Is Cholesterol Corrupted by the Dark Side?

What is Cholesterol?

Cholesterol is a molecule that looks sort of like the Olympic rings in which one ring was knocked off. You can get some cholesterol from your diet, but the vast majority is made by your liver (and brain cells called astrocytes too, for that matter).

Your body makes cholesterol because it’s an essential precursor to hormones like testosterone, estrogen, vitamin D, as well as to the bile acids that help you digest fat. It’s also an essential component of cell membranes and a building block for the brain! Without cholesterol, you’d literally drop dead in an instant.

Your liver, and brain cells called astrocytes, make cholesterol because it’s an essential molecule for life. It’s a building block that forms hormones and cell membranes and the brain. Without it, you’d die.

Clarifying Terms: LDL, HDL, and Triglycerides

If you’ve ever gotten a basic cholesterol test, then you’ve also probably heard these terms: LDL, HDL and triglycerides.

The first thing you should know is that none of them are cholesterol. LDL is “low-density lipoprotein,” a particle containing cholesterol. And HDL is “high-density lipoprotein,” a particle containing cholesterol. Neither LDL nor HDL are themselves cholesterol, but little spherical molecular boats. These boats also contain a fatty fuel for the peripheral organs of the body (like skeletal muscles) called “triglycerides.”

LDL is not cholesterol. It’s a molecular boat that carries fat fuel and cholesterol building block to organs that need them.

Typically, it’s LDL that’s perceived to be the heart disease-causing villain. HDL is accepted to be anti-atherogenic (good) and high HDL levels are preferable. Triglycerides are fat fuel and low triglycerides in the blood are a marker of good metabolic health.

Aside: Why do Carbs Increase Triglycerides in the Blood?

Carbs are stored in your liver as glycogen. However, the carb storage tank is very small and usually remains relatively topped off. But your body isn’t going to just waste carby fuel that you so graciously provided it. Thus, it needs to store the carbs in another form: triglycerides!

De novo lipogenesis is the process by which carbs in the liver are turned into triglyceride fat. These new fat molecules can’t be stored well in the liver (although too many carbs can force this to happen, leading to fatty liver disease). So, the newly created triglycerides need to be shipped off in very low-density lipoprotein (VLDL) boats to sites around the body that can either burn or store the triglycerides (like those love handles and spare tire!).

The hormone, insulin, increases when you eat carbs. In turn, insulin increases the expression of genes coding for de novo lipogenesis proteins and increases the production of triglyceride-filled VLDL particles by as much as 300%!

So that’s why carbs, not fat, really spike your triglycerides.

And here’s the kicker: de novo lipogenesis mostly produces saturated fat — you know, that type that everyone says will clog your arteries. It’s ironic. The bread-and-butter of lowering saturated fat in your blood stream may just be forgoing the bread and enjoying the butter.

But don’t take my word for it. Human randomized controlled trials have even shown that trading calories from carbs for those from fat decreases fat and saturated fat in the blood even when protein and calories are controlled.

Furthermore, chronic consumption of refined carbs can leads to insulin resistance and hyperinsulinemia, which causes your liver to dump more fat triglycerides and sugar into your blood stream, which is awful for your heart! ( Shijie Li et al, 2010)

It’s ironic. The bread-and-butter of lowering saturated fat in your blood stream may just be forgoing the bread and enjoying the butter.

LDL - The Young and the Good Converted to the Dark Side

So, now that we’ve clarified our main terms, let’s focus on the controversial topic of LDL. Most people think it’s “bad cholesterol” but we don't entirely agree. LDL is Anakin Skywalker, a good guy who only turns bad if he is allowed to age and become corrupted. Let’s unpack that statement with an analogy that’s more relatable for those who don’t like science fiction.

LDL is like a boat that transports two types of cargo through the bloodstream: cholesterol and triglycerides (fat fuel) from the liver to organs around the body that need building blocks and fuel. LDL boats are created and shipped out from the liver “harbor” as young, big, and fluffy “good” molecules.

