Lipids: What You Need to Know with Dr. Dayspring (Episode 2)

That's a great transition to the next thing I want to talk about, which is like lipids proper before we get to therapies because there's so much confusion. You know, you mentioned LDL and HDL. You mentioned APO. I don't think you mentioned A1B. We'll mention them here. You know, LP. And then there's all these other metabolic markers like fibrinogen levels, hscrp, homocysteine levels. A lot of people are confused about what these things mean. You know, what's the most important one? Is it total cholesterol? Is it apoa? And then where, where do like these other metabolic markers like homocysteine, hscrp, maybe that's how statins work, is inflammation, you know, all that kind of stuff. Could you kind of like, like I know I, I threw, I loaded your plate up. Right. For the next, you know, three hours. Right. But could you, like, as briefly as possible, kind of go through that whole thing?

Well, we'll try, of course, that would be an eight hour podcast type thing.

I've heard a couple, I've heard a couple of those. And so we're trying not to.

So we're not going to go there, but yeah. And the first thing is to understand when you have a disease you're trying to eliminate. In this case it's atherosclerotic coronary disease or atherosclerotic vascular disease, because you can get it obviously in arteries apart from your coronary tree. You have to understand what are risk markers and what are risk factors. So there's a subtle definition. Many of the things you mention are risk markers. They're not risk factors. Risk factors. You should have solid data that the particular thing you're analyzing is causal of the disease you're trying to eliminate. Basically the causal risk factors for atherosclerosis are, look, apart from gender, male gender is a little higher risk than women, so we can't do anything with that. Age is a major risk factor. Good luck trying to stop aging. But the ones that we can measure, smoking is a major risk factor.

My smoking, obesity, diabetes, like all day one.

Eating, Obesity is not a risk factor per se, but obesity is associated with risk factors and a bunch of risk markers. So at the end of the day, you're very concerned about obesity, to be sure. But there are obese people who somehow escape the more severe forms of atherosclerosis in every so with risk. Everything else that contributes to atherosclerosis is going to be in the risk marker. Category, to prove causality, you have to basically get to that by passing through three stages of proof. One is a ton of epidemiological proof. Now, as you know, they're mostly observational trials, which when you have 20 or 30 of them, they're pretty believable. But you still can't say it's because of all the confounding things that go into epidemiologic observational trials. The next thing would be randomized controlled trials, almost all of which are done with a therapy where you take a group of people who have similar risk factors, risk markers, and you decide this group is going to get a placebo and this group is going to get some action. Maybe it's a diet, tough to do diet, randomized controlled therapies, because you pretty much know what group you're in, so it's really not blinded. But then you have the pharmacological treatments which can be blinded, and you will prove, at least as a pharmacological agent, gonna reduce major adverse cardiovascular events or not. And then, as you know, in all of those trials, there's secondary and tertiary endpoints, and that's where they're looking at some of these, what things come into risk marker things ultimately. So in the randomized controlled trials, you can certainly prove that modifying certain biomarkers seem to reduce it. So all of the early cardiovascular trials were aimed at lowering LDL cholesterol. Ultimately, those of us in the lipid world knew LDL cholesterol is just the poor man's way of doing apob, or LDL particle concentration. But when they started testing LDL cholesterol, APOB wasn't even known, or you certainly couldn't order it if you're as a doctor. So those markers came in later in the game. So LDL cholesterol, hey, because cholesteramine lowered LDL cholesterol and it worked. Probably everything that lowers LDL cholesterol is gonna work. It turned out that way.

Let me stop you there real quick. So am I hearing you correctly that even if your LDL is like 160, 170, if it's possible to have an elevated LDL that's that high with a normal APO, you know, B, or elevate A1? What I'm hearing is that even with elevated LDL, if the APOB is lower or normal or optimal, that higher LDL is not really as much of a concern?

