If you look online, you'll often find YouTube videos talking about cholesterol that reach completely different conclusions. Why does this happen? Well, that's what this entire series I'm about to put out is going to be about.
But before we dive in, we need to understand a bit of the underlying science when it comes to cholesterol and heart disease. It lays the foundation for everything I will cover. So stick with me on this one.
And so cholesterol is frequently described as a purely pathogenic substance, right? A toxic agent responsible for the occlusion of arteries and the onset of cardiovascular disease. Or on the other side, it's sold as a harmless molecule that has been inappropriately villainized.
And like most things in science, it's never quite that simple because from a biological perspective, cholesterol is a critical molecule. We need it for human life. But it also plays a critical role in atherosclerosis.
So, how do we make sense of that? Let's dive in. So, first of all, we do have to talk about what cholesterol is.
Cholesterol is a critically important molecule, it plays a huge role in structural support, and it also makes your hormones like testosterone, cortisol, and estrogen. And you can get cholesterol either by the food you eat in your diet or you can make it from your body naturally. And the vast majority of cholesterol in your body is made by itself and synthesized by the liver through something called the Mavonlight pathway.
However, when we do get cholesterol from our diet, we absorb it in our intestines from a transfer known as the NPC1L1. So, like I said before, you can either make this, which is the majority of your cholesterol, or you can eat it in your diet. So, now that we know what this does and where it comes from, we need to understand how our body moves it in the body.
So, cholesterol can't just float in your blood because it's hydrophobic, meaning it doesn't mix well with water. And so it needs to be carried by something. And this is where I'll bring in my first analogy of the day.
We can think about a bloodstream like a river. So let's step back one second. Hopefully, this river analogy makes some sense.
And so, because cholesterol and triglycerides, which are fats, right, they're highly hydrophobic. They are entirely insoluble in the water-filled environment of blood. So, to overcome this barrier, the human body has designed a sophisticated transport system called lipoproteins.
These complexes act as biochemical vehicles or boats, packaging insoluble lipids into water-soluble particles. So essentially, the outside, you'll see in a second here, is Can react with the water, but the inside is where we contain all the hydrophobic stuff. And so then they can navigate and move into the circulation.
So, to get back to our analogy, we can think of lipoproteins as boats that are carrying cholesterol through the river, right? So, that's what we think about. And the fundamental structure of a lipoprotein is pretty much the same regardless of what lipoprotein type there are.
There are multiple types to talk about, but they all look the same. Each particle consists of a highly hydrophobic core, right? So the hydrophobic core is where all the good stuff, triglycerides and cholesterol, are.
Surrounding this core is an ampipathic, which means water and fat-loving outer shell. So, the outer shell can do both. It's composed of phospholipid monolayer, interspersed with different types of cholesterol as well.
Ones that are necessarily free, they interact better with water. That's we don't have to get too deep into that, but they also have specialized proteins known as apo-lipo-proteins. So, if you look at the image here, you can see we have that phospholipid core on the outside.
Inside where we have the hydrophobic stuff, and then we have these apolepiproteins interspersed on the surface as well. So, those are the proteins that are very, very important. And apolipoproteins are the proteins that are on lipoproteins.
That's kind of confusing. There's a lot of words going on there, but hopefully that makes sense. Structure in this outer shell allows the particle to remain buoyant and soluble in the plasma while shielding its hydrophobic lipid core from the aqueous environment.
So it lets it transport through the blood. Now, let's talk about the different types of lipoproteins. All of them carry cholesterol in some way, shape, or form.
But the way I think about it is there's typically a process of a much bigger And very buoyant particle that offloads some of its cargo, which leads it to shrink and become denser. That's the general pattern we're seeing. And this slide here shows the different types.
But for example, chylomicrons, they are the largest and least dense of all the lipoproteins, and these are synthesized exclusively in the intestines after a fatty meal is consumed, right? So they're actually so big that they need to be secreted into the lymphatic system before entering circulation. But when they get there, their triglyceride cargo is rapidly broken down, and their half-life is super short.
We're talking like 30 minutes here, so they're not hanging out very long, and so they're not around in the bloodstream for a very long time. Now, when we're talking about making our own cholesterol, though, we have a VLDL as kind of the first start. Essentially, this is the liver's equivalent of a chylomicron, if you want to think about it, meaning they have the largest size, the lowest density, and carry lots of triglycerides.
And their half-life is also pretty short, but this is anywhere from like one to three hours. And then, as VLDL, as it circulates around, they undergo continuous lipolysis or stripping away their triglyceride cargo. This results in intermediate remnant particles or something called IDL.
