Cholesterol Story Part I
Cholesterol Story Part I
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Cholesterol Lipid Hypothesis Part I
Is cholesterol really the problem? Or is cholesterol, at least in part, responding to inflammation, dysbiosis, infection, genetics, and the metabolic environment in which it finds itself?
Why do we need cholesterol in the first place? Is the cholesterol we eat the issue, the cholesterol our bodies make, the number of lipoprotein particles carrying it or genetic differences in the receptors responsible for clearing those particles?
The answer, unsurprisingly, is complicated.
Over the next several articles, we are going to unpack these questions and try to understand what actually drives cardiovascular disease.
Coronary artery disease, or atherosclerosis, is the disease process underlying most heart attacks.
Here is an excellent description of the term:
“The etymology of atherosclerosis derives from athero, meaning a gruellike substance, and sclerosis, meaning a hardening.” (Link)
That “gruel” consists of oxidized sterols, lipids, cholesterol, macrophages, calcium, fibrin, and other cellular material accumulating within the arterial wall. Influenced by multiple risk factors, this process can begin surprisingly early in life, infancy, and progress silently for decades before a plaque narrows an artery, erodes, or ruptures and produces an ischemic event such as a heart attack or stroke. (Luka et. al. 2023)
When I was in medical school in the 1990s, the story seemed relatively straightforward: cholesterol causes heart disease, and lowering cholesterol reduces/fixes the problem.
The truth is considerably more complicated as witnessed by the persistence of death and disease despite medical interventions.
Are we barking up the right tree?
Lipidology, the study of lipids, lipoproteins, and their relationship to atherosclerosis, is one of the most challenging areas of medicine that I have tried to understand. Simply identifying an elevated cholesterol concentration and prescribing a cholesterol-lowering medication does not tell us the entire story of cardiovascular prevention, not even close.
There has to be more.
This subject is also personal for me. Cardiovascular disease runs through my father’s side of the family, and I have wanted to understand its root causes more deeply than I did when I first wrote about this topic years ago.
It matters to my pediatric patients as well. Atherosclerosis does not suddenly appear when someone turns 50. The biological processes that ultimately contribute to cardiovascular disease can begin during childhood, making early prevention enormously important.
To understand the disease, however, we first need to understand cholesterol itself. Cholesterol is not simply a harmful substance floating around the bloodstream. It is an essential molecule used to make:
· cell membranes throughout the body
· steroid hormones
· bile acids
· vitamin D
Without cholesterol, human life is impossible.
We obtain some cholesterol through animal foods, but the majority of the cholesterol in our bodies is synthesized internally, particularly by the liver. Dietary cholesterol generally represents a minority of the body's total cholesterol pool.
Plants do not contain cholesterol. Instead, they contain related molecules called phytosterols.
There is another important issue: cholesterol is a lipid and therefore cannot simply dissolve and travel freely through our water-based bloodstream.
It needs transportation. Enter the lipoproteins. I like to think of these particles as little cars traveling along our circulatory highways. They transport cholesterol and triglycerides from one place to another, delivering their cargo where it is needed.
Understanding these “cars” turns out to be critical to understanding cardiovascular disease.
Lipoproteins are complexes of lipid and protein whose major jobs include transporting triglycerides and cholesterol throughout the body. There are several types. Large triglyceride-rich particles such as chylomicrons might be thought of as buses. As triglycerides (energy stored) are delivered to tissues, other lipoprotein particles become progressively smaller and relatively more cholesterol-rich. Eventually we encounter the particle most people know by name:
LDL.
LDL is commonly called the “bad cholesterol.”
But LDL itself is neither a toxin nor an evolutionary mistake. These particles perform necessary biological functions.
The problem appears when the system becomes unbalanced.
The number of circulating atherogenic particles matters enormously. LDL particle number, LDL-P, is one way of estimating that burden. ApoB, which we will discuss later in this series, gives us another important way to assess the number of circulating atherogenic particles.
When large numbers of these particles circulate through the bloodstream, more of them have the opportunity to enter and become retained within the arterial wall. That retention is a critical early step in atherosclerosis.
So the question is not simply:
Is LDL good or bad?
A better question may be:
Why are there too many atherogenic particles, what is happening to them, and what biological environment are they traveling through?
Let us use an anthropologic lens.
Why Did Lipoproteins Evolve in the First Place?
This is where the story gets particularly interesting.
I have spent a large part of my career studying the immune system and intestinal microbiome, so I was fascinated when I began exploring the relationship between lipoproteins, immunity, and infection.