In a metabolically healthy body, LDL drops off its cargo around the body and then returns to port at the liver, where it’s taken back up. In this circumstance, only young, good LDL exists, and Anakin is never allowed to become Darth Vader. But this process can go horribly wrong if the sea is choppy and full of glaciers!

Now for THE critical question of this piece: What are these glaciers? (Otherwise put and mixing analogies, what is “the dark side”?) These glaciers that are ruining LDL (the "dark side" that's converting good LDL to bad LDL) is, in part, sugar.

Sugar — and diets rich in refined carbs and processed seed oils that contribute to oxidative stress and inflammation — damage LDL so they can’t return to the liver. LDL end up stuck in the blood, linger, and sink to the bottom of blood vessels.

The Science of Plaque Build Up

Nerd alert! You can skip this section if you’re not scientifically inclined, but we’d be remiss if we didn’t reveal that the situation is a lot more complicated than the dark side and sugar glaciers analogies can communicate.

Sugar increases in your blood when you have carbs, and these sugar molecules attach to the ApoB lipoprotein on LDL particles in a process called “glycation.” ApoB is supposed to act like a passport to let LDL back into the liver, but glycation breaks this passport, forcing LDL to linger in the blood. High sugar levels go hand-in-hand with oxidative stress, inflammation, and insulin resistance. They are all part of the same complex of metabolic disease pathology.

Oxidative stress and inflammation also cause damage to artery walls. Older and Vader-like small, dense and/or oxidized LDL particles can get inside the wall and eventually end up in a clot that we call a plaque. With continued oxidative stress and inflammation, the plaque can build until it breaks off and causes a heart attack or, more rarely, simply occludes the entire blood vessel.

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If this were true, when we would expect that pathologies like insulin resistance would be stronger risk factors for heart disease than LDL cholesterol, and that only small LDL could correlate positive with heart disease. In fact, this is exactly what we observe. In the most comprehensive study of cardiovascular risk to date, the Women’s Health Study, 28,084 women were followed for an average of 21.4 years, over which time over 50 clinical and metabolic markers of coronary heart disease were measured.

Insulin resistance, even absent of diabetes, was a much stronger risk factor than LDL cholesterol. Insulin resistance predicted a 540% increase in heart disease risk as compared to only 38% for LDL. Plus, when the researchers looked closer, it was only the small LDL that drove the risk, and small LDL itself associated with insulin resistance. These and other data are consistent with the idea LDL is not the root cause of the problem. It’s the scapegoat. Insulin resistance is more likely the problem and insulin resistance is improved on a low carb diet.

In fact, it gets even more complicated still. There’s speculation that damaged small, dense and/or oxidized LDL doesn’t actually get into blood vessel walls from the inside, or lumen, of the vessels but from the outside. Some evidence suggests that oxidative stress and inflammation inside blood vessels cause the small “vasa vasorum” vessels that themselves supply blood vessels to grow inward and deposit LDL cholesterol from the outside ( Subbotin V. 2016).

What Causes Heart Disease: Oxidative Stress, Inflammation, and Insulin Resistance

The point is this: LDL doesn’t cause heart disease (at least, there is no evidence suggesting LDL is sufficient to cause heart disease), the “metabolic circumstances” of oxidative stress, inflammation, and insulin resistance do. That said, high LDL can potentially exacerbate heart disease in those who are metabolically unhealthy. And…

Unfortunately, about 88% of Americans have at least one of the markers of metabolic syndrome ( Araujo J. et al. 2019)! The features of metabolic syndrome, which indicates poor metabolic health and confers an increased risk of obesity, diabetes, Alzheimer’s, other dementias, cardiovascular disease, and so on, include:

• (i) high waist circumference
• (ii) high fasting glucose
• (iii) high blood pressure
• (iv) high triglycerides
• (v) low HDL

Clinical criteria aside, the point we are trying to make is that the “metabolic circumstances” of oxidative stress, inflammation, and insulin resistance that cause metabolic syndrome at the molecular and cellular levels (the dark side, if you will) are increasingly becoming the population norm. Therefore, is it really any surprise that LDL levels are correlated — in some, but not all epidemiological studies — with heart disease? It doesn’t surprise us. Plus, correlation does not show causation. And, when you look at LDL (and total) cholesterol in context, LDL’s villainy is diminished.

