Cholesterol Code

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.

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