Yes, and we'll get to that. So the early trials to be co causal, epidemiological, the randomized control trials. And then in came the Mendelian randomization trials that they're Mother Nature's randomized trials where you can take people, analyze their genes, look at a biomarker and say, hey, people who have these genes are probably going to have this, the biomarker. Let's see, how long did they live? Did they have heart attacks? So all of a sudden you had genetic causality. And that's pretty much the most definitive way to say something is causal or not. And LDL cholesterol has entered that world of epidemiologic data. Randomized controlled data in Mendelian randomization trial. Ultimately, so did APOB when they went back and looked at it, because they could go back to all those trials and almost all of the randomized control trials that were looking at LDL cholesterol, the researchers were doing APOB2. So that data does exist. And they could go back and look at that and say the APOB is also causal. Now, we have several societies that have declared LinkedIn LDL cholesterol in APOB is causal for atherosclerosis. Triglycerides entered that group. But the data's a lot weaker on triglycerides, and they got it through the Mendelian pathway. There are certain triglyceride genes that are causal for atherosclerotic disease. Most of them are not, but some are. So H triglycerides is probably in the picture, something you better look at. Seriously funny. The HDL metrics, which are either HDL cholesterol or measuring its structural protein apoprotein A1, were not shown to be causal. And that really shook up the world a little bit because what is everybody measuring and putting high emphasis on HDL cholesterol. Not Many were measuring APOA1. Some were and were betting the house on that too. Now we know you cannot. And if you're ordering those tests, you should know what they tell you and what they don't. So the causality in the lipid world right now is APOB LDL particle count, which is an APOB. It's a different assay, but APOB is you're measuring all of the APOB containing lipoproteins, but 95% of them are LDLs. So APOB is really an LDO particle test. So those are your most superior tests that I wish everybody was doing, because then you wouldn't need any cholesterol metric, because in retrospect, it turns out total cholesterol was the first biomarker they're looking at. It proved to be. Hey, this is in the causal range, but it's a weak thing. Total cholesterol is just a very poor man's APOB test. If you came to me with a total cholesterol really above 250, I know when I get around to doing an APOB, it's going to be true. Total cholesterol alerts me to that. LDL cholesterol is a better predictor of APOB than is total cholesterol. Because total cholesterol, you're looking at HDL cholesterol plus LDL cholesterol plus V LDL cholesterol. But HDL cholesterol is out of the causal mix now. So that gives total cholesterol some weak variability. LDL cholesterol. Hey, you're just looking at the LDL particles. 95% of APOB is LDL particles. So LDL cholesterol. That's why it's important. Then they came up with this. Let's calculate non HDL cholesterol. It's a freebie. You take total cholesterol, a direct assay that's accurate, and you subtract from it HDL cholesterol and direct assay. That means nothing, but it's an accurate measurement. If I subtract HDL cholesterol, the cholesterol that we now know is irrelevant from total cholesterol. What's left? APOB cholesterol. Non HDL cholesterol is the best biomarker in a lipid profile of what your APOB level is.

So are you saying that having an elevated APOA1HDL is not protective?

No.

It's not protective.

No. And now why did we believe it was for so long? Because we were all preaching low HDL cholesterol. You're a dead man walking. I'm going to raise HDL cholesterol even though I have nothing but niacin, which ultimately proved to be a futile drug even though it raised HDL cholesterol.

Have you heard about the recent article put out about niacin dosing increasing heart disease? By chance, I've had several patients this past week send me messages about that.

I did see something. I looked at it personally. I believe it. And because I know the bad things that niacin does. Niacin? Totally. Even though we. The main reason we were drowning people with niacin was to raise HDL cholesterol. We now know it makes HDL particles dysfunctional.

It makes HDL particles dysfunctional.

So what we now know is HDL cholesterol. APOA1 is irrelevant, because it doesn't tell us what the HDL particles are doing in your body.

We have dysfunctional versus functional.

It's not a window. So as much as I blast it in the year 2024, looking at HDL cholesterol, or APOA1, HDL particles are incredibly important for your cardiovascular health and probably many other aspects of chronic disease health that you have. Why? Because HDLs don't carry lipids. There's 45 molecules of cholesterol in an average mature HDL particle. LDL particles carry 15 to 1800 molecules of cholesterol. VLDLs carry 5 to 6000 molecules of cholesterol. But what do HDLs, why are they the densest particle in a centrifuge? High density. They sink in a centrifuge because they don't carry lipids, they carry proteins. And it's the proteomics of an HDL particle that is brought to tissues. And if they're carrying good proteins, anti inflammatory antioxidant proteins, anticoagulant proteins, immunological proteins, they can do wonderful things. We have 28 times more HDL particles in our plasma than LDL particles. Remember an LDL particle count. If you are doing the nmr, as you mentioned, you're maybe happy if it comes around 1000 nanomoles per liter, 1100. That's an average, probably safe in most people. Allele particle count. LDL particles are reported in nanomoles. Now, if you're getting the nmr, you get an HDL particle count back. They're counting HDL particles in a very different way than Apoa1, which is faulty, but the HDL particle count is 38, maybe 40, 35. But it's not nanomoles, it's micromoles per liter. If I want to convert micro to nanomoles, I have to multiply by 1000. If your HDL particle count is reported to you as 38 micromoles and your LDL particle count is 1000, you actually have 38,000 HDL particle animals of particles that would tell you, God, we got quadrillions of these HDLs floating around, and we have distinct subpopulations of HDLs because each HDL can't carry every protein. They each carry a couple of proteins. We have groups of HDLs that do anticoagulant things. We have groups of HDLs that do antioxidant. We got HDLs carrying tumor things, antibodies that can fight carcinogens. And so you and I can't measure HDL function. There's no such thing as a total HDL functionality test. We have one or two things that you can order experimentally that check one aspect of what HDLS do. But we're never going to know what HDLS do until we do advanced proteomics coming but years away. So that's why HDLs are out of the picture. An HDL cholesterol level or an APOA one can tell you zero about the functionality of our HDL particles.