So that's kind of where it is. About half of the circulating IDL is either cleared, while the remaining half undergoes further. Breakdown by an enzyme specifically called hepatic lipase, condensing the particle into LDL.
So VLDL goes to IDL, goes to LDL. And LDL is often coconutly kind of called bad cholesterol, right? And that's not accurate.
I'm going to say that right now. It's not accurate. But it is the final downstream product of the VLDL IDL cascade.
And nearly. It has lost almost all of its triglycerides and it is small and dense and filled mostly with cholesterol. And the primary physiologic role of LDL is to deliver cholesterol to peripheral tissues, right, that require it for membrane synthesis or hormone production, something like that.
But critically, LDL particles have a dramatically longer half-life, approximately two to three days. And so this extended circulation time Is the central mechanism behind why they are so associated with atherosclerosis, right? So if they're around in the blood, they're more likely to get trapped in the wall and begin the process of atherosclerosis.
And then finally, we also have HDL, which is often labeled as good cholesterol, which is also not necessarily true, but HDL is the smallest and densest liboprotein. As it circulates, HDL orchestrates Reverse cholesterol transport, a vital process where it extracts excess cholesterol from the peripheral tissues, including inside of the arterial walls, and then transports back to the liver for excretion in the form of bile. And I know I'm saying a lot, but here let's talk about something called apolipoproteins again.
I mentioned them before, let's talk about them again. The lipoproteins can't function without apolipoproteins, right? They need these protein components because they do a bunch of things.
They have three primary functions. One, they stabilize the structural integrity of the particles outer shell. So, very important.
Two, they act as a specific ligand that bind to cellular receptors for particle clearance, meaning how do we get them out of there? And three, they serve as crucial cofactors that activate. or inhibulate circulating metabolic enzymes.
So we need these apolipoproteins. Essentially, they're telling these lipoproteins where to go, what to do. So we'll talk about it here.
So let's keep talking about apo-lipoproteins. Let's talk about ApoA and Apo-B. So we'll get APOA out of the way. Apo-A, those are important for HDL.
They are found on HDL molecules. ApoB are on all the other ones. And so, APOB, though, is by far and away more commonly talked about, probably because it's a little more important in terms of what we discuss about.
So, I want you to think about APOB as a permanent license plate or a boat identification number. However, as I mentioned, not on HDL, but it's on every other athogenic lipoprotein. What I mean by that is every molecule that could potentially cause atherosclerosis.
Chylomicrons, VLDL, IDL, LDL, LP little A, we'll talk more about that later. All those are technically potential to cause atherosclerosis, right? So all those though have some sort of ABO B. Now technically, chylomicrons have ApoB48, and that's their molecule and their protein they have there.
And all the other ones have ApoB100. And so They still have APOB, slight differences, but we can make note of that. In reality, though, chylomicrons, as we mentioned, are cleared so fast that the vast majority of ApoB-containing particles are APOB100.
And this is really, really important because this plays a big role in our clinical testing and new guidelines that we have. Because when you measure APOB in your blood, you are counting the exact number of atherogenic lipoproteins you have floating in that river. Think about that.
So, standard lipid measurement, they kind of usually measure LDL, right? But what they're measuring is the cholesterol content and not the lipoproteins themselves. And it's been shown that measuring the lipoproteins is a far more accurate measurement of risk.
When comparing just a regular cholesterol, right? So when someone says their LDL is 100, what does that actually mean? Well, they're measuring the weight of that cholesterol in milligrams per deciliter.
So now they're telling you essentially how much cargo is on the boats, but they're not telling you how many boats are there. Whereas ApoB is telling you how many boats are actually on the river, and that's actually more important. A little confusing there, I apologize, but hopefully that makes sense.
Next, we have a few more lipoproteins we need to talk about that aren't as widely known, but I want to mention them so we have a good understanding of how cholesterol is controlled in the body, right? So, typically, our APOB molecules are permanent. Meaning, once they are on there, they are on there until it's completely recycled there.
However, these next ones jump on and off the different lipoproteins and can be transferred back and forth. So, APOC2, we start with that, that activates an enzyme called LPL. And LPL, what that does is that offloads the triglycerides from these lipoproteins into your body's different cells so they can use that fat-free energy.
Essentially, we can think of this as a worker with a key to the cargo bay and helps you unload triglyceride. Then we have APO C3, which essentially acts as the brakes, and it's the counter-regulator to APO C2. It also acts on LPL, but it works by slowing it down and delaying the offload process.
So if you have too much, you're saying, hey, we got all we need, ABO C3 puts on the brakes. And then finally, we have APOE, like we mentioned before, where this is essentially the return-to-sender barcode. And the recycling of these lipoproteins typically happen in the liver.