Lipoproteins such as HDL, and to some extent other circulating lipoproteins, participate in our innate immune defenses.
Montecucco and colleagues described HDL as part of the humoral innate immune system, noting that proteins carried on HDL particles can contribute to antimicrobial defenses against pathogens. (Montecucco et. al. 2015)
In other words, these particles are not merely cholesterol delivery vehicles.
They participate in biology far beyond cholesterol transport.
That observation raises an intriguing question:
Could very low lipid concentrations sometimes be a marker or potentially a contributor to altered host defense?
The epidemiologic literature provides some interesting clues.
In 1998, Dr. C. Iribarren and colleagues at Kaiser Permanente reported an inverse relationship between cholesterol concentrations and subsequent infectious disease requiring hospitalization. Lower cholesterol concentrations were associated with greater infectious-disease risk. (Iribarren et al., 1998) In 2007, Shor and colleagues examined patients with LDL cholesterol concentrations below 70 mg/dL. Very low LDL-C was associated with several serious illnesses, including fever, sepsis, and hematologic malignancy. (Shor et al., 2007) Then, in 2019, Feng and colleagues studied more than 7,000 patients hospitalized with infection. Lower LDL-C concentrations were associated with an increased risk of sepsis and ICU admission. (Feng et al., 2019)
These studies do not prove that lowering LDL causes infection. Illness itself can lower circulating cholesterol, and underlying disease can confound these relationships. But taken together with experimental work demonstrating interactions between lipoproteins, microbial products, and innate immunity, they raise an interesting biological question worth exploring:
Is there a level, or a clinical context, in which very low circulating lipoprotein concentrations could influence host defense?
That is a much different question from saying that lowering LDL is inherently harmful.
And it brings us to another important distinction.
LDL-C Is Not the Whole Story.
Historically, cardiovascular risk assessment focused heavily on total cholesterol and LDL cholesterol.
Yet cardiovascular disease occurs across a wide range of cholesterol concentrations.
Ravnskov and colleagues argued in a 2003 review that the relationship between total cholesterol and cardiovascular mortality varies considerably by age, sex, population, and underlying disease. (Ravnskov et al., 2003)
Likewise, many people who experience myocardial infarction do not have dramatically elevated conventional cholesterol measurements. As Dr. Deepak Bhatt explained in the Harvard Heart Letter, roughly half of heart attacks occur in people whose cholesterol concentrations would traditionally have been considered “normal.” Other contributors, including smoking, diabetes, hypertension, obesity, physical inactivity, air pollution, genetics, and lifestyle, substantially modify cardiovascular risk. (Bhatt, 2015)
That does not mean LDL is irrelevant. Far from it.
It means LDL-C alone cannot completely describe an individual's cardiovascular risk.
Particle burden, genetics, metabolic health, blood pressure, smoking, insulin resistance, inflammation, environmental exposures, and other factors all contribute to the biological environment in which atherosclerosis develops.
So Where Does That Leave Us?
So far, we have established several important ideas:
1) Cholesterol is essential for human life.
2) Lipoproteins are not simply “good” or “bad".
3) They are essential transport particles with important metabolic and immune functions.
4) At the same time, an excessive burden of circulating atherogenic particles increases the opportunity for those particles to enter and become retained within the arterial wall, the initiating event in atherosclerosis.
And conventional cholesterol measurements do not capture the entirety of cardiovascular risk.
5) Finally, low cholesterol concentrations have repeatedly been associated with serious infection and critical illness, although these observations do not establish that low cholesterol itself is causative. This relationship is further complicated by the physiology of early life: infants naturally have very low cholesterol concentrations during the first months after birth, yet this physiologic hypocholesterolemia has not been clearly linked to a corresponding increase in severe infection. Interpretation is difficult, however, because infancy is also a period of substantial immune protection from maternally derived antibodies, breastfeeding, vaccination, and other preventive measures. Thus, the relationship between low cholesterol and susceptibility to infection remains associative and highly context dependent. (Holven et. al. 2023)
This leaves us with a much more interesting question than the one I learned in medical school:
What causes a normally useful lipoprotein system to become a driver of disease?
That is where we will go next.
Dr. Ravnskov and colleagues published an interesting review of the literature examining infections and lipoproteins. (Ravnskov et al., 2003)
In Part II, we will dig deeper into that relationship and continue building the story of how cholesterol, lipoproteins, inflammation, immunity, and atherosclerosis intersect.
To be continued...
Staying alive despite my genetic risks,
Dr. M
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