But the particle number, that can be helpful for protection if you have because.

NMR reports those have functional HDLs. But if you don't having a high HDL particle number, I can show you articles where They've measured both APOA1 and HDL particle count. And these people had very high HDL cholesterol. That means above 75-80mg of HDL cholesterol. And yet a bunch of them got coronary artery disease. And when they analyzed it came down to other proteins that the HDL was carrying.

I'd read some things where they, you know, obviously the HDL number in males and females is a little different. Optimal.

There's a gender difference like there is with HDL cholesterol.

But you get to a point where as it gets higher, it's more likely to have dysfunctional hdl. Does that hold true or is that still.

There's just no way to predict. There are people with very low HDL cholesterol. Now, most of them are at risk for atherosclerotic heart disease. And I'll tell you, has nothing to do with their low HDL cholesterol. Low HDL cholesterol is a signal that something else is floating around and that's what's causal. Turns out to be guess what apob. The first thing you should do if you see a person with low HDL cholesterol before you say, oh my God, you're at risk for some cardiovascular complications. Measure apob. And if it's normal, you can pretty much ignore their low HDL cholesterol unless it's extreme Low HDL under 20. That could be a certain genetic disorder. But if it's in the 30s, virtually all of them will have a high APOB. All those early studies, Framingham, Mr. Fit, you name it. Which suggested to us that low HDL cholesterol is so dangerous they never adjusted for apob. Once we have gone back and done that, now HDL cholesterol disappears as a risk factor and HDLP emerges.

And where do you. From a clinician's perspective, because I'm ultimately a Clinician, that kind of information, where do you find that? Is that going back to like, is that in one of your lipidology journals that comes out or is that just you're in, you're still self studying, self learning and you're digging into stuff.

All I can tell you is self learning is a lot easier than it was in my day where I had, you know, spent hours in libraries in stacks. There was no Internet where I could look up stuff real quickly. So it was a lot of unnecessary reading and reading things I couldn't understand because I wasn't a laboratorian or deep read. So but now there are great textbooks. You can understand this stuff very rapidly. So maybe you buy one textbook, Valentine's Quiddervich and when you understand lipids, you can buy the therapeutic lipidology textbook or even those textbooks would ultimately get to therapy and you will understand. Here's. And this came out in 1960s in a five part treatise in the New England Journal of Medicine. Been around a long time. I don't remember the New England Journal ever publishing a five part treatise on anything. But it was done by the guys working at the nih. They published five heart Lipid Disorder or Understanding Lipids. And all you have to know about that five part thing was they said and they knew it in 19, they knew it in the 50s, but they're publishing this in the mid-60s. We have to transfer our knowledge from lipids and start analyzing lipoproteins. Atherosclerosis is ultimately the end of the day. It is a lipid mediated disease and it's one lipid called cholesterol. But lipoproteins is what traffics lipids in our bloodstream. So if lipids are causing a pathology in anything outside of the brain, because what's floating in lipids in your bloodstream has zero to do with the brain. The brain's got its own lipid and lipoprotein system. But the lipids get trafficked in the bloodstream inside of lipoproteins. And unless a lipoprotein either invades a particle and dumps its lipids or is delipidated by a certain lipid receptor receptor, what the lipoproteins are carrying is never going to get into any tissue. We know the arterial wall lipoproteins have a way of saying it's time for me to leave plasma. The liver didn't clear me, so I'm going to invade a tissue. And the most common tissue that lipoproteins carrying cholesterol invade that it's going to result in a disease is the walls of our arteries and it's the apob particles that invade, leave plasma, invade the artery, get trapped, and through a multi, multi, multi step process, you have cholesterol plaque, you have atherosclerosis.

So what are, what are some triggers, like before? I also want to ask you about LP because we haven't talked about that.

Yes, that would be the third thing I was going to do on the causal list.

Like what are some triggers that trigger the lipoprotein carrying particles to invade me here at this part of this. Maybe, maybe that gets into the dysfunction, maybe it gets into some other issues like that.

