The Peter Attia Drive - #21 - Tom Dayspring, M.D., FACP, FNLA – Part II of V: Lipid metrics, lipid measurements, and cholesterol regulation

Episode Date: October 16, 2018

In this five-part series, Thomas Dayspring, M.D., FACP, FNLA, a world-renowned expert in lipidology, and one of Peter's most important clinical mentors, shares his wealth of knowledge on the subject of lipids. In Part II, Tom provides a 101 on lipids and lipoproteins. Tom and Peter also discuss the history and techniques used to measure lipoproteins, and more.   We discuss:  Lipoprotein basics [1:30]; Gofman and the ultracentrifuge [5:15]; Lipoprotein structure, function, metabolism [6:45]; Lipoprotein and cholesterol measurement, and NMR technology [15:15]; LDL-C vs LDL-P and apoB [30:45]; Sterols and cholesterol synthesis [39:45]; and More. Learn more at www.PeterAttiaMD.com Connect with Peter on Facebook | Twitter | Instagram.

Hey everyone, welcome to the Peter Atia Drive. I'm your host, Peter Atia. The drive is a result of my hunger for optimizing performance, health, longevity, critical thinking, along with a few other obsessions along the way. I've spent the last several years working with some of the most successful top performing individuals in the world, and this podcast is my attempt to synthesize what I've learned along the way to help you live a higher quality, more fulfilling life. If you enjoy this podcast, you can find more information

on today's episode and other topics at peteratia-md.com. [♪ OUTRO MUSIC PLAYING [♪ Hi, everybody. Welcome to episode two of five in the week of day spring. This episode we cover lipoprotein basics, what's lipoproteins and lipids 101. We talk about Goughman and the ultra centrifuge and how we came up with these whole ideas of densities of lipoproteins. We get into very specifics around the lipoprotein structure, their function and their metabolism.

We talk about how to measure the lipoprotein in the cholesterol content and what NMR is and how it has changed the game a little bit. We get into the distinctions between LDL cholesterol, LDL particle number, and APOB. There is some confusion here amongst physicians and presumably amongst patients, so hopefully that will clear that up. We get into the biochemistry of lipids, and then we talk about sterols specifically as a more broad category. Now, before we could measure anything to do with lipoproteins, if my memory serves me

correctly, it would have been the late 40s, very early 50s, when the first assays were developed, maybe it was 1951, that could actually just measure total cholesterol. So you would take plasma from a patient, you would presumably in an assay break down all of the lipoproteins and just aggregate the total amount of cholesterol and you would yield that number, which still amazingly shows up on a panel today. You go and get a blood test and it might say your total cholesterol is 200 milligrams per decilator. So that was, am I correct? That was the early 50s, maybe? No, I think they were analyzing cholesterol long before that because that was, that's a molecule. You can

take blood and dissolve whatever you got to dissolve and cholesterol appears. So they had cholesterol measurements for a long, long time. I like the first lipid anybody could ever measure. What you're talking about in the 50s is where John Hoffman discovered that, hey, wait a minute, there are no lipids floating around in plasma because lipids are incredibly hydrophobic. Your plasma's water, you can't have lipids circulating in plasma. So lipids obviously have to be within what I call water soluble lipid transportation vehicles. And that turns out, of course, to be a lipoprotein, a protein-wrapped collection of hydrophobic and ampypathic lipids that just

wouldn't be in your plasma unless they're attached to a protein. Peter mentioned albumin. It's a protein. So lipids can attach to albumin and be circulated around. And other type proteins, but albumin is the most frequent protein in the blood, so it serves as a carrier. I think an albumin can carry like 17 molecules of cholesterol, a few of phospholipids, too. So it's a player out there. We got a ton of albumin in our plasma, so you'd be shocked to find out how much cholesterol is in it, not quite as much as in life.

Albumens kind of an amazing protein. It'll carry hormones. It'll carry just about anything. It's remarkable. Yeah, and it has everything to do with osmotic pressures and things like that. So, albumin is kind of an essential little routine to say the least, performing many, many functions. But when John Hoffman, a physicist by the way, who had physicists been playing with ultra-centipuges for a long time, separating their radioactive particles and stuff, he somehow wound up separating lipoproteins or saw things floating around

in a centrifuge test, that he then identified as the lipoproteins. So if you learn nothing else today, learn the first thing is lipids for the most part go nowhere in the human body unless they're a passenger inside a lipoprotein. So if you believe there are a lot of lipid associated diseases and I certainly believe atherosclerosis, you cannot have atherosclerosis without a star roll and lipid being in your arterial wall. And I know that arterial wall did no oversynthesize star rolls, creating a star roll build up. Somebody had a

deliver those star rolls there and that of course turns out to be a lipoprotein. And one of the places a lipoprotein should never deliver starrals to to any serious degree. Of course, as your arterial wall intima. So being a gerzy guy, one of my standard jokes on a lecture circuit was ather sclerosis, just the evidence of illegal dumping where a lipoprotein instead of bringing lipids to wherever it's supposed to be bringing, it was bringing starr to the arterial wall and over decades, you got a problem. You know, it could do it for a few days, six months, you're not going to die of atherosclerotic disease.

So when did it become clear? So Hoffman figures out by first principles, basically, he imputes that there's got to be something that is transporting this very, very hydrophobic molecule through plasma. It doesn't, you know, I mean, it's an easy and retrospect to make light of what an observation that is, but the next observation would be, it would lead to be spherical, right? I mean, it's to optimize the volume in which you could transport, it would have to be spherical. You're a mathematician of volume of the spirit, the third power of the radius, so if you're going to devise a transportation vehicle, a spear is better than a slap-bed

truck, you know? So how long was it until, I mean, I know the answer to this question, but I just have to sort of tee it up. Who then went on to figure out these things occur in different densities? It's not just one. There's not just one spherical molecule that's transporting these things, because this is a beautiful story, right? No, it was Hoffman.

He noticed that there, and I weren't calling them April, B, and April, they were particles at today, but they were different densities. They were gigantic. So explain what you mean by density, because this term, you know, we talk, everyone knows low-density, like Broden, high-density, but would tell me where that terminology actually came from. Well, I think it has to do with water, it has a certain density, so it's whether things float in water or sink in water.

We know rocks sink if we throw it in a pond, so they're very dense things, whereas other things float on top of water. They obviously are less dense than water is, so everything is relative to water there. So if you establish what you think is a density of water, things that float. So when he separated these things in a centrifuge, the lipoproteins or these fat balls that didn't move at all were obviously very buoyant.

Some sunk just a little bit, so they were less buoyant, but still pretty buoyant and some went right to the bottom and the test tube, obviously incredibly dense. And it turns out what makes a lipoprotein boi in is a ratio of its lipid fat content because I think we all know fat floats on water. Or proteins, check out the molecular weights of proteins. Really heavy, they sink. So they're the rocks. So your density of a specific particle here,

a lipoprotein particle, is gonna be related to its lipid content versus its protein content. So our big monsters that are delivering, as I told you, triglycerides, but have a lot of phospholipids, under thing. They have some proteins, but they have so much lipids, they float, they're the buoyant ones. And as they lose the lipids, they become smaller.

Now they lose a few proteins as they shrink, but they're really using the lipids. But they're fundamentally concentrating protein, as they get, I mean, because when you look, when you go from chylomicron, even though they're not the same lineage, so I want to be very careful, you'll explain this in detail. You do not go from a chylomicron to a VLDL,

to an IDL, to an LDL, to an HDL. There are three separate lineages I just described. But in size, they loosely track as the smaller they get, the more they've concentrated protein. Within every category of lipoproteins, B.U. talk, chala microns which intestinesly produce, VLDLs, hepatic produce, and the classic teaching

is as VLDLs become smaller, you call them intermediate density and low density, we now know a little liver can produce an LDL without making a VLDL first. High densities which form themselves in the things sort of go the opposite way, whereas the VLDLs and Kylos come out as big fat monsters and lose lipids and become smaller and denser. The HDL is a gathers lipids, becomes bigger and more buoyant.

But within every class of lipoproteins, you're gonna have a heterogeneous range of densities from big species to small species. And this is why to me, I like to tease you because you always hear people talk about the small dense LDL. Within every lipoprotein classification, the smaller particle is always more dense than the, so that's a redone. Just tell me dense LDL, just say small LDL. I know it has to be dense or if it's dense, I know it has to be small compared to its sister particles within that family or so.

