Thread by @POhukainen

🚨 Watch out, time for another #cholesterol #tweetorial! 🚨This time we’re going to take a look at the very fundamental nature of cholesterol molecule. It has biochemical properties that make it 1) essential to life but 2) problematic in excess. So let’s get to it! (1/33)

First, as everyone can read in wikipedia or a high-school level biology book, cholesterol is used to make many things. It’s a good building block for certain hormones, cell membranes and bile acids. But why? (2/33)

The reason is this sturdy multi-ring structure that has many “corners” for attaching stuff. Depending on specific needs, different types of molecular side chains can be attached to this basic frame (3/33)

This means the molecule can be fitted with parts that make the whole package recognized by cellular receptors (chol as a hormone) or it can be made more soluble in more aqueous environment. The basic frame is only soluble in fat (more on that later) (4/33)

It’s a one-size-becomes-many -type of package. And not only that, it’s also a VERY strong molecule.

I’m talking *geologically* strong.

In fact, certain steroids with a cholesterol backbone are routinely used to identify ancient fossils! (5/33)

For example, a paper published in Science last year suggested that this little guy was one of the Earliest. Animals. Ever. It was confirmed as an animal because there was some 500 MILLION year-old cholesterol next to it!
science.sciencemag.org/content/361/64… (6/33)

So how do cells handle this geologically indestructible molecule? In a classic comprehensive review on the topic, Kai Simons (renowned expert in chol biochem) explains the main principles that haven’t significantly changed in 20y (7/33)

As pointed out, excess cholesterol is TOXIC to the cell so there must be a very tightly regulated homeostasis that regulates how much cholesterol is inside the cell at any given time. This means, there must be a constant balance between synthesis, influx and efflux. (8/33)

As a side note, “cholesterol toxicity” is a thing. It’s involved in many cellular disruptions, especially #atherosclerosis, and we’ll get there soon. For more, check out this review (esp tbl 1 for summary of mechs) ncbi.nlm.nih.gov/pmc/articles/P… (9/33)

Back to cellular homeostasis. Notice how there’s one particular type of pathway missing from the regulatory processes? For a reference, think of amino acids (AA), used to build important molecules. How are they DIFFERENT from cholesterol? (10/33)

Correct answer is the last. As mentioned before, cholesterol is MAD strong and there appears to be no significant degradation or metabolism in any eukaryotic cell - it may not even be possible. This is why the only way to get rid of chol is to excrete it through.. poop (11/33)

To be exact, in addition to bile acids, we also lose chol with intestinal and skin cells. Whole body chol balance remains an active area of research but degradation is not considered a part of it (some latest data: ncbi.nlm.nih.gov/pmc/articles/P…) (12/33)

Remember when I said that chol can be considered geologically indestructible? Well, there are ways to break it but evolution has given those tools only to some specific species of bacteria (13/33) ncbi.nlm.nih.gov/pmc/articles/P…

So let’s recap what we’ve learned so far:

👊🏼Chol is a versatile, important but crazy strong molecule
👊🏼Any excess is *toxic* to our cells so a delicate homeostasis must be maintained
👊🏼Tools are to regulate synthesis, influx and efflux - there’s NO chol degradation

(14/33)

This should already give you some pause: when your body produces something that it can’t break down, you should be very concerned about accumulating too much of it. Also, you should make sure you’re effectively getting rid of it.

But wait, there’s more! (15/33)

Since we’re in the business of chol biochem, there’s one particular aspect of it that MUST be looked at. Another set of high-school level facts are that

🔬chol is fat-soluble
🔬you are mostly water
🔬oil and water don’t mix
(16/33)

So what happens when this sturdy, non-degradable stuff exceeds it’s solubility? That’s right, it starts to precipitate. And oh boy, is that a nasty sight! Earliest report of this comes from Rudolf Virchow himself in “Cellular Pathology” published in 1863 (17/33)

In early 1900’s, pioneering researcher Nikolai Anitschkow described chol crystals in rabbits fed an atherogenic diet (more in this series: ncbi.nlm.nih.gov/pubmed/15102877). Note that crystals remain even after other signs of athero are gone (18/33)

In histological scale, these crystals were MASSIVE - visible through relatively primitive light microscopes! This is again caused by the molecular characteristics of chol. As it crystallizes, it *expands* academic.oup.com/eurheartj/arti… (19/33)

100y later and with modern microscopes, we’ve seen some thousand-fold smaller crystals in both animals and humans. And it’s a big deal: they’re small enough so that our immune cells try to eat them but end up in big trouble - they’re literally more than they can digest (20/33)

This has been shown in a very nice complementary set of papers published almost back-to-back in 2010:
journals.plos.org/plosone/articl…
ncbi.nlm.nih.gov/pmc/articles/P…
(21/33)

Some of the key findings are that chol crystals activate the same inflammatory signals in macrophages than do uric acid crystals (causing #gout) and asbestos. And just look at this magnificent pair of figs showing that cells are *actively* trying to eat the crystals! (22/33)

These are pretty big discoveries now widely replicated and extended. A 2016 review in NEJM summarized the pathological processes of these so-called “crystallopathies” and #atherosclerosis definitely makes the list: nejm.org/doi/pdf/10.105… (23/33)

There are several ways for chol crystal formation. Key thing is for local concentration to cross the precipitation threshold. This can happen in the arterial wall when #LDL particles fuse together - a widely studied process: ncbi.nlm.nih.gov/pubmed/11060340 (24/33)

Other ways are 1) formation *within* cells that have eaten a bunch of LDL particles and become foam cells, and 2) the sudden release of chol from a dying foam cell. In all cases, crystallization is much faster once there’s a “nidus” - much like with a rolling snowball (25/33)

A key question obviously remains: what if you already have some chol crystals in your arteries? That’s a tricky one! As alluded to earlier, many animal studies have looked at regression of atherosclerosis and it seems that the crystals just won’t go away (26/33)

There’s been one study suggesting that a compound called cyclodextrin could be able to facilitate dissolving some cholesterol crystals but this still requires a lot of confirmation and clinical trials: ncbi.nlm.nih.gov/pubmed/27053774 (27/33)

So there seems to be two known problems related to
small crystals

🔥 cause inflammation

larger crystals

💥 cause mechanical damage (rupture plaques etc)

And one BIG one for both

🤷🏼‍♀️ we don’t know how to get rid of it
(28/33)

So it’s probably safe to say it’s NOT a good idea to have ANY crystals in your arteries which is why early prevention of #atherosclerosis is key. This means making sure there’s as little LDL cholesterol in your blood as possible and for as long as possible (29/33)

In this thread, I’ve gone through ONLY the very basic biochemistry related to the inherent problematics of cholesterol. Population studies, genetics, drug trials, animal models, all support this data but they’re topics for later (30/33)

So to recap the key hits of knowledge of cholesterol biochemistry:

👊🏼Important but toxic even in small excess
👊🏼can’t be degraded in the human body
👊🏼insoluble in water, thus easily crystallized
👊🏼crystals cause damage and inflammation and can’t be dissolved (31/33)

Anyone who claims that cholesterol is “natural” and thus harmless is dangerously ignorant. Same goes for claims about it being a “soft” or “waxy” substance. Many endogenous molecules are tough, harmful in excess and need to be carefully regulated - you DON’T want too much (32/33)

To conclude, this is a thread about chol biochem. I won’t go to tangents about “French paradox” or any other general talking point, and attempts are deemed #whataboutism. As said, those are specific topics for another day. Thanks for reading this one! ☺️👍🏻 (33/33)