So every little avenue you talk about is, oh, now here's the 42 steps, but we'll dumb it down a little bit. So first of all, it is cholesterol deposition in the artery wall. If you do not have cholesterol in your artery wall, you do not, exclamation point, have the disease called atherosclerosis. So it is cholesterol that is the causal agent for atherosclerosis. But your artery didn't oversynthesize cholesterol. So obviously there is what I call an illegal dump job of cholesterol in your artery wall over years, resulting in plaque. The illegal dumping didn't occur last week, it occurred for the last 20 or 30 years. So how is cholesterol a hydrophobic lipid? How are triglycerides a hydrophobic lipid trafficked in your plasma? Because they are. If nobody was bringing triglycerides to your muscles, you would have no fatty acids to oxidize and create ATP. Try moving a muscle without ATP. So triglycerides have to be brought to muscles, but cholesterol, here is what is not taught. Has to be brought to almost no tissue in your body, because every tissue in your body. Even if we wanted to talk about the brain, which has nothing to do with your plasma, lipids, synthesizes all the cholesterol molecules it needs. So your what is the primary carrier of cholesterol in the plasma? It's the APOB particles, 95% of which are LDLs. So it doesn't take much imagination to realize it's the apob particles that carry the most cholesterol, that if they crash your artery wall, they're going to initiate atherogenesis. And the most common apob particle is LDLs. So we could know how many LDLs are floating in your plasma by two and only two tests. If you want a measurement of it. I don't want to guess it anymore by using LDL cholesterol or non HDL cholesterol. And that would be APOB or the LDL particle count, which for decades was only brought to us through nuclear magnetic resonance. But Quest probably 10 years ago brought a secondary apparatus that it can count APOB particles and it's called ion mobility transfer. The first I got here, a little history here. The first back in the 30s way we knew there were particles that carrying cholesterol because it used to be thought cholesterol was like potassium, just a solute in the blood that floated around by itself. In 1930s electrophoresis was invented to separate proteins to let's study proteins. And they discovered alpha and beta proteins and gamma proteins. They did an electrophoretic with a more advanced type of electrophoresis in 1940 when they separated the alpha and beta proteins, they looked at other things as good God, there's cholesterol associated with the beta proteins and there's cholesterol with the alpha. Twenty years later, the alpha proteins turned out to be your HDLs. The beta proteins turned out to be the VLDLs and LDLs. We no longer used alpha and beta lipoproteins. It was now we can put them in a centrifuge, high density, low density, and that's where we are today. Many of us still use the beta lipoprotein because it is APOB that is, it was only the 70s when somebody said hey, there is APOA1 and APOB. Let's separate them and measure, analyze them and sequence them. So the APO proteins came much later. So it is the APOB particles that leave plasma and into the artery wall. Why do they leave plasma? To create pathology. Evolution didn't want it that I guess for most of the human existence, evolution didn't care about atherosclerosis because you were going to die or something long before you were going to hit age 60 or 70 and have a heart attack or stroke, some infection or trauma was going to take you out. So ultimately it did become important. So we now know once your APOB concentration, your LDL particle concentration crosses a certain threshold which we can measure, they will leave plasma and start inverting the artery wall. The higher that level, the more that will leave plasma and invade the artery wall and the sooner you will get atherosclerosis. Depending on the intensity of your escalation of apob, that should make sense. But what is the cause of high APOB in plasma? And it's One thing, your liver's function is to grab circulating apob particles and pull them into the liver. Because what are the apob particles delivering to the liver that the liver must have for a crucial thing that it does? They need cholesterol. So the liver can de novo synthesize cholesterol and it's good at it, but it cannot synthesize all the cholesterol it needs. So it must remove cholesterol carrying particles or delipidate them in plasma to get the cholesterol pool that it needs. So how does the liver hit LDL particles or APOB particles? VLDLs. Because remember, once a VLDL delivers triglycerides to the muscles, its primary function, it's only carrying cholesterol, which it delivers to no cell in your body. The LDL is out there floating around for several days full of cholesterol, which it doesn't deliver to any cell in your body. The VLDLs and LDLs are waiting for the liver to express a couple of receptors, mostly the LDL receptor, which is stoichiometrically designed to recognize the apob peptide on these particles. So the LDL receptor grabs apobio, internalizes that particle into the liver. It goes into an endosome that turns into what we call a lysosome that digests the particle. And whatever was in those particles, mostly lipids and a big protein, gets dissolved the protein into amino acids, triglycerides, any that are left, fatty acids and glycerol cholesterol ester into free cholesterol and more fatty acids. And then the liver uses those molecular lipid species for whatever it wants to do. But why does the liver need cholesterol? What are the three major things the liver needs so much cholesterol for? The one should be obvious, but you got to go back probably to college physiology, early med school, nursing school physiology. You need to make bile acids in the liver and send them down to the gut