Somehow small has only been applied more frequently to LDLs because that's the killer one or HDLs. Oh my God, you want to have the big HDLs, another joke that's turned out, but for a long, this while, if you don't have big HDLs, you're in big trouble or so. And if you've got the small LDLs, you're in the biggest trouble, that basically turns out to be because if you have small LDLs, you need a ton of them to carry whatever your lipid load is. So you've got a super high LDL particle concentration if you have small LDLs, and that's more related

to it's pathology per se than the size, not that that wouldn't cause certain functional characteristics of the LDL. But the VLDL, the chylose come out big in a shrink. Now, the reason though, that differentiate chylomicrons and the VLDLs, IDLs and LDLs, is they have a lot of apoproteins on their surface, which they do lose as they shrink, but there's one protein they never lose, and it's the one that has the most massive molecular weight, apoliproprotein B. So that's why they are never going to be as dense as an HDL particle,

because an HIA doesn't have this monstrosity high molecular weight APO B on it. It's got other things, far less lipids, but to some, the LDL's, IDL's, VELD, he's always going to be way more buoyant because they do have a little bit of an anchor on him creating to their densities that APO B. And it's the only, as you study APO proteins, probably up to 20 to 30 of them now, all of which have certain functions that sort of directs a lipoprotein down which path it's going a catabolic path. The only APO protein, by the way, it gets definitions out the way, APO protein, APO lipoprotein, APO protein,rotein, lipoprotein. And apoprotein is the protein your cell makes.

Once it binds to lipids, it's called an apolipoprotein. And of course, the whole particle itself is called a lipoprotein. So let me re-synthesize that. The lipoprotein is the spherical structure whose membrane is made up of mostly these phospholipids, but also other lipids. The apoprotein is the thing that kind of gives it its signature. So for example, the chylamychron has a B48, the IDL, VLDL, and LDL have a B100, et cetera. That's just called the APO protein.

It's once the APO protein, and I assume it's covalently bound to the LIPO protein that becomes the APOipoprotein. And we abbreviate that apofill in the blank. Yeah, so if I took a VLDL particle and later on I'll tell you, boy on a VLDL you're going to find apoc1, apoc2, apoc3, apoi5, and including apob, but it's going to lose everything but APO B as it to be the ligand for receptors that internalize those particles when your body don't need them anymore. So the LDL receptor that everybody knows. So the ligand just forgives us. Some people are saying it's like the key that fits into

the lock. If the receptor is the lock, the ligand is the key. And in biology, that's sort of how everything works. The key has to fit the lock. Correct. And if it didn't, then that lipoprotein is going to stay in your plasma and probably wind up going somewhere where it's going to create a pathologist. So when was it figured out that apolipoproteins are going to come and go? But there's one of these ones that not only always stays, but you have one. Because that's a big deal, the realization that APO B100, if you knew that concentration,

you had a proxy for how many particles you had. Yeah, so Goughlin, I'm certainly figured out there were proteins involved here, but he wasn't applying that nomenclature to him and everything. It's guys who furthered, a few years further down the road, Fredrickson, Levy and Lee's. So we've talked about those with Ron Krauss. Yeah.

And these are really, there are some very important structural and functional proteins on these particles that we better start investigating and giving names to. So they're a research led to the identification of them. And ultimately, I mean, we know now the amino acid breakdown of every darn apoprotein that's in our body or on our particles and everything. So it just when one research in vents a little bit of the story, other ones pick up the pieces and start further elaborating on it with different studies and technology improves and some of these things that were not

a sail ball at one point become that you can measure them and identify their structure and everything. So it's one of these evolutionary things. And it just made such perfect sense too because we knew these particles are changing, so they're undergoing catabolic processes. Why? What's doing that? And then all of a sudden, you figure out that these ligands, these apoproteins, are keys to various receptors. Some of those receptors pulled the particle

next to where the expression of a lipid dissolving enzyme or lipace and it starts to all make perfect sense to us. Over time, we've identified numerous of these enzymes that can metabolize lipoproteins, numerous of the receptors that temporarily bind these particles in place so they can undergo this thing. Ligants that lipidate fill the particles with the lipids or de-lipped atoms. So if you're listening to this and you're confused at this point, it's okay. One, there's going to be killer show notes, but more importantly, we're going to take a step back now. I'm a guy listening to this. I'm a girl listening to this. All I know is every time I go to the doctor, he or she gets a blood test and it spits out the following. Total cholesterol equals this, LDL, and they won't even, let's, let it'll be worse.

It'll say LDL equals this, HDL equals this, triglyceride equals this, and maybe it will say non HDL equals this. What do those things mean in relation to everything you just said? Yeah, first of all, the misinformation on labeling lipid metrics is one of the things that miracle hasn't given me a stroke yet. I do a lot of peer review. I'm going to one of the associate editors. That's why we're fasting, you Tom. Journal of clinical lipidology. And I will reject a paper instantly that uses improper lipid metrics. Don't tell me the LDL is this because LDL is a low-density lipoprotein.

It's not a laboratory metric. You want to tell me what the LDL cholesterol is, the LDL particle number is, the lipidomics of an LDL is the LDL oxidizer, not great. We do have assays that we'll measure that. So let's please all you don't identify yourself as an ignoramus. And like I've told this to many of the top lipidologists in the country, Please, all you don't identify yourself as an igneoramist. And like I've told this to many of the top lipidologists in the country who lectures, stop telling people, watch your LDL. Ask them, what is your LDL cholesterol, what's your,

if we don't all talk to talk, you're never gonna understand the process. So this patient almost assuredly is talking about total cholesterol, LDL cholesterol, HGL cholesterol and non-HL cholesterol. Yeah, so it'll give you a quick to. And by the way, Peter did mention something very quickly before I just wanted to explain what he talked about. Hey, APO B100, APO B48. APO B is a giant structural non-transferable APO protein that's on chala microns or VLDLs. The intestinal machinery that synthesizes a chala micron makes a certain type of APOB and the APOB that is made in the liver makes a much bigger APOB as a higher molecular weight.

So they knew the APOB that's being made in the intestine is much smaller. So it turns out to be that the apo B in the intestine is 40% of the molecular weight of the hepatic produced apo B. If you get into genetic apo B, you'll see apo B 31 that has 31% of the molecular weight of what's considered a normal apo B. So when you hear apo B 48, that should identify it as an intestinal produced APO B particle, and a liver would be an APO B48. And LDLs that come out of the liver, I have no sugar, have APO B100, I don't like the VLDL,

or VLDL, the LDP comes in LDL, the APO B100 is still there or so. So just keep, if you hear 148, what does that mean? And so it tells us the origin. We are going to be talking about nuclear magnetic resonance and one of the parameters that you see give you a lot on less so nowadays is VLDL particle concentration. When you analyze the lipoprotein using nuclear magnetic resonance,

it cannot tell the difference between a column micron and a VLDL, because NMR doesn't measure the proteins. It's, hey, that's a very big particle. So it has to be a VLDL because NMR doesn't measure the proteins. It's, hey, that's a very big particle. So it has to be a VLDL or Kylos. Most of your big particles are VLDLs. But if you're fast, VLDLs, yeah, and even in a post-pranidial state, conno microns have half-lifes and minutes. They're gone.

So the vast majority of VLDL particle number of VLDL is still VLDL. See, VLDL. But there could be some problems. All right, but I want to go back to our lady. So her total cholesterol is 190 milligrams per desoleter. So total cholesterol, remember my

premise that lipids go nowhere in the body unless they're within a lipoprotein. It's not exactly true, but for today's purposes, that is true. And certainly I'm just standing lipid metrics. That's true.

So total cholesterol would be the laboratory has separated all your lipoproteins from the serum and they're take how much cholesterol is in this serum tube. So where would that cholesterol be that they're analyzing? Well, it would be found in, if there were any column microns there, that were hanging around, or maybe they didn't fast,

some of it would be chala microns cholesterol. Some of it would certainly be VLDL cholesterol, a lesser amount because there's just so many so fewer of them would be intermediate density cholesterol particles. And the rest would be in either LDL particles, low density lipoproteins, or the high density lipoproteins. There are other types of L, the L particles called Lp little A, which we'll talk about. Total cholesterol is all of the cholesterol. It is every single lipoprotein that's in a desolator of your plasma. And that is directly measured.

