itself to pathogens, binding to them. Just like a security guard tackling someone trying to cause harm, lipoproteins appear to be able to do the same with bacteria, viruses, and even with some parasites. By binding to the pathogen in this way, LDL can block its entry into our cells, leaving the pathogen vulnerable to clearance by immune cells. This appears to be the case with salmonella, where a 7-fold increase in LDL in the test mice resulted in a 95% survival rate, compared to a 0% survival rate in the controls.1 This difference was assigned to the high levels of LDL in itself, due to its binding capacity. This binding capacity is not common among all viruses and bacteria, but has been seen with the Herpes virus, as well.2

Calming the Storm

Beyond infecting cells directly, pathogens can cause damage in other ways – including exposing cells to toxins that they carry. One example is an endotoxin, called lipopolysaccharide (or LPS, for short), found in the membrane of some bacteria.3 High levels of exposure to LPS can result in immune activation that is so severe it cause problems like sepsis, which can be fatal.4

Lipoproteins, like VLDL and LDL, can circumvent this problem by binding to LPS, neutralizing it and lessening the need for further immune activation.5 Animal studies have shown that mice with low cholesterol, compared to those with normal levels, are more at risk of fatal sepsis when exposed to LPS6, and higher levels of cholesterol are even more protective.7 Lipoproteins have also been found to neutralize an endotoxin, lipoteichoic acid (LTA), found on the bacteria that cause staph infections.8

Help From the Sidelines

Endotoxins from bacteria aren’t the only thing that lipoproteins may help clean up, though. While fighting pathogens, immune cells use something called oxidative burst, where they use Reactive Oxygen Species (ROS) to harm or kill the invading organism.9 Reactive Oxygen Species are often painted as bad things, because they can cause damage and oxidative stress if they are allowed to run rampant. However, it has been proposed that LDL can be one way we keep our own cells safe during times where levels of ROS need to be higher for our own protection.10

“Lipoprotein oxidation during APR initially is likely to serve a beneficial purpose. Reactive oxygen species and free radicals are part of the local host defense mechanisms, […] Thus, lipoproteins may scavenge these free radicals to prevent systemic toxicity and membrane damage.”

Memon RA, et al (2000); PMID: 10845869

I also learned another way LDL can be used to fight infection from the sidelines – Nadir Ali was the first to bring to my attention that LDL can interrupt bacterial scouting missions. In order to determine if an environment is ideal for replication, bacteria will essentially send out probes to gain information and figure out if the environment is hostile or not, a process called quorum sensing. If the probe doesn’t come back, it’s determined the environment is not ideal, and replication does not occur. LDL can attach itself to these probes, ensuring they never return to the bacteria that sent them out, and giving the impression that it isn’t the best place for the bacteria to settle into.11

Musical Chairs

Lipoproteins can also indirectly block pathogens from entering cells – in this case, the lipoprotein may not be interacting with the bacteria or virus directly, but may instead be using something that the pathogen needs to get into the cell. Some examples of this are LDL preventing the virus that causes the common cold from entering through the LDL receptor12, or VLDL preventing invasion of Malaria into the liver via the VLDL receptor.13 Essentially, it’s a game of musical chairs, where the lipoproteins are taking up some of the seats, resulting in a higher chance of the pathogen being the one to be “out” – making it more likely that our own immune cells can capture them.

Passive Accomplices or Active Participants?

After reading over these potential uses of lipoproteins, a question came to mind: if lipoproteins can be used as a defense against various assaults, as the literature seems to suggest, is this only a passive defense? In other words, are only the VLDL and LDL that you already have around used, or are there ways to get more of them onto the field if needed?

It didn’t take long before I started to come upon terms like “the hypertriglyceridemia of infection”14, which gave a hint to the answer. Why would high triglycerides be important? Because these triglycerides are, by necessity, carried by lipoproteins! During infection, more fat is coming from fat tissue to the liver, and there is an increase in new fat being made in the liver, as well as an increase in production of cholesterol – all materials necessary for making lipoproteins like VLDL.15

This is the result of many changes during infection, however, not just one solitary cause. For one, some infections cause transient insulin resistance as a protective mechanism16, which could lead to high triglycerides in-and-of itself, but inflammatory signalling can also set off a cascade of reactions that ultimately result in high triglycerides, and high cholesterol during infection.17

“VLDL production during infection most likely represents a part of the acute phase response. […] In this manner, the anti-infective, protective effects of lipoproteins are maintained.”