if you would like to absorb a lot of things. Malnutrition, if you don't send bile acids down, cholesterol gets converted to bile acids, by the way, and then bile acids are reabsorbed at the ileum. And most are reabsorbed and reused, but some are not. If bile acids are not reabsorbed at the ileum, they go out your rear end into the toilet bowl. That is the primary way the human body gets rid of cholesterol, changes it to a bile acid, and do not reabsorb the bile acid in the ileum. And there Are forces at play to determine how much reabsorption you get. Number two. What does the liver do with cholesterol? People are going to be shocked if I ask anybody. Tell me what your HDL cholesterol is, and they'll give me a number. Where did it come from, the cholesterol that's in an hdl? Oh, it pulled it out of my artery wall. Well, maybe if you have atherosclerosis, it pulled a few molecules of cholesterol out of your artery wall, which have zero influence on your total HDL cholesterol level, Even though that may be a good process, pulling some cholesterol out of your artery wall. But it doesn't contribute to your HDL cholesterol. So where does most of your HDL cholesterol come from? 40% of it. The liver lipidates your HDL particles. There's a receptor, the scavenger receptor B1, that pumps elk cholesterol ester into HDLs. There's another receptor called ABCA1, which pumps out free, unosterified cholesterol into your HDLs. So your HDLs fill up at least halfway with cholesterol. They have another source of cholesterol, which I'll tell you about. Two other sources. HDLs make a pit stop at your small intestine. Your intestine is absorbing cholesterol from your gut, and it makes. It absorbs free cholesterol. And some of that free cholesterol we all think is going into a chylomicron and going to be brought into the circulation. A large part is efflux into HDL particles that make a pit stop at the blood barrier to the side of an enterocyte. So a significant amount of your HDL cholesterol comes out of your gut. A clue for any practicing physicians or laymen listening to this. If you have high LDL cholesterol but also high HDL cholesterol, you might be an overabsorber of cholesterol. Because if the intestine is over absorbing cholesterol, it got to get rid of it. Because too much cholesterol will kill that enterocyte. It puts some of it in an hdl. Your HDL is filling up with mostly liver cholesterol, maybe 20, 30% from the gut. Where does the rest come from? HDL particles can stop at any cell in your body that says, I have too much cholesterol. Too much cholesterol in any cell will crystallize and kill that cell. So evolution has given our cells great power to efflux cholesterol but it has to efflux cholesterol to a cholesterol acceptor protein, APOA1. So if I'm a no cell or a kidney cell that says I got too much cholesterol, it's going to crystallize and kill me. I upregulate ABCA1, a membrane cholesterol efflux protein, so that free cholesterol can come out of the cytosol of the cell and join into a baby HDL particle. The HDL pulls unwanted cholesterol out of cells, a source of cholesterol. The HDL then has an enzyme that rapidly esterifies the free cholesterol to a fatty acid. Cholesterol ester goes into the core of the particle. Hydrophobic makes the particle get bigger. The amount of cholesterol being effluxed out of your peripheral cells is trivial. It contributes a little bit, but not much, just like pulling out of your artery wall, because most cells are not overproducing that much cholesterol that they have to get rid of. But it is mother Nature's protective way to avoid cellular cholesterol toxicity. So where is the other significant part of your hdl? Cholesterol has come from? Wow. If an HDL now has accepted cholesterol and is a big, fat, large, mature hdl, it can go back to the liver, be delipidated, it can go back to the intestine, be delipidated. But before it gets delipidated, it's got that final source of cholesterol floating around. There are, like I said, 28 times more HDLs than LDL. So they crash into one another. And once they align, there's a protein carried by HDL that gets activated. It's almost, it sticks straight up and it's almost like a needle sticking off of the HDL and it penetrates the LDL particle. It's a lipid transfer protein. So the cholesterol ester, which your HDL is full of in its core, gets transferred out of the HDL into the LDL to make room for the cholesterol in the ldl. The LDL says to the hdl, wait a minute, if I'm taking your cholesterol, you have to take my triglycerides. So it's a one for one swap. Cholesterol exits, DHDL goes into the LDL triglycerides, which is about 20% of the core of an LDL. So an LDL has a lot of triglycerides and HDL has none, so to speak. But before you Know it. All of the cholesterol in the HDL is now in an ldl. Oh, and you mean the good cholesterol suddenly became bad cholesterol? That demonstrates the absurdity of those terms. So the LDL says, thank you, hdl, I'll bring it back to the liver and save you a trip. The primary function of LDLs in our plasma is to return cholesterol to the liver as a major part of the reverse cholesterol transport process. Now, look, it's a combination. HDLS pulled it out of the cells. Without that, cells would be dying of cholesterol excess. But the HDL sent to the LDLs, you complete the touchdown. It's like a forward pass to a tight end. He carries the football into the end zone. The LDLs carry the cholesterol that used to be in the HDLs into the liver. That is called indirect reverse cholesterol transport. 40 to 50% of reverse cholesterol transport. By the way, the HDLs can also be delipidated at the liver. That's direct RCT. So total RCT reverse cholesterol transport is direct HDL mediated, indirect LDL, and a little bit VLDL mediated. You have to remove the APOB particles from plasma and. And that is the sole bailiwick of LDL receptors.