It is not computed. It is not a calculation, that is a state. So it's, anyway, there's always a coefficient of variability, that's inaccurate. And so if you want to use cholesterol for anything nowadays, because let's face it, that was the first parameter looked at in the epidemiogenase, certainly correlated total

cholesterol levels with the risk for heart disease. But think about what I just told you, it's the cholesterol within all the lipoprotens. What is the, if you count it particles, what is the most numerous particle in your bloodstream, the APOB particles? Well, actually the HDLs are more, but they're so small, they don't carry much cholesterol.

So most of your, if you wanna put a parentheses around it, atherogenic cholesterol, would be within your APOB particles. So if you want to describe any use to total cholesterol, it's a real poor man's APOB level. In general, most people with very high total cholesterol levels will have a very high APOB level. And that's the real reason there are risks for atherosclerosis because those are the particles.

Yeah, I mean, the original epidemiology basically said, you know, you have to sort of applaud them for doing the best they could with the tools they had, but let's take total cholesterol, which is at the time the only thing we could measure clinically, let's take the patients who were in the top 5% and the patients in the bottom 5% was there a difference in their risk

of MI? And the answer was yes. Now, it would be another at least decade until framing him. This kind of an interesting story, right? This part of the story got ignored in framing him was that low HDL cholesterol and high triglyceride turned out to be four times more predictive of MI than high LDL cholesterol. And again, this is still crude measurements. But that sort of didn't come back into, people didn't come back to try to explain why that might be the case until Jerry Riven

had sort of done his work on metabolic syndrome. But I also realized I'm gonna get a soft topic. I wanna go back to the other question. So we've just explained what 190 milligrams per desk leader means. When it says HDL, it really means HDL cholesterol as evidenced by the units. So those will either be measured in millimole or milligrams per desk a liter. That's a direct assay or an indirect assay.

Yeah. So, Framing, of course, did measure total cholesterol was easily available again. They measure triglycerides too, they really had no clue what they were they related to. But it was measurable. Glisterides, they called it glisterides back then. And they did have a direct assay for HDL cholesterol. You could also measure, you know, you can send a huge particles, you can take out the LDL fraction and analyze how much cholesterol is in them. That's theoretically the gold standard. You can separate the HDL particle,

but that's two time consuming. Nobody's got ultra-sendiffuges. So to have real world tests, chemists had to develop direct assays. So HDL assays were developed really early on. So framing him could not only measure total cholesterol, they could measure directly measure, not calculate HDL cholesterol, what they could not measure. And it took a long time was LDL cholesterol without...

Without ultra-centrification. Without ultra-centrification, correct. In the 70s, somebody came up with a formula that hears a way of at least estimating or calculating LDLC, which took fire because by the seven days they realized the most numerous atherogenic lipoprotein were the low density lipoprotein. So it's framing him, started calculating LDLColestrol. Whoa, this is the story here. So they calculated it. So just to be clear, what they're doing is they're directly measuring total cholesterol because you can just do that off serum.

They precipitate out the HDL, right? So you could measure the HDL without ultra centrifugation and you could measure triglycerides. So now the formula for estimating LDL cholesterol became total cholesterol minus HDL cholesterol minus triglycerides over five. Why the triglycerides over five? Yeah. So, free to walk, put two and two together and realize, hey, total cholesterol is in essence VLDL cholesterol plus LDL cholesterol plus HDL cholesterol A equals B plus C plus D. So,

if I know parameter A and I know parameter D and I know parameters say I can figure out what parameters and So what what he did was he said I'm gonna ignore Kyla micron an ideal and LP little a well LP little a was at that point Probably being not even there was being it's included in the LDL They were basically counted is yeah the Carlos are counted as VL the else in the IDL is counted as L Yeah, okay, so therefore if I and the IDL is counted as LDL. Yeah, okay. So therefore, if I know the HDL cholesterol, and I know the total cholesterol, if I only knew VL, the L cholesterol, I could easily calculate what your LDL cholesterol was. So then it becomes, you have to know what is a VLDL particle. And at least if you have a physiologically normal VLDL particle,

most of those lipids are in the core of the particle. There are no triglycerides on the surface, no cholesterol ester on the surface. If I only knew the composition of these particles, I could figure out. So they came to the realization that on average, a physical, at least in the 1970s, a VLDL particle composition had five times more

triglyceride than it did cholesterol. And virtually in a fasting state, all of the triglycerides are not in HDL, they're not in an LDL. We're not measuring column icons, because you're fed they're in a VLDL. So cholesterol in a VLDL has to be triglycerides divided by five, because there's one fifth as much cholesterol

in a VLDL particleizer. So VLDL cholesterol is triglycerides divided by five. So now if I have HLDL cholesterol, VLDL cholesterol, total cholesterol, you do the math. You're a mathematician, Peter. It's very easy to, ah-ha, this is what your LDL cholesterol is. And as they calculated that,

and they applied it to clinical trial data, partylations are very, very good. And they knew that's probably where the money is, because of our APOB particles, the particles that are the ones delivering these Star Wars City Audery War, the overwhelming majority of them, 95 percent, at the lowest, and 90 percent are LDL particles.

It's where the money is, we need a metric of LDL, and the calculated LDL-C was early since introduction to that. Now, down the road, people have developed direct assays of LDL cholesterol. But you know what turns out it's not that much more accurate than the calculated LDL cholesterol unless as you start to go up, up and triglycerides that calculation fault. Which is something we're seeing more and more of today. And then we saw in the original framing him. Dad, who said, oh boy, if your triglycerides get above 400, don't use that calculation, it's ridiculous. So they actually developed a direct LDLC to give us an LDL cholesterol metric and

people with triglycerides of 800, 1200, 4000, where now you know what their LDL cholesterol is, whereas the formula would be useless there. We now know that formula starts to become kind of erroneous at somewhere between a trig 150 and 200 and higher to go above 200. Be careful with a calculated LDL cholesterol and rely on direct LDLC. But and here's what nobody realizes. The only value that calculated or directly measured LDL cholesterol brings to the table is it's a better poor man's estimate of your LDL particle concentration than is total cholesterol. So an LDL cholesterol would correlate better with APOB or LDL particle concentration and

would a total cholesterol. Down the road a little bit, we've come to the realization and if we get another calculation called non-HL cholesterol, that even better correlates with APOB or LDL particle concentration, then does LDL cholesterol. So that's why that's the new thing that's in Vogue. We also, thanks to you, I know you spent a little time down in Hopkins, some of the lipid guys down here have invented

a much better calculated LDL cholesterol, which they're trying to get incorporated rather than the older calculation of the free to world that we've been using forever in most labs, entirely using nowadays or so. So NMR, which is my first exposure to NMR, was in high school. When we were taking organic chemistry and you learned that we had these tests,

I still remember how fun these tests were where they would show you an NMR spectroscopy and you had to figure out what the molecule was by knowing where those spikes were. So it was Jim Ottvost, the guy that first figured out that you could use that stuff to actually count the number of these apobies? Yeah, I think Ottvost was certainly one of the early pioneers and over time, the real pioneer who evaluated lipids and lipoprotein using nuclear magnetic resonance spectroscopy. He knew that lipids would emit specific spectral signals

that he could analyze and through very complex mathematics, turn them into a variety of lipoprotein metrics, including you can do an NMR LDL cholesterol level and LDL triglyceride level. In the future, that's one of the ways we're going to be measuring phospholipids on various lipoproteins is NMR spect spectroscopy because as Peter says, every lipid has a different spectral signal.