Grunfeld C, Feingold KR. (1992); PMID: 1374564

During infection, more VLDL being made is paired with a longer residence time of the lipoproteins, due to a combination of factors.18 This increase in production and decrease in clearance would result in a higher total levels of lipoproteins in the blood, which may be beneficial. Similar to a dozen policemen more quickly being able to capture multiple criminals compared to half a dozen, the same principle may apply here, as well.19

A Small Part of the Whole

The mechanisms discussed here only cover a tiny part of the whole – the focus remained on VLDL and LDL, and some has still been left out for the sake of brevity, but immune involvement has also been seen with HDL, chylomicrons, and even lipoprotein(a). Further posts on the topic are sorely needed, but until then a question is left – with no certain answer. Although the mechanisms outlined here are intriguing, and some have been seen in both animal and human studies, whether this has any noticeable impact in the day-to-day human is unknown.

While there are some observational studies, which tie lower cholesterol to death from infection20, it is possible this is due to conditions that can result in lower cholesterol, such as cancer, also being linked to a weaker immune system.21 Although it’s clear that there is much more to investigate on this topic, the plausibility of LDL – and other lipoproteins – acting as a part of the innate immune system, in a protective role in humans is certainly an interesting one worth exploring further.


Citations

1 Netea, Mihai G et al. “Circulating lipoproteins are a crucial component of host defense against invasive Salmonella typhimurium infection.” PloS one vol. 4,1 (): e4237. doi:10.1371/journal.pone.0004237

2 Huemer H, P, Menzel H, J, Potratz D, Brake B, Falke D, Utermann G, Dierich M, P: Herpes Simplex Virus Binds to Human Serum Lipoprotein. Intervirology 1988;29:68-76. doi: 10.1159/000150031

3 Morrison, D C, and R J Ulevitch. “The effects of bacterial endotoxins on host mediation systems. A review.” The American journal of pathology vol. 93,2 (1978): 526-618.

4 Bone, R. C. “Gram-Negative Sepsis. Background, Clinical Features, and Intervention.” Chest, vol. 100, no. 3, Sept. 1991, pp. 802–08. PubMed, doi:10.1378/chest.100.3.802.

5 Cavaillon, J. M., et al. “Cytokine Response by Monocytes and Macrophages to Free and Lipoprotein-Bound Lipopolysaccharide.” Infection and Immunity, vol. 58, no. 7, July 1990, pp. 2375–82.

6 Feingold, K. R., et al. “Role for Circulating Lipoproteins in Protection from Endotoxin Toxicity.” Infection and Immunity, vol. 63, no. 5, May 1995, pp. 2041–46.

7 Netea, M. G., et al. “Low-Density Lipoprotein Receptor-Deficient Mice Are Protected against Lethal Endotoxemia and Severe Gram-Negative Infections.” Journal of Clinical Investigation, vol. 97, no. 6, Mar. 1996, pp. 1366–72. Crossref, doi:10.1172/JCI118556.

8 Sigel, Stefanie, et al. “Apolipoprotein B100 Is a Suppressor of Staphylococcus Aureus-Induced Innate Immune Responses in Humans and Mice.” European Journal of Immunology, vol. 42, no. 11, Nov. 2012, pp. 2983–89. PubMed, doi:10.1002/eji.201242564.

9 Amulic, Borko, et al. “Neutrophil Function: From Mechanisms to Disease.” Annual Review of Immunology, vol. 30, 2012, pp. 459–89. PubMed, doi:10.1146/annurev-immunol-020711-074942.

10 Memon, R. A., et al. “Infection and Inflammation Induce LDL Oxidation in Vivo.” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 20, no. 6, June 2000, pp. 1536–42.

11 Peterson, M. Michal, et al. “Apolipoprotein B Is an Innate Barrier against Invasive Staphylococcus Aureus Infection.” Cell Host & Microbe, vol. 4, no. 6, Dec. 2008, pp. 555–66. PubMed, doi:10.1016/j.chom.2008.10.001.

12 Hofer, F., et al. “Members of the Low Density Lipoprotein Receptor Family Mediate Cell Entry of a Minor-Group Common Cold Virus.” Proceedings of the National Academy of Sciences of the United States of America, vol. 91, no. 5, Mar. 1994, pp. 1839–42. PubMed, doi:10.1073/pnas.91.5.1839.

13 Sinnis, P., et al. “Remnant Lipoproteins Inhibit Malaria Sporozoite Invasion of Hepatocytes.” The Journal of Experimental Medicine, vol. 184, no. 3, Sept. 1996, pp. 945–54. PubMed, doi:10.1084/jem.184.3.945.

14 Grunfeld, C., and K. R. Feingold. “Tumor Necrosis Factor, Interleukin, and Interferon Induced Changes in Lipid Metabolism as Part of Host Defense.” Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.), vol. 200, no. 2, June 1992, pp. 224–27. PubMed, doi:10.3181/00379727-200-43424.

15 Beisel, W. R., and R. W. Wannemacher. “Gluconeogenesis, Ureagenesis, and Ketogenesis during Sepsis.” JPEN. Journal of Parenteral and Enteral Nutrition, vol. 4, no. 3, June 1980, pp. 277–85. PubMed, doi:10.1177/014860718000400307.