LDL in Context - What to Look for on a Lipid Panel

When HDL is high and triglycerides are low — a marker of good metabolic health — LDL levels likely become less relevant. For example, one study found that if HDL was high (above 57 mg/dL) and triglycerides were low (below 97 mg/dL), incidence of heart disease was about 5%, irrespective of LDL levels (above or below 170 mg/dL). But, if HDL was low and triglycerides were high, incidence of heart disease jumped to about 12%, again, irrespective of LDL levels ( Jeppesen J. et al. 2001).

An easy number to remember is if you can get an triglyceride/HDL ratio of 2 or below (1.7 or below if you want to get technical), you get a gold medal (you placed in the cholesterol Olympics, wink)! Furthermore, analyses that “subfractionated” LDL into young, big, healthy “Anakin” particles, and old, small, dense “Vader” particles, reveal that it’s only the small, dense particles that are associated with cardiovascular disease ( St-Pierre A. et al. 2004,  Hoogeveen RC. et al. 2014, Dugani S. B. et al, 2021).

Cholesterol & triglycerides on a high-carb vs low-carb diet. (Source: The New Mediterranean Diet Cookbook)

Cholesterol and Lipids Panel Dictionary

We’ve indicated the markers that will be on a standard lipid panel. See if you can get a full subfractionated panel instead,  as in this paper. ( Norwitz et al, 2020)

Total Cholesterol (Found on a standard lipid panel)

A total of all the cholesterol in your blood. Alone, total cholesterol means little. You need to know what contributes to total cholesterol.

LDL Cholesterol (Found on a standard lipid panel)

The cholesterol contained in LDL particles. Often, LDL is not directly measured, but calculated (The Friedewald formula is LDL-C = Total Cholesterol − HDL-C − Triglycerides/5). Like total cholesterol, LDL cholesterol is most meaningful when you know how its broken down into its subfractions: large, medium, small, and oxidized.

LDL Particle Number

LDL is not itself cholesterol, but cholesterol carrying boats that also contain proteins and fat fuel for organs. Lower LDL particle number is typically assumed to be better, but high LDL particle number might not be dangerous in the context of low oxidative stress, low inflammation, and insulin sensitivity.

Large LDL

Large LDL is big, fully, young and healthy. It’s the LDL that released by the liver to traffic cholesterol and triglycerides as fuel to tissues that need them.

Medium LDL

As LDL hangs around in the blood, it starts to shrink.

Small LDL

(Important marker) Older LDL is small and dense. It is the small, dense (“Vader”) LDL that contributes to atherosclerosis and heart disease.

LDL Pattern (A/B)

(Important marker) LDL pattern refers to the distribution of LDL particles that contribute to your total LDL. It’s among the most important measures on a proper lipid test. Pattern A is good and suggests you have more large healthy LDL. Pattern B is bad and suggests you have peaks of medium and small LDL, suggesting the presence of oxidative stress, inflammation, and insulin resistance.

oxLDL

oxLDL is a marker of oxidative stress and, therefore, considered to be bad. Furthermore, it is only oxLDL that is recognized by immune cells called “macrophages,” which engulf oxLDL particles and then become “foam cells.” This is part of the cascade of events that leads to atherosclerosis. A caveat to this is that oxLDL should be interpreted in the context of LDL particle number. Each LDL has one ApoB. Therefore, oxLDL tends to run proportionally to LDL particle number. If your LDL-P is very high, it’s best to have a secondary marker of oxidative stress (e.g.s urine F2 isoprostane or blood malondialdehyde), against which to compare oxLDL.