So let's transition to the lp, which you said is, I think, the third causative agent for disease.

Atherosclerotic disease. Yes.

And so where does that fit into everything that you just mentioned? Or is it its own creature that has a different.

No, it's its own creature, but it's a lipoprotein. So they were right in the 1960s when they said atherosclerosis is a lipoprotein mediated disease, and it's because of what lipoproteins carry, that disease results with the regular APOB particles. It's the cholesterol they're carrying, has nothing to do with the triglycerides they're carrying, or certainly not the APOA one that they're carrying and everything. By the way, the last part of my Jacob story was clearance of APOB particles is mediated by the liver manufacturing and expressing at its plasma surface an allele receptor which grabs the APOB particles and pulls them in, completing the indirect reverse cholesterol transport process. If, for whatever reason, your liver has not manufactured enough LDL receptors or guess what your plasma APOB level is going to be, it's going to be high, then where are the particles going? Into your artery wall? So the. If you Want to? Yes, cholesterol is causal, but it's really the APOB particles carrying a cholesterol. They go hand in hand together. So they're both causal. But what generates APOB concentrations above the safe threshold is dysfunctional or lack of enough LDL receptors or also their cellular half life. The longer they live, the better. So LDL receptors are the reason that we all have high apob. We don't have enough LDL receptors. We can increase LDL receptors through lifestyle, nutrition or drugs. And that's how we lower APOB. What is LP? Well, LP is a marriage of an LDL particle. An LDL particle is a collection of cholesterol ester, 80%, 20% triglycerides, an entire surface full of phospholipids, a semi soluble lipid and some unesterified or free cholesterol. That's what an LDL particle is. But it is soluble because it's wrapped by a gigantic protein. A protein that binds to lipids is called an apolipoprotein. So there is one basically apoprotein, which is called an apolipoprotein when it attaches to cholesterol, and that's apolipoprotein B. It's the biggest apoprotein that we have, over 500 kilodaltons in our. If you are measuring molecular weights, so that's an LDL particle. LDLs come in different sizes in different core compositions, but they're a heterogeneous mixture that has densities in a centrifuge within a certain range. So how do I change an LDL particle into what? Yuri just asked me about glycoprotein linole. I just attached to the apob, the structural protein and ectopic protein. It shouldn't be there. And when I attach another protein to apob, I'm going to totally change the function of that LDL particle. Because all of a sudden it's not APOB that's determining the function of the particle, it's this other protein. So APO protein, little A. That nomenclature comes from the professor who discovered it, I believe 1963. Carrie Burr.

1963, yeah. Okay, long.

He was experimenting with lipoproteins and trying to find out what the heck's on these lipoproteins. So he's looking at a bunch of. He was exposing these particles to antigens and he was making the antigen. He was using rabbit syrup and he would throw in antigens in. And if an antigen stuck to something, he's identified something on a lipoprotein we didn't know existed before. And all of a sudden he's this antigen is sticking to, or this antibody is sticking to an antigen that's on some of the particles but not on all of them. What the heck is it? So he had a name it and he says, well, wait a minute, it's an antigen on this particle that the antibody is sticking to. I'm going to call it antigen a small case, not a capital A. So it was lipoproteins carrying a LP for lipoprotein and small A for an antigen. That's where the initial terminology, long story short, many years they find out, what the heck is this A. It's a protein much smaller than apob, but a protein nonetheless that we now know has incredible atherogenic properties. And if you attach it to an ldl, an LDL is basically atherogenic once it crosses a concentration threshold. But now if it's carrying something that might worsen its atherogenicity, oh my God. So who's got, who has the ability to make this apoprotein little A? Anybody's liver. Who has inherited the gene that tells the liver endoplasmic reticulum, the protein making apparatus to make a protein called apoprotein. If you don't have the gene, your liver can't make apoprotein, so you can't have LP particles. Now how do we get our blood types, mom and dad and we sort of combine our genes for that's called CO dominant inheritance and that's what LP is. So you get one LPA is the gene, capital L capital P, capital A in italics. When you're talking about a gene, the protein it creates, capital L, capital P, capital A, not in italics. Genes and proteins italics proteins, non italics. So if you inherit an APO little A gene from mom, your liver is going to produce too much LP if you acquire from dad, if you acquire from both mom and dad, you're going to produce two types of apoprotein little A because each APO little A creates a slightly different isoform of the APO protein.

Is there a functional utility for apo?