16 Šestan, Marko, et al. “Virus-Induced Interferon-γ Causes Insulin Resistance in Skeletal Muscle and Derails Glycemic Control in Obesity.” Immunity, vol. 49, no. 1, July 2018, pp. 164-177.e6. Crossref, doi:10.1016/j.immuni.2018.05.005.

17 Glass, Christopher K., and Jerrold M. Olefsky. “Inflammation and Lipid Signaling in the Etiology of Insulin Resistance.” Cell Metabolism, vol. 15, no. 5, May 2012, pp. 635–45. Crossref, doi:10.1016/j.cmet.2012.04.001.

18 Feingold, K. R., et al. “Endotoxin Rapidly Induces Changes in Lipid Metabolism That Produce Hypertriglyceridemia: Low Doses Stimulate Hepatic Triglyceride Production While High Doses Inhibit Clearance.” Journal of Lipid Research, vol. 33, no. 12, Dec. 1992, pp. 1765–76.

19 Netea, M. G., et al. “Bacterial Lipopolysaccharide Binds and Stimulates Cytokine-Producing Cells before Neutralization by Endogenous Lipoproteins Can Occur.” Cytokine, vol. 10, no. 10, Oct. 1998, pp. 766–72. PubMed, doi:10.1006/cyto.1998.0364.

20 Shor, Renana, et al. “Low Serum LDL Cholesterol Levels and the Risk of Fever, Sepsis, and Malignancy.” Annals of Clinical and Laboratory Science, vol. 37, no. 4, 2007, pp. 343–48.

21 Sharp, S. J., and S. J. Pocock. “Time Trends in Serum Cholesterol before Cancer Death.” Epidemiology (Cambridge, Mass.), vol. 8, no. 2, Mar. 1997, pp. 132–36.

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Joe Kalb
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What an enlightening, well-written post. Thanks Siobhan!

John Pavao
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John Pavao

As someone with selective IgA deficiency, it makes me glad to have very high LDL reading this… it’s probably all that’s saving me from being sick all the time!

Laura Smith
Guest
Laura Smith

I have a very high LDL (over 300) and low white blood count. I wonder if it is connected?

Derek Green
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Derek Green

Great post!

Damien Sanderson
Guest
Damien Sanderson

Siobhan . . . the following piece of history may interest you . . .

THE NATURE OF ANTISTREPTOLYSIN ” S ” IN THE SERA OF MAN AND OF OTHER SPECIES: ANTISTREPTOLYSIN TITRES IN NORMAL AND DISEASED STATES.
J H Humphrey 1949

This was before lipoprotein fractions had been identified . . . . that was a year or 2 away.

He noted evidence that showed the haemolytic toxins were produced by streptococci. – 2 identified (1938)

(a) Toxin: Streptolysin “O” – was known as a strong antigen, inactivated by O2 – produced antibodies (anti-streptolysin “O”) – On infection there was sharp rise in titre of the anti-streptolysin “O”antibody.

(b) Toxin: Streptolysin “S” – not give rise to antibodies – but there was clear evidence of some inhibitory agent in the blood. (1931)

Called this unidentified serum agent anti-streptolysin “S” (AS-S) . . [We would identify as a lipoprotein]
AS-S did not appear to be an antibody

Describes studies (1939) trying to see the effect of AS-S against infections but had difficulties because they found AS-S in several species of animals that clearly had not had a streptococcal infection.
[It would appear AS-S is not highly specific for pathogens]
Describes some evidence of AS-S titres lowering on infection

From Humphrey’s study – – – – – –

Did a load of work on infected rabbits and horses to test his assay of AS-O and AS-S anti-sera.

Measured the AS-S and AS-O levels in people with various illnesses

No of sera AS-S AS-O
Range. Mean. Mean.
Scarlet fever – acute . . 8 3 – 2-8 6.3 35
Convalescent . . (14-16 days). 8 4 – 8 6.2 240
Streptococcal pharyngitis – acute 4 4.6 – 7 5.2 410
Sub-acute and convalescent . 4 2 – 9.5 6.1 240
Rheumatic fever – acute . . 8 5.6 – 7 6.3 428
Sub-acute . . . . I6 4 – 10 6.7 261
Convalescent . . . I5 5.3 – l2.5 8.4 275
Rheumatoid arthritis – acute . 4 5.3 – 9.5 6.5 92
Sub-acute . . . . 4 4.7 – 8 6-3 130

Normals (Controls) . . . . 14 8 – 12-5 9.7 48

Points from table . . .

• AS-O behaves like antibody: lower in normals . . . rises in ill people – falls on convalescence
• AS-S is lower in all infections than the average level in ‘normals’
• AS-S rises in convalescence
• AS-S Not behave like antibody

Also . . .