And if you know what you're doing, you can look at a spectral signal and know what its molecular composition is and everything. So Jim turned it into, you know, as we had all these lipid metrics that we're talking about cholesterol, even triglyceride metrics, deep down the guys, no, these are just poor man's way, easily assayable ways of quantifying lipoproteins, and it's a quantification. It matters in many cases or so. So we have, it turns out, in the long run, it's the number of apobapoticles that primarily is what forces it into the artery wall, very little L. I mean, there are other factors, but that's the number of apob particles that primarily is what forces it into the artery wall, very

little L. I mean, or other factors, but that's the number one. But when was that pathophysiology first stumbled upon that it even mattered how many of these particles you have versus, so let's just take out the estimates and let's assume that you have the ability to measure the total cholesterol concentration within an LDL particle, which is what's showing up when someone gets a blood test and it says direct cholesterol concentration within an LDL particle, which is what's showing up when someone gets a blood test and it says direct, when it says LDL C direct, that means they've actually measured it, so now it's better than

Friderwald's estimation, but that's different from, if you have an NMR, where it says LDL P, an animal per liter, and that's counting the number of those particles, so one is the number of particles, the other is the amount of cholesterol animal per liter. And that's counting the number of those particles. So one is the number of particles, the other is the amount of cholesterol contained within them. We'll get to what a revisiting of mesa and framing him made unambiguously clear,

which is one of those predicts better than the other. But was that really the realization that it was a gradient-driven process by number or was that understood beforehand, or at least hypothesized beforehand, and then more verified by the experimental evidence? No, early on, they discovered it was the APOB particles going into the artery wall,

delivering these starrows and everything that set off this maladaptive inflammatory process that led to a whole other area of investigation or so. So the particle number, data came, once they sort of identified in a way of asking particle numbers, and they almost evolved that this maybe APOB came a little bit first, but then Jimovos' work on the old particles came at the same time, and it clearly became evidence that APOB is a better risk factor.

And remember, there is one apob on every VLDL, ideal and LDL, but 95% of the apob particles are LDL, so apob is just a way for the labs to report to you what an LDL particle concentration is. It is opphos identified in LDL particle concentration using these methyl signals coming out of the methyl groups that are on cholesterol, ester, and triglycerides, and phospholipids, and translated into a particle number that, wow, either APOB or LDO particle number, correlates a lot better with clinically vents or the presence of atherosclerosis.

You don't have an event, but if we do some imaging, we see plaque in your wall, then does the cholesterol measurement per cell? So it's not a surrogate of particle. They are particle measurements, APOB or LDLP. So APOB is an LDL particle metric. What too many people get lost at? Hey, VLDL particles are an APOB particle,

so VLDL, there's no doubt that VLDLs can get in the artery wall and contribute to it. But it's like a minor, the number of VLDLs that get into the artery wall are infinitesimal, the number of chylos that get in are infinitesimal compared to the number of LDL particles. So yeah, they're all bad guys. And a VLDL per particle have significantly more cholesterol molecules in it than an LDL, but there are just so many more LDLs that collectively, the LDLs deliver more cholesterol to that artery wall. But an 8-Bot-B by the way gives us no

information on VLDLs. It's an LDL particle metric. You can't use it for anything else. So don't call me up and say, my APO B is high because I got too many VLDL particles. Unless you have a rare lipid disorder where there are no LDL particles, the type three, this beta-lipoproteinemia. That's the only time an APO B is measuring.

It's a VLDL measurement or a remnant measurement. It's not an LDL measurement. But everybody else, APOB, LDLP, those are the test you need because although they correlate very well with LDL cholesterol, if they're both high in a given person, that person's a terrible risk. But as you well know, and probably because of the metabolic makeup of our existing humans, at least throughout the world now, is some people have a very high-apal-BLDLP, very good LDL cholesterol. Some people have high LDL cholesterol, perfect, APO LDL particle counts. When those metrics agree, they're said to be concordant. Hey, use them both.

Eterone will give you the same information. But what happens if you get a patient where they don't agree these metrics in virtually every single trial ever looked at, the risk follows the particle metric more than the cholesterol metric. So the only way to know who is discordant with a cholesterol metric and an APOB or an LDL particle metric is to do both of them.

You could also say, hey, if I'm just doing APOB or an LDL particle count, I don't even need lipids. And I'd agree with you, except I think there is value in knowing what a triglyceride is for other reasons. So that's the real key. And if you ever go to a doctor and you're told I'm very happy because your LDL cholesterol is normal. So you also in my doc, but by the way, what was the APOB or LDL particle count? And if the doctor didn't do it, you demand you do it instantly. Because otherwise you don't know your lipid-related risk. Yeah, we're going to upset a lot of doctors here because I've already, and you've already

been in the business of that, where people will hear you talk or something or read something you've written or something I've written, and they'll go to their doctor and say, hey, I want my LDLP or my EpoB and the doctor says, that's nonsense, you know, fill in the blank TBD blah, blah, blah, blah. And it puts patients in an awkward position. That's nonsense. You know, fill in the blank, TBD, blah, blah, blah, blah. And it puts patients in an awkward position. I mean, I really feel bad about this because especially depending on what country they live

and at least in the United States, I think anybody can go to lab court directly and get the assay without a physician's prescription. But it upsets me, I think the patients even have to do that. It upsets me that something that is such an important metric, I would list LDLP as one of the five most important metrics I've talked about this, that every patient should know

their LDLP or APOB, and that that wouldn't be sort of fundamentally a part of screening somebody for disease in that a patient would get into a position where they're having to argue with their doc about that is, is disconcerting and look hopefully this is sort of what I do these podcasts is I think it's just as much to help physicians say look just because I didn't learn this in my training doesn't mean I don't need to sort of pick it up today. Amen and I'm sad there's so much what I consider inferior lipid care being administered by healthcare professionals in the United States, but there's nothing I can do about that is try and teach them one at a time or

expose my writings and other people's writings and the data on this as much as I can. And is tragic with public health problem number one or number two that this is lagged so far behind. In part retarded by guidelines and third party payers who just don't want to pay for different metrics and stuff, so there's other reasons behind it. But a big part is they don't understand it. You have had cardiologists call you up. I have had, being recognized as maybe in northern New Jersey,

wanted to, hey, Tom, you know, you told my patient that, you know, what I said about LDL cholesterol is a matter because you've done an LDL particle, but you know, not everybody believes that or they give you some horseshit like that. I said, I'm going to say, hey, doctor, would you like 200 manuscripts delivered to your desktop tomorrow? I'll do it. If you promise me you'll read them every single one. So, you know, it is what it is.

I think the internet is help people in certain ways. I think the internet is confused people in a lot of ways too. Because there are people out there who what we just talked about, and it's pretty much fat, who become deniers of the particle concentrations because whatever else they're exposing as their way to cure heart disease, somehow aggravate till the oparticle count, they just choose to ignore it.

And look, are there people with high-yieldy oparticle counts who don't somehow, yeah, they're out there, but the overwhelming amount of literature says the odds over if you keep this for 20, 30 years, you're going down until somebody does a serious study showing there are people who can escape this for, you're playing with fire to ignore an elevated, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old,

old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, old, metric there is somehow protected against atherosclerosis? Well, I have lots of thoughts on this myself, but maybe we'll come back to it.

I think we've gone back and forth. We had this fun email string a while ago with you, Ron, me, Alan. I think Josh Knowles was on it as well, where we just, you guys were the first people to be exposed to my new model, which is the necessary, but not sufficient, sufficient, but not necessary, neither necessary nor sufficient causalities, because you can actually have causal metrics that fit each of those buckets. But we'll digress and come back to that.

I want to go back to one semantic thing. You use the word sterol a lot. I'm very comfortable with it. I want to make sure the listener knows the difference between a sterol, a stand-all, a zoosterol, a phyto sterile. I think we're going to touch on this later, so let's just hammer out the semantics. Right.

Well, cholesterol, of course, is the molecule we all fare because it's been drummed into our head that cholesterol in an arterial wall is what is plaque. It's a cholesterol core, and that cholesterol can cause impaired vastascular biology, resulting in clinical events. So what is cholesterol? And we certainly, in Peter's notes here, you're gonna have pictures of the cholesterol structure. And it's got four rings, it's an aromatic compound. And off the fifth ring is a little tail sticking out,

which is a carbon chain. So the precursor molecule is called the starrain. So you have the rings, the four rings, and you may or may not have this tail sticking off of the 17 carbon and the fourth ring. So all of the bonds are saturated, that is called the starrain. So if you unsaturated one double bond in that sterine,

it's called the sterine. And if you then stick a hydroxy group on the third carbon in the first ring, it's called the sterile. It's an alcohol, because you got a hydroxy group now sticking out. Hydroxy being OH. Oxygen. Yeah.xy being OH oxygen. Yeah, excuse me.