We're starting to understand. So now if your liver, you have the wrong genes, your liver is going to produce apoprotein little A your liver. Everybody has thought that LDL particles come from VLDL particles that lose their triglyceride. That's where about 60% of your LDLs come from. 40% of your LDLs come from DE novo production in the liver. So your Liver is shooting LDL particles all day long, 40% of your LDLs. So when the liver makes a primordial LDL particle, it's taking cholesterol, triglycerides, phospholipids, and it's wrapping them with APOB100. But if your liver is producing apo protein little A, it has an affinity for a certain segment of the apob. So here comes apo little A. Bingo. It attaches to apo B on the primordial LDL particle. Now your liver has produced an LP particle which the liver secretes. Now you have an LP particle floating in your plasma. So we know LDL particles are bad news if they invade your artery wall. But what if the LDL particles are carrying a passenger? What attributes of that passenger might do if they enter the artery wall? Well, for the longest time, because apoprotein A has great homology, that means it's very similar to a coagulation prote protein called plasminogen, which is involved with our clotting system, what's called fibrinolysis, getting rid of clots. But if you inhibit fibrinolysis, you keep clots. Not good. So looks the thought was, oh my God, apo little A, it's like plasminogen. It's a defective plasminogen. It's a clotting factor. The last thing you'd want to send into an artery wall is a protein that has clotting attributes or inhibits. So and there were other fact things in the coagulation system that it looked like apo little A had the ability to interfere with. So for the longest time, all of the pathology associated with LP was attributed to its thrombogenicity. We now know that it inhibits platelets, it affects tissue factor. So there is a lot of the probably coagulation disturbance associated with it, but it's taken a back seat to something else apoprotein carries to make this easier. Apoprotein A is a protein of a certain length. It could be long or short. But the segments of apoprotein little A are made up of loops of proteins called kringles. Kringles are just a bunch of amino acids, some that bind to each other. So it looks like a curlicue named after a Danish pretzel. You know, pretzels are curly looking things. So there is one kringle on the entire apo little a protein that has tremendous affinity to bind to what we call oxidized lipids, most specifically oxidized phospholipids. Phospholipids are the lipids that live on the surface of every cell in our body and on the surface of every lipoprotein because they're partly water soluble. That's why they're on the surface of cells that interact with plasma or lipoproteins. But if you start giving the person abnormal phospholipids oxidize people. If you don't know what oxidation is, ask a fireman. It means something's on fire. If you don't have oxygen, you can't have a fire. Oxygen fuels fire. Oxygen attaching to certain lipid moieties causes oxidation of lipids. Oxidized lipid moieties are incredibly dangerous tissue destructive, associated with any number of diseases. So if all of a sudden you have a protein that is a magnet for oxidized phospholipids, when it enters the artery wall, it's basically bringing a particle, it's on fire. So whatever inflammation is already going on in the artery wall thanks to the APOB invasion is now made 10 times worse. So it's a very pro inflammatory particle.

So I'm not hearing. Typically the way I think about things is when you hear a story like this, usually there's like a negative side and the positive side to having something. And so I'm only hearing downside to the apo. Yeah, lipoprotein little A. And it's an impact on the apob and how this is a pro inflammatory plasminogen like particle. Is there actually a benefit to this at all? Is there only downside?

You have to be a teleologist to answer that question. Why did evolution give us an LPA gene? For God's sakes? At one time in our evolution, was it good to produce a lot of apoprotein? And the answer, the thought is now that yes, at one time in our existence, it was good to have a lot of clotting factors because trauma was so prevalent in the early human existence. Falling down, getting bit, scraping yourself. People were bleeding all day long. So those who had a propensity to rapid clotting had survival. Nobody was worrying about atherosclerosis 40 years later. So having a clotting factor was probably good at a certain point in our evolution, but at a certain point it became deleterious. So all of a sudden there's been a loss of the LP gene. And so that's the. Who really knows, you know, now with the weight, we don't need a coagulation factor today in our blood yeah, but.

So with the way you described it, can you have. Is this possible? I'm just thinking here, having an elevated lp, but if your APOB is low, it won't have anything to attach on and so you mitigate some of that negative impact. Does it work like that or is that. Do you always have an elevated apob? If the LP is elevated?

In general, yes, because lp, the risk of lp, is related to its concentration in plasma. And we measure LP particles and basically you're measuring a tiny subsegment of apob LDL particles, so you can't separate apolo. So it's not like it's not impossible if you, you see, everything depends on what you consider a normal apob is. If we consider what for the average person is a good APOB might be 80, but it's carrying APO little A, that's probably a very deleterious APOB concentration and we might want to lower it in that patient. That's the novel thinking that's coming below. So whereas in General, an APOB of 80 isn't going to hurt most people, if it's carrying apolita, it is. And if your apob is in the stratosphere and it's carrying apolitically, both your LP is also in the stratosphere. So it is highly related to apob. The one last thing to figure where we now have dismissed a lot of the coagulation stuff or put it as a second reason LP is dangerous is because if it was such a bad clotting factor as one's LP goes up, why don't they get venous thrombosis? And they don't for years once they started analyzing that and the Mendelian study started to show that there's no venous thrombo thrombosis in these people. Well, holy crow. So it's an arterial coagulation bad news protein, but it's not a venous. Turns out it might be, but only for those from like in the 98th percentile of LP. They have so many that there might even be some degree of venous thrombosis in those people. Most people never get that extreme LP concentration. Thank God.