Noted that the AS-S appears to have properties of “lipo-nucleoproteins”.
Also noted that AS-S had no immunization properties unlike AS-O

—————————————

In 1950 a paper by Gene Stollerman . . .
“The association of lipoproteins with the inhibition of streptolysin S by serum.”

Showed that one particular fraction was most potent . . . VLDL? LDL?

Damien

Terry Lazarou
Guest
Terry Lazarou

Insightful and thought provoking. Thank you.

Philippa
Guest
Philippa

Do we know if the protective effect is predominently linked to higher levels of LDL-C or LDL-P?

Stephen Thomas
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Stephen Thomas

The flood of evidence that high levels of LDL are possibly protective does not appear to making any inroads to mainstream medical thinking? I honestly wonder why this is.

Bob Dennis
Guest
Bob Dennis

Stephen,

My guess is, inconvenient information! Not good optics to report that avoiding what we thought would kill you might just kill you instead!

gia best
Guest
gia best

beautifully put. Thx

Paul Travis
Guest
Paul Travis

In addition to ref 20 above, see doi: 10.1186/s13054-016-1579-8 “In this large, prospective cohort study, low LDL-C was associated with increased long-term rates of community-acquired sepsis.”
and
doi: 10.1016/j.jcrc.2015.01.001 “Low levels of plasma lipids, particularly low HDL and LDL cholesterol on day 7, was predictive of adverse outcomes in patients with severe community-acquired pneumonia who needed ICU admission.”

— more evidence that low levels of LDL are associated with sepsis risk.

Then this: doi: 10.1001/jamanetworkopen.2018.7223 published this year using measured LDL-c, and genetic risk score which they say correlated with measured LDL-C levels (though no reference is given). Although measured LDL-c was inversely associated with sepsis, the genetic model did not, which led to the conclusion “Levels of LDL-C do not appear to alter the risk of sepsis or poor outcomes directly in patients hospitalized with infection.” — a conclusion I can’t get my head around. ????? I still can’t see how they generate a ‘genetic risk score’ or what this means????

Two of the authors declare they have previously received grants from Amgen — who make the PCSK9 inhibitor evolocumab (Repatha). Could it be that the manufacturers of drugs to drastically lower LDL wouldn’t want the possible link between LDL and immunity known too widely particularly as their drugs could lower a patient’s LDL greatly? Just saying.

Tony
Guest
Tony

This is a great article and a breath of fresh air, because it add art, music and engineering sense to the dry science most physicians just pass on without any intention to dig deep into or make something off of

Willa
Guest
Willa

Dave-I’m a hyper-responder. Are you still doing a study on this? I heard or read you were looking for people to enroll in this study. Is this still true? Is so how can I do this?

Weekly Link Love — Edition 35 – healthydaysclub
Guest

[…] Article I found interesting: LDL and the Immune System. […]

Carlo Barrientos
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Carlo Barrientos

Thanks, that is very clear, concise and easy to read without getting a headache 🙂
So are you saying that the research is suggesting that high LDL may be an indication that the immune system is “fighting off” infection and disease… NOT causing it ?
In an analogy, if we used conventional medicine’s reasoning, doctors would be saying that because there are lots of police cars found near the site of a crime, it must be that police cars cause crime which is the kind of ludicrous and faulty reasoning which can be inferred by naive researchers who tie correlation to causation. Yes, there are police cars at crime scenes but unless you know why they are there, you can’t conclude they cause crimes.
Is there research as to “why” atherosclerosis occurs? Is the cholesterol plaque building up at sites because it is trying to attach to a pathogen or virus or cell wall damage in order for it to be
carried away by the immune system ?
And here’s another question? If an elevated LDL is part of the immune system response,
does taking a statin suppress our immune system’s ability to fight heart disease ?
I know that in my own N=1 experiments, when I stopped taking my statin, I felt “less sickly” and my health improved. Then, when I began Keto and stuck with it for a few months, my health
improved even more, my lymphedema in my legs went away. I stopped being sick and tired and felt energy returning. It is only N=1 but it is consistent with the idea that conventional medicine and pharmaceutical companies may be very wrong about the role of lipids in the human body.

Michael Babcock
Guest
Michael Babcock

Meanwhile, back in 2003 Uffe Ravnskov wrote:

High cholesterol may protect against infections and atherosclerosis | QJM: An International Journal of Medicine | Oxford Academic
https://academic.oup.com/qjmed/article/96/12/927/1533176

Karen
Guest
Karen

Great post!

Weekly Link Love — Edition 35 – SPOOKY FAST HOSTING NEWS
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[…] Article I found interesting: LDL and the Immune System. […]

Stephen
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Stephen

Great article. Iam assuming this is why people on a LCHF lifestyle are less prone to get sick.