Correct. So you'll see the pictures in my illustrated diagrams there. And that little tail that sticks out on the other end of molecule has a lot to do with what exactly type of sterile that is and how it will function in a cell or in a cell membrane or so. So cholesterol would be this four ring structure. Three of the rings have six carbons in it.

The fourth ring has five carbons in it. You have this tail sticking off of a carbon 17. It goes out and then cholesterol, that's a totally saturated tail. Every bond in it is a saturated fatty acid. And then on the three position, you'd have this OH group, the hydroxy group. By the way, since OH is sort of soluble in water, that part of the cholesterol molecule is soluble in water,

whereas that carbon chain sticking out, so it's a little pure lipid, that's not soluble in water. So when cholesterol does exist in a surface membrane, like a cell membrane or lipoprotein, it's cholesterol. It's the hydroxy group is sticking out and that alipathy tail is sticking into the core of the particle. So now the cholesterol, it's in the middle of the particle. Oh, that's the hydroxy group can't be in the middle of the particle, that's water. So they stick a really long

chain fatty acid, they replace the hydroxy group with a long chain, or really any chain fatty acid, mostly it's a long chain. So you will starify cholesterol, remember I told you, attaching a fatty acid to something is called a star, so cholesterol, which is the active form of cholesterol that can be changed into a hormonal bile salt or function in a cell membrane, becomes a storage form of cholesterol or a lipid core transportable form of cholesterol called cholesterol. Real, now it's YL, it's not OL, Esther. And we abbreviate that as CE. So free cholesterol is either gonna be abbreviated as a C or an FC and cholesterol ester. It's very difficult.

If I want to, if I'm an adrenal gland and I got some cholesterol ester stored and I wanna make a hormone because I need cholesterol, I have to de-esteroify that cholesterol ester to free cholesterol. If the liver has cholesterol ester storage poles and it does and it wants to make a bile acid, it has to de-astarify cholesterol, ester.

Cholesterol is stored in huge quantities and fat cells as cholesterol, ester. And it would have to be de-astarified to be utilized to do something else or so. One little story I'll just tell before we get to this. Stannels and all the other stuff is one of my prouder moments in front of Bob Kaplan was when you sent an email, like this a couple of months ago, you sent this an email and you said, see if you can spot the error in this figure. And it was like a figure that had a million things on it

and I was like, oh, I'm not getting up until I figure out where the mistake is and sure enough, somewhere in there it took me about 10 minutes. The illustrator had written, because this was out of a paper, they had written cholesterol, O. L. Esther, instead of cholesterol, Y. L. Esther. And when I responded to you and you responded in the affirmative, I was like, I've got my stripes. And that figure, he's talking about, came out of one of the productions for the company

that I worked for. We developed educational pieces for physicians and I obviously drew it in label there, but you send it off to medical illustrator who formats it for the PDF or whatever and cholesterol and cholesterol and they make the mistake. Even though I sent in the picture where it was properly labeled, of course, I had a heart attack the first time I saw it. And we've since changed that but somehow Peter got a whole of an older version or something. Probably even I sent out and didn't recognize initially, but yeah, so it is cholesterol, is there anything that's a sterified becomes a YL, so you'll see lipids.

This discussion illustrates one of the challenges of lipidology, which is I find this to be certainly among the two or three most complicated subject matters I've ever tried to master. And again, no one masters anything in life. I mean, that's sort of the beauty of this. You haven't mastered this, but this journey of trying to learn it, I am constantly humbled by how hard it is. It's just so goddamn complicated.

Well, that's true, especially if you want to take it to the nth degree, but you need to invest yourself in some degree of education to at least be competent in today's world or so. So you have to know some of this stuff. Well, and that's the thing, you have to be willing to learn some of this chemistry. I mean, you have to steep yourself in biochemistry and understand that because the significance becomes enormous. One double bond in one of these things

completely changes its properties. And not to say that that's not true in general in biochemistry, but it's much easier to talk about blood pressure or to talk about elevated levels of uric acid or insulin or glucose without getting into that level of minutia. It is not possible to discuss lipids without that. That is a problem with a lot of people are spouting off on the internet and elsewhere, but

I always just want to have them understanding of the complexity of how this all works and fits together and why what you just said is wrong because there's something going on still, cometrically, that you haven't even considered. So to finish the sterile, so a sterile aid is a sterile that's got another keto group stuck on it someplace. Look at all the hormones. You'll see a double bomb with oxygen attached.

But a stand all is you take, and let's take cholesterol as a stand all, or a sterile. And remember cholesterol at the third carbons and OH group, there's a double bond at carbon 5 to 6 in the first ring and then there's that tail at carbon 17. If I desaturate it cholesterol, the double bond at C5 and 6 disappears. It's called cholesterol. it's a stand-all, a stand-all essentially a saturated star-all. Changes the characteristics of that cholesterol, free cholesterol can be readily absorbed in your intestinal walk. Stannels cannot be absorbed.

And it's kind of funny, our liver, our body to get rid of cholesterol, but sends it to the liver, the liver sends it through the bile to the intestinal pool as free cholesterol. And your intestines more than capable of just reabsorbing that cholesterol that the liver's trying to evict, except our little friendly microbes down here in a gut convert a ton of the biliaryx rate of cholesterol

into a stand-all, called cholesterol, or there's an isoform, but called coprostinile. It's a stand-all, cannot be reabsorbed, so you poop it away, and that's out of body, it's rid of cholesterol, it changes a lot of it to a stand-all. Anthropologists have been measuring specimens

for coprostinile, that tells them humans lived there at one time, because they find that in certain specimens, and that human had to excrete it. You know, so a stand all is simply a saturate, and that adds other applications, because hey, if stannels cannot be absorbed, and I would like to have a metric of whether you're absorbing cholesterol or not.

If I measured cholesterol in your blood, shouldn't be there to any appreciable degree, because it tells you that. It tells you that. It tells you that. If it is elevated in your blood for whatever reason, and we now know why, you're in testing just absorb that colestinal. And if it's absorbing colestinal, which it tends not to, what is it absorbing in humongous excess cholesterol? So colestinal serves as a biomarker of,

are you or are you not, or what degree of cholesterol absorption is going on in your intestines. And the last thing Peter did mention, he said phyto sterols, he called it a Zeus sterile. I the last thing Peter did mention, he said, phyto sterile, he called it a zoo sterile. I call it zoologies, cause I call it a zoostarile.

So I don't know who's right on that. I'm gonna go with your right. Yeah, yeah, I'm just gonna give you that. And I do have a degree in zoology when I went to college, and I was one of my majors. And you're wearing just so everyone knows, you're wearing your Rutgers t-shirt right now as well

from college, which is perfect. I wouldn't be here without the Earl Rutgers. That's medical school is in consequential. I learned everything in Rutgers, pre-med, at least the biochemistry and the physiology anyway. So phyto-starols, what? Plants are full of starols. Their cell membranes are not cholesterol.

Those, there are some plants that do have cholesterol and they most do not. But they have starrals that if I showed you, here's cholesterol and here's what's in this plant, you would think you're showing me a lot of cholesterol. But if you look closely, you'd see that tail that's coming out of carbon-17 is constructed a little differently.

Or wait a minute, there's another double bond in one of those rings in there. So it looks like cholesterol, but it's close, but it's really not. And since it was made in a plant, collectively, let's call them phytosteoroles. But we hopefully all eat a few vegetables during the day. So you're eating phytosteoroles unless you're a total non-venture. And they didn't even eat any other things, even you're eating shrimp and stuff, fishy, vital plankton and stuff,

so does phytosteorals and bunch of foods. But your body knows the only sterile I need to function is cholesterol. I don't need any plant steriles. Why would I want a human to ever absorb the plant sterile? They would get in a way. Could they even be toxic, you know? So evolution must have figured out they were.

So evolution made sure our intestine did not absorb phytostriols. Why? To me, it tells me there is a certain level of which phytostriols are toxic. Well, this becomes interesting because I had a disagreement with a physician recently who jointly takes care of one of my patients because the physician wanted to put this patient on phytosterols supplements because this physician became convinced that it was such an elegant way to lower cholesterol.