So those are the only three directly causal things for atherosclerotic disease.

No, there are other. Even that CETP I mentioned. Well, maybe I didn't mention that little tube that transfers cholesterol between an HDL and an ldl. Its name is cholesterol ester transfer protein. It really ought to be cholesterol ester transfer transfer Protein because it's transferring lipids in two ways. But they shortened it. What's the abbreviation for cholesterol ester transfer protein? Cetp. So we know that people who have genetic loss of function of cetp, guess what they have. They cannot transfer cholesterol from their HDLs to the LDLs. Their HDL cholesterol is in the stratosphere 140, 150. And yet that seems to be a longevity gene. They don't seem to get atherosclerosis. So there no doubt there are other genes that are causal. So I named one there Apoc3 and you almost have to bring me back for another lecture to get into the complexities of that that is causal for whether you have gain of function or loss of function. Loss of function, longevity, gain of function. You're going to be seeing a lipidologist early in your life. So there are other genes affecting lipids that are causal and for atherosclerosis. But we can only discuss so much. Most people are not measuring Apoc3.

I'd not heard about Apoc3 before actually.

So it's a big longevity gene. It's one of Peter's favorite genes. But you want to have loss of function. Yeah, most people have dinos function.

So as far as like a lot of the other non causal associative factors like hs, CRP, with some of the.

Original statins, Homocysteine measure.

Yeah, Fibrinogen, which is a clotting factor.

And so many of things. Any other inflammatory marker you may be measuring other than CRP, LP, PLA2, NPO all of those ADMA, you see, I mean worry. But ultimately at the end of the day you're going to lower apob. That's going to be the way to treat causality. And all of those markers are way more dangerous if the APOB is high, then if not. So you're always going to circle back to apob. But let's say I have two patients with APOB that I'm a little worried about. If one is APOB and I can find nothing else but in the others I find homocysteine, fibrinogen, you know, high absorption markers, APOE 4 strike 1, strike 2, strike 3, strike 4 on top of your APOB. So you don't dismiss those things, they're worth measuring. But at the end of the day you could and there's studies with a lot of them that lowering it, then things by themselves don't matter. You got to lower apob and in the process of lowering apob. I think you should use other therapies that probably do mediate at least homocysteine or some of the Omega 3s if you're. They're out of whack. So there are many other things you might want to address on top of apob. It's not all APOB and you're done. There are these other factors including building muscle mass and, you know, nutritional aspects.

Control your insulin level, again, your A1C.

Level, it's a whole another ballgame. And look, the low HDL cholesterol, who do you really see that in? Who's going to get a heart attack? Insulin resistant people. And what do insulin resistant people have? If you knew how to measure it and respect it at a certain degree, a triglyceride excursion at a certain plasma level of triglycerides. And it's way before 1:30 triglycerides start entering the HDL particle. And when a triglyceride goes into HDL, it knocks out a cholesterol. So the real reason diabetics and insulin resistant people have low HDL cholesterol is it's a hypertriglyceridemic state that's depleted the HDL of its cholesterol and put a molecule that an HDL should never carry. Trigs. If an HDL is carrying trigs, it becomes a substrate for a couple of lipases. Hepatic lipase first and an endothelial lipase. They hydrolyze the trigs, which are now the major lipid component. The HDL shrinks down to such a small HDL, it breaks apart. Apoa1 goes to the kidney where it is catabolized into amino acids and gets peed away. And that's why diabetics have low HDL cholesterol. Low APOA1 triglycerides has induced destruction of their HDL particles as well as induce some degree of inflammatory dysfunction to the HDLs too. So you can. It all ties into trigs. But what is the goal of therapy when you treat trigs? Non HDL cholesterol. If you're not measuring apob, that's the guideline of therapy. It's not to lower trigs to this level, that level, that level, because there would be zero trial evidence supporting that. But in all the trials that lower trigs, they only reduce MACE if they've lowered APOP or non HDL cholesterol. So again, do whatever you got to lower trigs through lifestyle, blah, blah, blah, maybe drugs. But at the end of the day, look, APOB is what you're measuring to attest to the efficacy of your multitude of treatments.

So a lot of information. So I'll make a transition now to therapies, which you've kind of alluded to, and you mentioned.