Cholesterol Story Part 2

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Cholesterol Lipid Hypothesis Part 2

Cholesterol, Immunity, and the Gut

The hypothesis: Cholesterol and the lipoproteins that carry it, including LDL and HDL, are inherently useful and necessary. Problems arise when these systems become chronically unbalanced through genetics, lifestyle, inflammation, or some combination of all three.

From last week: the carrier lipoproteins LDL and HDL are ancient components of our innate immune system with important roles in host defense. Humans have long used these particles not only to transport fats and energy, but also to bind and help clear infectious material before it can do further damage.

Remember that our major lipoprotein “cars” include chylomicrons, VLDL, IDL, LDL, and HDL. Their primary job is to transport lipids around the body. Yet while dutifully carrying fats and cholesterol, these same particles also interact with microbial products circulating in the bloodstream. They can bind bacterial endotoxins and participate in their transport and clearance. (Harris et. al. 1993) (Vreugdenhil et. al. 2003)

Imagine bacterial cell-wall debris entering the bloodstream from somewhere in the body. An HDL particle may bind part of that material and participate in transporting it toward the liver for processing and elimination. Now imagine that the burden of bacteria and bacterial debris rises substantially. It is reasonable to ask whether the body might alter lipoprotein production and metabolism as part of its response to that burden.

Interesting.

There is also an evolutionary piece to this story. Certain genetic variants, including APOE4 and PCSK9-related variants, can affect the number and behavior of circulating lipoproteins. Some of these variants may have offered advantages in environments in which infection was a dominant cause of death.

Remember: persistent genetic variants are rarely best understood simply as “mistakes.” If a variant remains common in a population, there may have been circumstances in which it conferred a survival advantage.

My hypothesis is that some variants now associated with cardiovascular risk may once have been advantageous in a world dominated by infectious disease. For most of human history, infection was among our greatest threats. Sanitation, vaccination, and antibiotics are extraordinarily recent developments on the timeline of human evolution.

Now we need to switch gears and look at the intestinal microbiome.

These metaphorical lipoprotein cars can bind bacterial endotoxins and participate in innate host defense. Meanwhile, the intestinal microbiome contains trillions of microorganisms and an enormous reservoir of bacterial cell-wall components, including lipopolysaccharide, or LPS.

The work of Patrice Cani, Alessio Fasano, and others has helped establish that disruption of intestinal barrier function and alterations of the microbiome can allow microbial products to reach the bloodstream and contribute to systemic inflammation, sometimes described as metabolic endotoxemia. (Amar J. et. al. 2008) (Cani P. et. al. 2008)

Lipoproteins have binding sites capable of interacting with LPS and other bacterial endotoxins and helping shuttle them toward the liver for processing and eventual elimination. (Harris et. al. 1990) In an infectious environment, this is a highly advantageous survival mechanism. (Read et. al. 1993)

Are lipoproteins part of the immune response?

We can see this principle experimentally.

Imagine two groups of animals exposed to a lethal bacterial challenge with E. coli. One group is simultaneously given an infusion of protective lipoproteins. The lipoprotein-treated animals are substantially more likely to survive the infectious insult. (Harris et. al. 1993)

That observation changes how we should think about cholesterol biology.

During severe acute inflammation and infection, lipoprotein metabolism changes dramatically. HDL commonly falls, while triglycerides and other lipoproteins may rise. As the inflammatory state resolves, those patterns may move back toward baseline.

This is not random.

The mammalian system appears to have taken molecules already circulating throughout the body for energy transport and recruited them for additional roles in host defense. Redundancy as expected in human biology.

Consider a medieval warrior cut by a contaminated sword or a modern human with intestinal barrier dysfunction and excessive exposure to microbial products. Having circulating molecules capable of immediately binding potentially inflammatory bacterial material is biologically elegant.

It is not difficult to imagine circumstances in which having more of those particles available could have been advantageous.

That raises an important question:

When cholesterol rises, is it always the primary problem or can it sometimes also be part of the body's response to another problem?

Acute infection gives us a clue.

Meningococcal sepsis is one of the diseases pediatricians fear most because a previously healthy child can become critically ill extraordinarily quickly.

When investigators examined lipoprotein levels in meningococcal sepsis, they found an inverse relationship between cholesterol concentrations and mortality. Patients who died had substantially lower LDL levels. (Vermont et. al. 2005)

One biologically plausible explanation is that lipoproteins bind bacterial endotoxin and alter its interaction with the immune system. By buffering exposure to LPS and other microbial products, they may influence the intensity of the inflammatory response.

This does not mean that high LDL protects people from cardiovascular disease. It means that LDL participates in more than one biological system. That distinction matters.

After years of studying the human microbiome, I believe intestinal dysbiosis belongs high on the list of upstream contributors to chronic inflammatory disease. There is extensive literature linking alterations in the intestinal microbiome with chronic disease states. (DeGruttola A. et. al. 2016)

Now imagine a patient with chronic intestinal dysbiosis, impaired barrier function, and persistent low-level entry of microbial products such as LPS into the circulation. Diet is one major influence on this ecosystem.

The body would then be dealing not with a single overwhelming infection, but with a persistent low-grade inflammatory burden.

Under those circumstances, changes in lipoprotein metabolism may represent part of the body's response to that environment. (Manco et. al. 2010)

In other words, elevated cholesterol may sometimes be both a contributor to disease and a marker of the biology occurring upstream of it. That is an important distinction. In genetically susceptible individuals, elevated lipoprotein concentrations may reflect not merely a disorder of cholesterol metabolism, but the intersection of genetics, diet, inflammation, microbial exposure, and hepatic lipid production.

None of this means that elevated LDL should be ignored.

Quite the opposite.

High concentrations of atherogenic lipoproteins are strongly associated with cardiovascular events and play a causal role in atherosclerosis. Once the particle burden becomes excessive and persistent, the biology that may originally have been useful becomes maladaptive.

Based on the evidence, I do not believe elevated cholesterol should always be viewed as an isolated event.

It may sit downstream from a broader network that includes systemic inflammation, intestinal dysbiosis, chronic infection, metabolic dysfunction, diet, and genetic susceptibility.

Inflammation clearly alters lipid and lipoprotein metabolism. (Feingold et. al. 2015)

Autoimmune disease provides another clue. Patients with autoimmune conditions have substantially increased cardiovascular risk, reinforcing the intimate relationship between chronic immune activation and vascular disease. (Onuora et. al. 2022)

Later we will examine the Tsimane people, who offer an intriguing counterexample and help illuminate the relationship among infection, inflammation, lifestyle, and atherosclerosis.

For now, the important point is this:

Cholesterol is not biologically evil.

Lipoproteins exist because they perform indispensable functions. They transport energy, participate in immune defense, bind microbial products, and help maintain human physiology.

The problem arises when particle concentrations remain chronically elevated in an environment of metabolic and inflammatory dysfunction.

In some genetically susceptible individuals, lipoprotein production may increase while clearance through hepatic receptors and intestinal pathways is insufficient. Particle numbers remain elevated.

At that point, the concentration gradient matters.

Atherogenic lipoproteins increasingly cross into the arterial wall. The immune system recognizes retained and modified particles, macrophages engulf them, foam cells develop, and the inflammatory process of atherosclerosis begins.

At this point, the traditional cardiology model comes fully into view.

The upstream causes and the downstream vascular consequences are not competing explanations.

They are different parts of the same story.