It turns out about 10 to 15% of people in whom you give massive doses of phytosterols, you do indeed lower their cholesterol. This physician felt that was a good idea. I felt otherwise, for reasons you'll explain, I'm sure, and needless to say after a long discussion, we agreed to stop the phytosterols. Yes. And again, to me, the best argument with that is if your evolution thought we needed phytosterols,

your intestine would be encouraged to needed phytosterols, your intestine would be encouraged to absorb phytosterols. If somehow they brought some miraculous property to the human body that enhanced survival, you'd want them in there. And everybody's like, oh, plants carry a lot of great stuff. We're only talking about the sterile. It's in the plant, the phytosterol. Other ingredients and plants do get absorbed and probably are good for you.

But not phytosterols. Well, there's data to show that phytosterols on a per molecule basis are probably more atherogenic than cholesterol. There certainly is that data there, but again, the people who are just so focused on lowering LDL cholesterol, don't even entertain it, won't even look at it, or they dismiss it as nonsense, you know, and it's never going to be studied in a proper type of trial that you'd have to study it in a proper type of trial that you'd have to study it and you know So and the spirit just hinted if you're not a hyperabsorber of sterols

Probably giving a phytosterels supplement is good because it does compete with cholesterol firms So you will absorb less cholesterol and Maybe that's one way of lowering LDL cholesterol I would say who cares, but it you would get a little bit of apob reduction in certain people with that But if you're a hyperabsorber, I'm polluting your body with something that evolution didn't want in your body. Why would I do that? So I beg anybody who's a big advocate of supplementing

phytosteorals, please monitor phytosteorals in the bloodstream. That's how you identify, oh my God, you're the one person I absolutely should not be given as to. And I can send you a lot of data Peter's thoughts about showing you phytostural toxicity and humans and stuff. So, and when we say someone's a hyper absorber, I mean, you and I have both written about this ad nauseam.

So we'll link to it rather than get into a diatribe. But we're basically talking about and your analogy is my favorite. I've always borrowed it, outright stole it. I, hopefully I've always given you credit. You got a ticket taker in the bar. Neiman picks one like one transporter. He lets everybody in. If you can fit through the door.

Yeah, he lets any sterile in. If you can fit through the door, you're coming in. But then you've got this ATP binding cassette G5G8 and that's the bouncer. That's the enforcer. That's the one who, in theory, probably informed by Alex R is making some sort of decision about you're a good guy, you're a bad guy, you got to go, you got to stay.

When someone is genetically a hyperabsorber, is the quote unquote defect more on the ticket taker or on the bouncer? It turns out that it's both because now when we talk about absorption, let's face it, there's a million molecules that can be absorbed by urine test And we're talking about sterile absorption right now and cholesterol is a key ingredient for human life So evolution not only gave every cell in your body the wherewithal to synthesize cholesterol It allowed urine test into absorb cholesterol because it certainly didn't want any cellular and test into adsorb cholesterol because it certainly didn't want any cellular deficiency of cholesterol, which has nothing to do with plasma cholesterol, by the way.

You can have an LDLC of three and have perfect cellular cholesterol metrics. So keep it up on the stand. As evidenced by the hyperfunctioning PCS-K9 patients. Yeah. So this Neiman Pixi one like protein in our proximal intestine recognizes stirls and there's a stirl domain on here that binds tightly to stirls but it binds most tightly to cholesterol because cholesterol has that structure. It has a less avid binding to a phyto stirl and it has minimal binding to a stand-all.

Now ultimately it'll bind to all of them but cholesterol gets the first preference to a phytostarol and it has minimal binding to a stand-all. Now, ultimately, it'll bind to all of them, but cholesterol gets the first preference to be pulled into the enterocyte. Zeno-starol, as I call it, rather than phytostarol, zeno-meaning other starol, a starol, other than cholesterol, would get in secondarily and a stand-all, they get in, but at much less concentrations.

So now the enterocyte has has this star roll you just absorbed. Now the enter site's position is, I got to get this to the rest of the body. So I have to take this star roll and put it in a column, micron that I'm going to make. Or I could also reflux any star roll out to a baby HDL. Let's look in for star rolls. I can lipidate an HDL. So that's how sterols get out of the intestine or the intestine and say, we don't need any more

sterols. I'm getting rid of you and that's where the bouncer comes in. So these AT binding cassette transporters, ATP binding cassette transporters are a sterile efflux membrane transporter. And this is important to distinguish because, and I get it, might be confusing, but the diagrams transporters are a sterile efflux membrane transporter. And this is important to distinguish, and I get it, it might be confusing, but the diagrams will make it easier. There's two effluxes you've referred to. There's an efflux on the lumenal side and then an efflux back into the body. Both of them are leaving an enterocyte.

One ends up leaving the body. If it goes out the ATP binding, it's going into the lumen. It's being excreted with stool. If you efflux on the other side of the cell into either the chylamychron or into the HDL, you're actually putting it right back into circulation. And that is such a crucial point, Pierre, where you're lucidated on that more. So yeah, remember we're talking about the enterocyte. Like the liver and enterocyte have a lot of things they can do with sterols.

So they can get rid of it or they can even use it. Remember, entercytes have cell membranes. They need some cholesterol for their own cell membranes and everything. So they can ship it out. Hey, body needs cholesterol in a colomarkin. They can lipidate in HDL or they can return it to the lumen of the gut where it'll go out your rear end. So these ABCG5 or GA transporters

as you're called, and it's a hetero dimer, so you have one of each, well, E-flux, and they also have different affinities. So unlike the Neiman pick, which really wants cholesterol to come in less so phytostarols and not so stannols, which tells me evolution didn't want those other products in your body. The ABC Transformer exporters, they, number one, evict phytosterols first. That's another evolutionary, happenstance to me that tells me the body, evolution didn't want phytosterols in your damn body. Because why is it giving you a phytostero-ephlex protein in your intestine? And the liver has it too, just in case a phytostero-el ever makes it as far as the liver.

It could see victim back to the biologist back to your intestine. So second in line for expectation would be a stand-all, and third would be cholesterol. So your ability to absorb cholesterol is a happy working relationship between the expression of your Neiman-Pix C1-like protein and your ABCG5-GA transporters. So technically, if you even had a good normal degree of absorption, but you couldn't

evict any starrals because you got a loss of function of an ABCG5-GA, you're going to be a hyperabsorber because then the only way those starrals can get out of the enterocyte is in a column micron or in an HDL. And by the way, when you do measure these phytostarrals in the blood, people, it's like when you measure cholesterol in the blood. You understand? I've already told you where to cholesterol, man. It's the cholesterol within all of the lipoproteins. So if I'm measuring cytoesterol, stigmasterol, campesterol, which are some of the names of the 50 phytosterols that are in our plant products, what am I measuring? Well since the vast majority of lipoproteins are LDLs, I'm measuring LDL cytoesterol,

LDL cholesterol, like I'm measuring LDL cholesterol. So you're measuring there, but God forbid that particle invades an artery wall, the steriles go with it. And one last intriguing part of this story, which better put the fear of God to phytosteuros into, that evolution didn't want it in. So it gave you a protein that will not absorb phytosteuros if it's working right. It gave you a protein that immediately vix phytosterols of its work and write, he gave you a protein that immediately vix phytosterols, but for any sterile to go in a chalamicron, what does it have to be? A sterified. How does the intestine and starify cholesterol into cholesterol ester, which is what makes up a giant part of the core of a chalamicron? There's an

astrophying enzyme, acyl cholesterol, acyl transferase, ACAT. Guess what is the favorite ligand for ACAT? Cholesterol. Guess what is not a favorite ligand for ACAT? Phytosterols. So they just don't astrophythytoster, which retards them getting into your body. And you know, the real way to get in that ABCA1 eff E flux transporter, which is what lipidates a baby HDL part. It's not ABC G 5 G 8, right? ABC a one exports

starls into baby HDL. And just for the listener again, you're saying ABC what you're saying is ATP binding cassette. So when they hear you say ABC, that's what you refer to. It's an managed driven process. So some of that phytostars you're measuring in the blood and HDL particles also, so that's a way to get in. And I always make, and you'd have to do a study and prove it, we're going to be talking about HDL dysfunction.