And lipoproteins at the liver have APOE. They're much more likely to be brought up and recycled as opposed to those that don't have it. And typically the larger lipoproteins like chylomicrons and BLDL have more APOE molecules.
So as particles shrink into their final form, specifically LDL, they're left with only ApoB, and which has a much, much weaker affinity for the liver 's LDL receptors. And so Because of this, as I mentioned before, the LDL is circulating much, much longer. Now, the next question is: how do we know when we have enough cholesterol?
We're making it, we're bringing it in. How do we kind of regulate it? That's a great question.
And every cell has a built-in thermostat, involves something called the SR-EBP2 pathway. And without getting too deep in the biochemical weeds, because honestly, it's over my head. What you need to know is that if a cell runs low on cholesterol, essentially an alarm goes off and sounds and says, Hey, we need to take two actions.
First, it turns on an enzyme called HMG cholirreductus, which cranks up these cells. Internal cholesterol synthesis. And second, it builds tons and tons of LDL receptors on the outside of the liver.
And essentially, these receptors aggressively pull in APO-B-containing molecules to get more cholesterol into the cell. So taking a step back and say, hey, if we are running low in cholesterol, let's bring up the receptors to bring in more, or we can actually make more through the HMV cholera reductase. And so you may be asking, Jordan, why did you just bore me with all that?
Well, first of all, I'm very offended. That is not nice. But second of all, I did it because it's very important to understand all these pathways so we can understand how people are currently being treated for high cholesterol.
Big into that. So, you know, on that last slide I mentioned the thermostat. Well, we can trick our body into turning on the thermostat almost all the time by using different medications, or we can force your body to clear LDL by doing different medications.
And so that's really what it comes down to: how do we regulate it? Most notoriously, we'll start first with statins. Statins block the HMG choliereductase enzyme, so which blocks your body's internal synthesis of cholesterol.
When this happens, your body sends an alarm saying, hey, We're not getting enough, we're not making enough. It sends more LDL receptors to get that LDL out of the bloodstream. So that's a big one.
Coming from another angle, we have azetamide. So, azetamide blocks the NPC101 enzyme, which I mentioned, which we talked about before in the exogenous pathway. Essentially, it doesn't allow the cholesterol you eat to get into your body.
So that's really what it comes down to. And so once your body detects that, hey, we're getting less cholesterol, once again, another alarm set off and it builds more LDL receptors to get more of the LDL that it's circulating around. And then we also have the PCSK9 inhibitors, which are very clever.
Normally, the LDL receptors are broken down by a molecule called PCSK9. What these inhibitors do is they prevent that molecule from binding to the LDL receptor, which means the LDL receptor doesn't get broken down and stays on the liver surface longer and it helps clear a lot more LDL. And there are lots of other medications that can be used for lowering cholesterol, but I just wanted to use a couple of these big examples because they're the most commonly used medications we have and kind of set the foundation for how cholesterol is currently managed.
And so now that we understand the basic mechanism of how cholesterol moves to the body, let's move on to what the current thinking is as to how atherosclerosis starts in your body. And I think every once in a while you'll see someone talking about cholesterol like it's a plumbing analogy, meaning that cholesterol kind of passively coats inside your arteries. It's like a sludge in a pipe until you get heart disease.
Well, I'm here to tell you that is not correct, and that's way too simple. Atherosclerosis is an active biological disease. So, because these LDL particles are in the bloodstream for days, they physically crash into the artery wall.
That happens all the time, they're kind of hitting the artery wall, and every once in a while. They get inside that artery wall, and once they're inside, they can bind to tissues in there and get stuck. Now, much of today's online controversy comes from a disagreement over whether these APOB particles are sufficient by themselves to cause heart disease.
And we will cover that in future videos. But knowing that the retention hypothesis is the most current thinking, that's a very important place to start. And so Once an APOB particle is physically trapped in that sub-endothelial space, so the endothelium is the single lining inside of that blood vessel, it becomes isolated from all the antioxidants that are normally in your bloodstream.
And once it's in there, it's exposed to reactive oxygen species, and its lipid and protein components undergo severe oxidation, creating oxidized LDL. Which is not good. Spoiler.
Oxidized LDL is highly inflammatory and aggravates the endothelial cells, causing them to send a distress signal saying, hey, something's going on. And it calls these circulating immune cells, specifically monocytes, to that area. And then these monocytes squeeze through the arterial wall and become macrophages and attempt to clear up the toxic LDL.
And they do so by eating this. The cholesterol in these macrophages then. They essentially become engorged, right?