HDL-C (Found on a standard lipid panel)

(Important marker) The cholesterol contained within HDL particles. Unlike LDL, which is secreted from the liver in one form and decreases in size overtime, HDL particles are born is many different forms that each have distinct functions. Some HDL is good at “reverse cholesterol transport" and helps to clean up arterial plaques, while other HDL has potent antioxidant potential. Aim for a value >40 mg/dL, although higher is typically better.

As an added nuance — I promise I’m not intentionally trying to confuse you — it’s worth noting that even high HDL “good” cholesterol isn’t always a sign of health. It is most of the time, but in patients with inflammation and elevated matrix-metalloprotease 9 (MMP9) levels, HDL can become dysfunctional. ( Sini et al, 2014)

Furthermore, inflammation and MMP9 levels may also cause dysfunction in the brain’s ApoE-HDL particles. ( Montagne, 2020) The morals of the story are (i) it’s about the insulin resistance and inflammation and (ii) there’s usually an exception to any “good” or “bad” rule on a single marker. Metabolic markers should be read in context.

HDL Large

(Important marker) HDL large denotes the number of large HDL particles in your blood. High large HDL particle number is a good predictor of low cardiovascular risk. A level >7,000 nmol/L is excellent.

Non-HDL Cholesterol

As its name suggests, non-HDL cholesterol refers to total cholesterol minus HDL cholesterol. While you might assume this value would be equal to LDL cholesterol, it’s usually a little bit higher. This is because LDL actually begins its life as very low-density lipoprotein (VLDL). Thus, non-HDL cholesterol refers to VLDL plus LDL and other remnants.

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Triglycerides (Found on a standard lipid panel)

(Important marker) Fat carried by LDL (and VLDL) as fuel for tissues around the body, like your skeletal muscles and heart. Low triglycerides suggest your body is using fat efficiently and are a marker of good metabolic health. Aim for a level <100 mg/dL. (Tip: cut carbs to cut triglycerides.)

ApoA

HDL particles contain the lipoprotein ApoA. Therefore, ApoA is another HDL marker. High ApoA is good.

ApoB

ApoB is the protein on LDL particles and also Lp(a). ApoB is assumed by many to be bad, but, again, context matters. If your ApoB is high but you are LDL pattern A with low small and medium LDL and high large, heathy LDL, high ApoB may not be as bad.

Lp(a)

This is another lipoprotein particle that looks similar to LDL, but with a tail. This tail helps Lp(a) contribute to the formation of arterial blood clots, also known as plaques. Therefore, you ideally want low Lp(a). Lp(a) is largely genetically determined, although there is speculation and anecdotal evidence that certain lifestyle factors may help to lower Lp(a). Here’s a great lecture with more insight on Lp(a)

LP-PLA2

LP-PLA2 stands for lipoprotein-associated phospholipase A2, which is an enzyme that plays a role in the inflammation of blood vessels. In most people, high LP-PLA2 is not good. If you have an extremely high HDL particle count then a LP-PLA2 might not be as bad as LP-PLA2 associated with HDL particles can be anti-atherogenic.

Non-Lipid Tests Dictionary

hsCRP

(Important marker) hsCRP is a general marker of inflammation. It’s not itself on a standard or subfractionated lipid panel, but hopefully your doctor will order it. Low hsCRP is good. Ideally, you want a level <1.0 mg/L.

Insulin

(Important marker) Elevated fasting insulin suggests insulin resistance. Ideally you want you fasting insulin to be <5 uIU/L.

HbA1c

(Important marker) HbA1c is lets you know your average blood glucose over the past three months. You want a value <5.7% or, ideally, around 5.0%.

Disclosure

Especially for this topic, we feel it's important to emphasize that the above blog does not represent medical advice, nor the advice of a practicing MD, nor a consensus among medical experts. This blog was written as an education tool and in such a way as to engage our readers. There are many interpretations of a vast body of literature on cholesterol panels and heart disease risk. Herein, you have read one perspective. Be sure to consult your doctor before undergoing any lifestyle or medication changes.