Suppose I measured phytostars in your HDL, and it's very high, it's probably a type of dysfunctional HDL particle. You know, so there's also a sort of intriguing. HDL particle. You know, so there's all sorts of intrigue. It would also, you know, not to get too esoteric, but that would also suggest an erocyte dysfunction, because the anerocyte should also quote unquote, no better, that that's not the direction of efflux I want. It is, but it's relying on the ABCG5G8 to efflux it, then it wouldn't even get to an ABCA1 to E flux it on the other side. And AKAD is not going to starify it if it's all being evicted, or be very little, it

will wind up being a starifying. And the last part of this puzzle, as Peter thought, you have a gutlumin side, and you've got a plasma side or a lymphatic side, which is where column microns exit. We probably talk about it somewhere today is this crazy process they used to call reverse cholesterol transport, which is another one of these idiotic terms that should have disappeared a long time ago. At least if you think it's mediated by solely by HDL, high density lipoproteins, that's the part that's got to change. A big pathway of how does the body get rid of cholesterol, we're all told, oh, it brought it back to the liver and the liver will get rid of it in a

certain way. Guess what? A ton of it is just bought directly right back to the intestine and the cholesterol in the particle or the particle itself finds its way into the enter a site through the and then the enter site has another supply of stirls all of sudden that it didn't absorb. And so what? It then will do it. That's the story what it wants. It can efflux it through ABCG 5G into your gut loom and you can poop it away.

So the process of a lipoprotein or some other trafficker, how human, red blood cells, bringing cholesterol back to the small intestine, bypassing the liver, gets right out into your stool, it's called transintestinal cholesterol, e-flux, abbreviated as TIECE, and it's a major reverse cholesterol transport pathway now. Do we have a sense, because we're going to talk about direct and indirect RCT in a moment, I think that might as well, this is as good a foray into that as any. Do you have a sense of how much cholesterol is being reverse transported so to speak through TIES versus the sum total of direct and non-direct reverse cholesterol transport? Yeah, this has been studied in dynamically, but you know, the real small studies and it

probably varies individually depending on the complexity of your lipid, and lipoprotein, transportation systems, or so. And some people, it's probably 20% and other people, it's been reported as high as 60%. Wow. So it varies a lot, but it's a major player. It's not this infinitesimal minor baby pathway, it's in consequential acceptance, some rat

and a laboratory or something. This has been proven in humans now. I just read part of the review process and a really cool article coming out in a journal clinical lipidology where because of some biliary surgery to go ahead, the only way cholesterol gets out of this person's body was through the intestine and ate it. So he shows you the body can get rid of cholesterol without a billiard system. How many articles do you review a year? There's two things.

When you're an associate editor, the main editor will say, here's a submitted paper. Do you think this is pretty good? If so, send it out to four or five reviewers. They will send their review to you and then you make your decision and send it to me and I'll make the ultimate decision. But then also, I'm just also just a reviewer, where another associate editor would say,

I think Tom knows a lot about this subject. I'll ask him, would he please review this article to me? So, I don't know, I probably get about 15 articles a year where I'm the associate editor and probably double that where you're one of the reviewers or just one of several reviewers or so. But that's still about 50 papers a year that are coming across your desk. And I am blessed at my stage at a game to have a job where I do have, I don't have to see patients anymore. I'm not traveling throughout the United States a hundred times a year on flights doing lectures here and everywhere

So I am blessed in my current position or my true health diagnostic Peter probably when you hear this the first time you all get a list of my Who I work for and who I don't that's the only company I work for nowadays and I'm their scientific academic advisor. So my job is to stay on top of the literature, know all this stuff and explain it. So I have the freedom every day to spend time reading

and editing. And part of my education, anybody who's a reviewer or an editor with other, you don't learn a lot doing that because I don't know everything that's sent to me for review. But I'll assure this heck know way to go and get it. Well, there's a small group of us that are very lucky. We're having dinner with Jamie Underberg tonight, but Jamie said, there's like this group of like 10 people

that you always send out the most interesting papers to. And about a year ago, I had forwarded a number of these onto Bob Kaplan, and he was like, hey, can you put me on this email too? And I mean, we have to think about a way for you to create a special group where, because it strikes me that there's a broader group of people who would actually like to get the once a week email from Tom with the most interesting lipid paper I've read this week. Yeah, I think the best way to doing that is somehow contacting me at Dr. Lipfitter. I mean, you put a lot of this stuff out on Twitter too.

Yeah, I do, so you can research it. But you don't get the commentary because your emails are sometimes so great because what you'll do is you'll say, look, I know all of you aren't going to read this 12 page paper. Here's like a 300-word summary of what you would learn. And then that, like for me to read that, then open the paper. It's like, it's quick. And it was just a, I'm a lot, I really don't want to get, I don't know how many people listen to Peter's podcast, but it's immense.

I don't want 4,000 emails tomorrow, same for me on your, you know. And there's two things in spotted at email. One would be my interpretation of song, which is fine. That's Dave's friends of the media. No, but when we week, then we can attach PDFs to it that I might to an isolated friend of copyrights. Yeah, that's part of the bigger issue. That's part of an issue. So if it's open access, great. And if it is, I've probably tweeted it and you're best bed. And look, maybe I'm afraid it has to be questions. I mean, a lot of them are ass and I ignore them.

But I will answer it. My Twitter followers know, you're a legitimate, and I know, you're a direct message, you. Yeah, yeah. All right, so back to this. And if I don't, then there's a reason. Okay, so let's get back to the business of lipids here. So we've done a pretty good job explaining

one side of the equation at how cholesterol is regulated. A zoostarol would be cholesterol. It's the only sterile we, the animal kingdom produces. Yes, yeah, yeah. Cholesterol is the zoostarol. Yeah, yeah. Okay, so the other end of this regulatory pathway, so we've described the reabsorption side pretty well. There's

a synthetic side, which you've alluded to, obviously, by making the statements that, hey, every cell in the body can make cholesterol. And most of the time, it's sufficient for its needs. Obviously, exceptions, well, I'll let you explain what the exceptions are to that. There are certain scenarios and certain cells where they actually do need cholesterol from other tissues, but let's just go back to this synthetic stuff. Just briefly because I don't want to give anybody too much headache, how do we make cholesterol? Very complexly. It's a multi-stage process, 20 to 30 individual steps, where one molecule is changing into another, into another, and at the end of the day cholesterol is made.

And it starts very small. It's basically a cedal cohe, a cedal cohe, it's too carbon to carbon. A very small carbon chain molecule that keeps growing in length because cholesterol is 37 carbons in it. So it has to grow. Through much of that growth, it's just a linear structure. And at a certain point, this linear structure is long enough that it bends and changes into a sterile configuration.

Lannister, all being the first sterile that appears in the cholesterol synthesis chain. By the way, if I wanted a lab and labs with liquid chromatography and mass bag could give you a Lannister, a lanocostural measurement. And if it was up, hey, you're over synthesizing cholesterol, that's not the one they focus on. They pick a more downstream cholesterol precursor to do that. But even you could pick some of the earlier ones and they do serve as markers of cholesterol

synthesis, you know. Now, the cholesterol synthetic pathway is bifurcated. Tell me a little bit about that. So once you go through squalline and then it bends into a ring structure, lenoastral has to become cholesterol. So lenoastral and there's cross-thalk between the pathways, but it has one or two pathways that it's going to go down. And at the end of the day, both pathways

you'll wind up with cholesterol. And no good pathways don't come with names. So what are these names of these pathways? Yeah, Mr. Fesitius here. Yes. Well, my favorite, of course, is the block pathway. Because if you don't, and I put a lot, he was a lot of Twitter picture I had put up recently. He won the Nobel Prize for discovering this pathway in cholesterol. So it's probably important. They give you a Nobel Prize for discovering this pathway of cholesterol synthesis. So the block pathway would be,

then, Austral goes through a lot of precursors and becomes something called Desmostero, D-E-S-M-O-S-T-E-R-O-L. Desmostero looks exactly like cholesterol, except in carbon 24, there's a double bond. There's no double bonds in that tail. It's on the cholesterol molecule. So if I just saturate that double bond and does the monstral, I change it into cholesterol.