And they turn into something called foam cells. And these foam cells die and dump their toxic lipid content and cellular debris into the arteriole wall, forming a necrotic core. And this leads to plaque buildup.
And so We hear so much about plaque, right? And we care about plaque because if it builds up and it's unstable, it can break off, go further downstream, and cause a heart attack or a stroke. And so essentially, That was many weeks of lectures broken down into about 30 seconds.
So I hope you're still tracking. But essentially, what happens is we get something inside the sub-enotherap space, so underneath them. And we have this inflammatory reaction, and it kind of builds up and then eventually leads to atherosclerosis and potentially, you know, a heart attack if we have a Either enough blockage there or it breaks off and goes down the line.
So, hopefully, you're all right with that. Now, I want to circle back again and talk a little bit more about LDL versus ApoB. So, for decades, these standard blood tests measured LDL, and that's just the total weight of the cholesterol on glycoproteins, right?
So, just the total amount of weight. But as we just saw, Atherosclerosis isn't caused by the amount of cholesterol that's there necessarily, but it's much more correlated with the number of lipoproteins you get crashing into the wall. And so As we mentioned before, there's exactly one APO-B molecule on each atherogenic lipoprotein.
This gives us a much more accurate picture of the risk someone has for For developing heart disease. In this little animation, I have here, you have someone who has 100 milligrams per deciliter of cholesterol, since you have their LDL both sides, but you can see drastically different particle numbers. And so that's what we're looking for here.
We think particle number correlates much, much better with heart disease. And now, another reason why we like using AFOB is because it helps us when we have a situation called discordance. And so, discordance is a term we use when describing when someone has conflicting results in real life.
For example, Someone may have elevated LDL, but their APOB may be very low, or vice versa, where their LDL looks normal, but their APOB is very high. This is a situation we would call discordance. And this matters because it could affect the goals we have for someone when it comes to cholesterol.
And we can be inaccurate with our overall risk assessment. So specifically, in patients who have poor metabolic health, we tend to see this a lot. So when we have insulin resistance, the enzyme CTEP, so CETP, it swaps triglycerides into HDL, and then hepatic lipase shrinks them.
Doesn't really matter, but essentially, what we get is these small, dense, cholesterol-depleted LDL particles. And the semantics behind the whole equation aren't too important, as I mentioned, of what's going on. But what happens is you end up with millions of these tiny, dense LDL particles.
And because these cargo ships are almost empty, the total weight or the LDL looks normal or maybe low, saying, hey, looks good. So you get this situation, you go to your doctor, you get your blood test, and say, hey. Everything looks good, but in reality, if you check the ABOB, they have a massive amount of particles crashing into those artery walls, and you're at a much higher risk than your LDL would necessarily suggest.
And so, this is why we tend to think that particle count is better. And we've had massive studies looking at things like the UK Biobank that prove that when the two numbers disagree, your risk follows the APOB and not your LDL. And finally, there is one more bit of physiology I want to talk about here, and it's the concept of lipoprotein little A or L P little A. This is essentially a standard LDL molecule, but has a highly specialized and dangerous protein tail attached to it called the APOA, right?
Very clever there. And unfortunately, though, it's about 90% genetically determined, and so you don't have a lot of control in this. And we don't have a good way to treat it yet, but they're working on it.
But we care so much about it, not just because it's a little structural difference. We care because it's a super high-risk finding that can lead to early cardiac disease. We think it's so high risk because of three main things, kind of thought of as this triple threat.
What I mean by that is it's proathrogenic, pro-thrombotic, and pro-inflammatory. What this means is that You're more likely to get into your arteries, right? With LP little A, and when it's there, it's more inflammatory and also prevents your body from trying to break down clots that form, increasing risk for heart attacks and strokes.
And so that's why we care so much about it because you are at a much higher risk. For cardiovascular disease, if you have this, and I feel like this is a good place to stop. We could talk about this all day, and I have more content talking about this in much greater depth if you want, but we're going to stop here.
I hope you found this helpful as it will lay the foundation to help you have a better understanding of cholesterol. And what's going to come in the cholesterol series that I'm going to put out. And truly, thank you so much for listening.
I appreciate it. If you found this helpful, it means the world to me if you share this with someone. But that's going to be it for today.
Now, get up your phone, get outside, have a grace of your day, and we'll see you next time. This podcast is for entertainment, education, and informational purposes only. The topics discussed should not solely be used to diagnose, treat, or prevent any condition.
The information presented here was created with an evidence-based approach, but please keep in mind that science is always changing, and at the time of listening to this, there may be some new data that makes this information incomplete or inaccurate. Always seek the advice of your personal physician or qualified healthcare provider for questions regarding any medical condition.
