(Disclaimer: I am not a medical doctor or nutritionist. Please, be safe. Talk to a qualified health professional you trust before making important medically related or health-related decisions, especially regarding changes to your prescription regimen.)

Cholesterol: Not necessarily the demon it’s made out to be.

I recently had a conversation where the topic of cholesterol came up. They mentioned they had been afraid to eat eggs because of the cholesterol the yolks contain. This reminded me of my usual spiel of “clickbaity news articles twisting tenuous studies to make dubious if not entirely unsupported claims in their headlines”, but I realized something that gave me pause. I wasn’t entirely sure of the entire picture of cholesterol’s lifecycle; I knew of its cellular uses and its production by the liver, but not about where HDL and LDL “come from”.

So I looked into it. Below is a writeup of where this rabbit hole took me.

Cholesterol’s uses.

Cholesterol is needed by cells. The cell membrane is composed of both phospholipids (forming the general bilayer) but also molecules of cholesterol, helping the membrane withstand temperature fluctuations that would otherwise solidify or break apart the membrane. In addition, cholesterol is the precursor to the steroid hormones (e.g. testosterone, estrogen, progesterone) necessary for regular body function. No wonder then that when the body does not have enough cholesterol, it makes its own via pathways in the liver[1]. Of course, too much cholesterol (like too much of literally just about anything) is probably not good for you, but we can get to that later.

Cholesterol’s method of transport: lipoproteins.

OK, but if the cholesterol is made in the liver or consumed, how does cholesterol get to where it needs to go (which could be basically any cell in the body)? Ideally, through the pathway that circulates throughout our entire body: the bloodstream. But the blood, being mostly water, is hydrophilic and cannot normally transport hydrophobic molecules (like cholesterol or triglycerides).

How does the body get around this issue? Cholesterol and triglycerides get packaged together with proteins¹ to form lipoprotein particles or lipoproteins (LP). The protein characteristics allow the lipoprotein particles to emulsify with blood plasma and dot the bloodstream. These lipoproteins have different potential densities – the fewer triglycerides they’re carrying, the higher density they are.

A useful diagram from here (that we’re essentially going to walk through for the remainder of this section) is below:

Ingested cholesterol and triglycerides get packaged into chylomicrons (or “ultra-low density lipoproteins (ULDL)”, for a more provocative/familiar-sounding initialism) and enter the bloodstream via the lymphatic system[2]. As it circulates through the body, parts of the ULDL are “extracted” for use by different cells. Pieces of fat are cleaved off (with some taken in by nearby cells²) via the action of lipoprotein lipase, located on the endothelium of capillaries (where most transfer between tissues and blood occurs) [3]³. In the end, the remaining chylomicron remnants reach the liver, which recycles and repackages the constitudents into very low-density lipoproteins (VLDL).

This VLDL gets another pass through the bloodstream, where yet more fat is taken by lipoprotein lipase, eventually removing enough fat to become low-density lipoprotein (LDL), at which point (despite the name) it is dense enough to make it through the capillaries and be taken in by cells via receptor-mediated endocytosis[4]. The cells can then break it apart and supplement the cholesterol they have with the cholesterol provided by the LDL as needed. The “leftovers”, now mainly comprised of (relatively high-density) proteins and cholesterol, are spat back out as high-density lipoproteins (HDL). Some of the cholesterol (housed as HDL) is sent to endocrine glands to be converted into key steroid hormones, and the rest is recollected by the liver (to be reused later, or potentially be converted into bile).

OK, that’s great and all, but what about atherosclerosis?

Great question! We’re not actually sure what causes plaque formation [5] [6], but we have noticed associations/correlations which have led to the caution that high levels of LDL might be a problem.

What are some large risk factors that are under our control? Smoking. Lack of physical activity. Poor diet. (Some that aren’t so simply controlled include high blood pressure and diabetes.)

There is a leading theory that implicates LDL as the main culprit[7]. The idea is that excess LDL accumulates and oxidizes on the arterial wall, leading to the recruitment of macrophages, and an eventually pileup of necrotic cell mass covered by a waxy exterior (i.e., a plaque). What causes oxidation of LDL in vivo? A 2012 review[8] of oxidized LDL essentially says that we have no idea.

What might matter more for health are ratios.

The lifecycle hopefully makes clear that cholesterol isn’t inherently bad, and that presumably raw LDL count isn’t necessarily a strong marker for “healthiness” or lack thereof – for one thing, if LDL is a problem, there is a precursor in the form of VLDL not captured by the cholesterol count. And in fact, “non-HDL cholesterol count” seems to be a more informative measure than just LDL count [9]. Let’s not forget about HDL levels. From our discussion, we can guess that HDL levels could be due to a number of reasons:

1. Maybe the VLDL is not being cleaved by lipoprotein lipase. That could be due to already having a satisfactory amount of ATP, leading the cells that would otherwise “ask” for the lipids to say “Thanks, but no thanks”. (When the liver receives this excess fat, it doesn’t have much other choice but to send it to adipose tissue.)
2. Maybe there are faulty LDL receptors on cells.
3. Maybe the “repackaging” process into HDL performed by cells is faulty.
4. Maybe you’ve flooded the body with so much exogenous cholesterol that your cells have no need for many more, leading only a fraction of LDL (derived from VLDL) to become HDL.
5. Maybe hormonal dysregulation is leading to the consumption of a large amount of HDL (for their cholesterol) by the endocrine glands.

None of these sound all that great.

But let’s not forget – every person is different. So, too, are their metabolic demands. The desired cholesterol levels are determined by averages of tens of thousands of people – and often very distinct populations. For example, the main paper I can see describing empirical evidence for the relative information provided by LDL count vs. non-HDL count vs. non-HDL:HDL ratio was an observational study on roughly 30,000 Swedish people with Type II diabetes between the ages of 30 and 70[10]. Not quite a representative sample of the global population. Most of the guidelines I’ve read seem to rely on their authority rather than citing research papers. And fair enough – very few people would “check their work”, and the reputable sources I trust and have cited here (e.g. Mayo Clinic, Stanford Healthcare) have not claimed to know the cause of plaque formations or whether the risk factors are causal or just correlative. But it does make the curious mind feel let down.

But blindly pumping up HDL levels doesn’t necessarily work.

To throw an even bigger wrench into things, pulling some levers to increase HDL levels doesn’t seem to always magically improve cardiovascular outcomes – often because we don’t know for sure what else the levers do, and whether what we do know will happen (say, increasing HDL levels) will outweigh what we don’t know will happen. This ignorance can be deadly.[11]

In 2007, there was a clinical trial (named ILLUMINATE) for a new drug/antibody called torcetrapib, which inhibited the action of an enzyme called cholesteryl ester transfer protein (CETP), an enzyme in blood plasma that could cause the conversion of HDL to lower-density variants. Sounds like a prime target to boost the HDL levels of those with lower counts and presumably help prevent cardiovascular events, right? Well, the drug sure did increase HDL levels – up roughly 70%, in fact, along with a roughly 25% decrease in LDL levels!

What else changed by 25%? The risk of cardiovascular events. With a hazard ratio of 1.25, taking torcetrapib increased the risk of cardiovascular events by 25% per unit time compared to baseline. What about all-cause mortality? A hazard ratio of 1.58. With the trocetrapib arm being the more hazardous of the two.⁴

The trial was stopped prematurely. The review paper[11] concludes that “[a]lthough there was evidence of an off-target effect of torcetrapib, we cannot rule out adverse effects related to CETP inhibition.”

What really matters is a platitude: Live a healthy life.

I’d like to reiterate some of the big risk factors that are under our control:

Smoking. Lack of physical activity. Poor diet.

These risk factors have implications in so many cases of morbidity, mortality, and diminished quality of life in general that it’s kind of staggering. We even have direct causal evidence for some of these connections (e.g., smoking causing lung cancer).

These risk factors all have simple-to-prescribe solutions⁵ that require behavior change. What’s the issue then? Sadly, it’s the “behavior change” part that causes problems. We humans are pretty bad at that. And often it’s not (just) our fault – our environment or circumstances conspire against us⁶. Even for those with the technical means to change our behavior, and even armed with the relevant facts, you’re not going to get a conversion rate anywhere near 100% – anyone who has tried to convince a friend or family member to quit smoking can probably tell you that.

But the heartening thing is that people can change their mind, and change their behavior. And when they do that – and commit to it – miraculous improvements can occur.

References

URLs are linked inline with citations in main text. A list of the raw URLs used in this post follows:

1. https://doi.org/10.1007/s00109-002-0384-9
2. http://medcell.med.yale.edu/lectures/files/cholesterol.pdf
3. https://www.health.harvard.edu/heart-health/how-its-made-cholesterol-production-in-your-body
4. https://science.howstuffworks.com/life/cellular-microscopic/fat-cell.htm/printable
5. https://stanfordhealthcare.org/medical-conditions/blood-heart-circulation/atherosclerosis/causes.html
6. https://www.ahajournals.org/doi/pdf/10.1161/CIRCRESAHA.114.302721
7. https://www.nhlbi.nih.gov/health-topics/atherosclerosis
8. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3315351/
9. https://www.mayoclinic.org/diseases-conditions/high-blood-cholesterol/expert-answers/cholesterol-ratio/faq-20058006
10. https://www.ncbi.nlm.nih.gov/pubmed/23774274
11. https://www.nejm.org/doi/full/10.1056/NEJMoa0706628

Footnotes