And of course, there's a specific enzyme that does that. If you inhibit it. Can I guess it? Yes. So this is just so people can understand what these enzymes mean. So I remember learning this in college. All right, so our med school in my college.

Enzymes always end in ACE, right? Now you just told me it was carbon 24. So it's probably going to have something to have. It's going to have a 24 in there. It will. And we often throw deltas into these things because deltadinotes the position of the bond. And did you say that Desmastral has a double bond at 24 and it has to be saturated?

Saturated. So it would probably be something like a delta 24 saturase or desaturase. Correct. All right, so that would be the enzyme. So when you say that, when you rattle that off, it sounds crazy and intimidating, but it's logical, right? It is. And this is why what you were talking about before you really have to notice stuff or you might not be

And the presence or the expression or the lack of expression at that enzyme is gonna Are you gonna use that pathway if you're using that and you don't convert Desmastro into cholesterol? You're gonna have a lot of Desmastl in your system, other consequences to that. There's a human disease called Desmosterl or also statifidicurs, and you rode that kid and come out alive, or if he does, he can live him for more than a few days. And is that disease a genetic deficiency in the enzyme?

Delta 2040 saturated? It is, yeah. Now there's another pathway, Lenoastral doesn't, and what determines, if you've got a double bond at that 24, but it's going to go through that pathway. Now, there's a lenoastral, has another pathway that goes through that's going to wind up with cholesterol. And the pre-colorceral, the penultimate, as we call it, the next to the last cholesterol molecule in that chain is something called lethosterol. Some people call it lethosterol, I call it lethosterol,

L-A-T-H-O, sterol. And that is called the canned Dutch rustle pathway, obviously after the guys who discovered that. By the way, they didn't get the Nobel Prize for some reason, even though that was... I think the Nobel Committee said we already gave one of these things out. And also, you can only have three people receive a Nobel Prize.

Oh, so that would be two. So whatever, everybody else, I guess, who worked in blocks alive, got no credit. But anyway, so it's the canned Dutch Russell pathway. So and it's kind of interesting, because in most people, both pathways exist. And there are some ways of jumping from one pathway to another. So at the end of the day, you're going to make cholesterol or so. But if you want to start interfering with these pathways, there are specific enzymes in each pathway that maybe that's, would be something you could play with, or maybe if you're building

too much of something, there's a lack of expression of that enzyme in you, which maybe has consequences, maybe it does. And so it's all important to know. But some of this may be tissue specific. One of the things I know it's a big topic of yours, and I hope we get into today is the brain. Everything I've talked about cholesterol today that we're measuring in a blood has zero

to do with cholesterol in the brain. Collestrol, lipidology in a brain might as well be in another different body, it has nothing to do with what the cholesterol is going on in the rest of your body. The brain makes every cholesterol molecule it needs and therefore there are no LDL particles delivering cholesterol to your brain.

So again, if we've got super- And to be clear, this is because the LDL particle just doesn't fit through the blood brain barrier. Correct. Even HDLs, we're a little bit of our cholesterol might get into it. It's delipidated through these ABC things. And some of that might work in consequential amount.

The APOB is, I guess, too big. The brain doesn't make APOB, so but the central nervous system has to traffic lipids from brain cells to peripheral nerve cells. APOE is the protein transporter in the brain. So cholesterol or any star will is attached to APOE in the brain, and that's how it traffics around there or so. And again, I've got nothing, apoeed, it's involved

with whatever lipoproteins are doing in the rest of your body also. So just understand it, but obviously, I want to, this is such an important topic that I absolutely want to come back to some glad you brought it up. But that said, at the moment, I would love to go back to this synthetic stuff.

So you've got, each cell in the body can basically start with the most simple carbon subunit, which is a two carbon subunit acetyl CoA, and through a process of carbon fixation go on to make these very complicated four-carp, four-ringed structures, they, first and foremost, the cell uses these things. They make the important part of the cell membrane. If anyone... Orginal membranes in the posterior. That's right, so everything from the Golgi apparatus

to the ER, to this movie R, Ruffia, et cetera. You also, you don't have to be, I think, a biochemist who look at a picture of a molecule like cortisol, estrogen, testosterone, and I think you could show a four-year-old, a small picture of those, and then a molecule of cholesterol, and they would be like, hey, those look similar. Yeah, it's like maybe I look like my mother and father, or did they have an origin, or did they come for an answer?

Sure. So certain cells can certainly transform cholesterol into reproductive hormones, or adrenal cortical hormones. Certain cells, hepatocytes, can transform cholesterol into reproductive hormones or adrenal cortical hormones. Certain cells, hepatocytes can transform cholesterol into a bile acid. I don't think there's any other cell that can change cholesterol into anything else. So when people talk about cholesterol metabolism, there is no cholesterol metabolism. It can be converted into satin and specific tissues, but it can be excreted, that's it. There's no other way your body can handle this.

So do we, is there any evidence that we use cholesterol for energy? Zero. Why? There's no energy is really coming out of a saturated of the fats that have the most, no double bonds. That's the most they're carrying the most ATP. Cholesterol is not producing energy.

Collestral cannot be metabolized and produce ATP in the process. I mean, to me that's the bigger issue, right? I think, so some people get confused about this. It's not that there isn't energy in a carbon-carbon bond or a carbon-hydrogen bond because that's exactly what's being liberated in the metabolism of a fatty acid.

The point is we don't have the enzymatic machinery to undergo the chemical process of breaking down those bonds and liberating the chemical energy into electrical energy. Can't metabolize cholesterol. Cholesterol ester, which carries that fat, S can be deastarified, but your cells aren't making cholesterol ester. The liver is, the intestine is, but a etypusite's are. My hypothesis for why that's the case, which could be entirely bullshit, and I'm just making cholesterol ester, the liver is, the intestine is, but the etypusites are. My hypothesis for why that's the case, which could be entirely bullshit, and I'm just making it up, but that's what hypotheses are.

Their guess is, is that it would have been evolutionarily dangerous if we could have metabolized cholesterol. Because in periods of fasting, which we all did evolutionarily, the last thing you want your body doing is going after cell membranes and hormones as a source of energy. So I think it's actually a very deliberate design, quote, I use design in quotes, to say, hey, no matter what your cholesterol and your hormones are off limits during starvation. And instead, we evolved this other remarkable pathway of ketosis, which takes an ample substrate of fats and goes down

the path of metabolizing those, and actually saving our muscle from the catabolic destruction that we would undergo if we couldn't undergo ketosis. This is the brilliance of Peter Othia to me that he can come up with what sounds like a super plausible thing. I'm not smiling entirely bald shit. I can tell you how to sell Gachillesreau what it can do with it, but he's figured out what sounds like a really plausible reason. And everybody's so worried about depleting cholesterol in the plasma is measured by LDL

cholesterol, which has nothing to do with anything, because actually there's more cholesterol in your red blood cells than your own lipoprocess. Yes. And you're not making that zero by any means, by using lipid drugs or something. So, but you can't deplete a cell of cholesterol, be on a certain amount, so you're going to script cellular function. And you can't put too much cholesterol in its cell because it'll crystallize and kill that cell.

So, that's why it's so tightly regulated synthesis, influx and e-flux. Now are there cells under certain circumstances for whatever reason can't make enough cholesterol? Yeah, there are pediatric disorders where if you don't synthesize cholesterol, things happen to you and you to row. Well, the other thing we see this in, and I didn't, I don't even know why I started noticing this, but this is one of the things I used to do in residency that used to kind of piss off some of the attendings, is I would do little experiments. And it was always a measurement experiment. So it wasn't like I was putting a patient at risk other than a few more milliliters of blood were being drawn.

But I remember once happening on a finding, which was maybe by accident, I had checked a lipid panel on a patient in the ICU. And I saw something interesting and I kept rechecking it and other patients over and over again. I kept seeing this, which was, anytime a patient was having a SIR's response, that's capital S, I, R, S systemic inflammatory response syndrome. So this is the vaso, you know, metabolic response to sepsis infection, trauma, you name it, enormous drop in HDL cholesterol.

And I think we could look at that today and say it's very likely that what we were seeing was in that period of profound physiologic stress, the body is greatly ramping up its hormone production, leukocorticoids and others. And that would be one of the situations where cells were actually, you know, HDL was now delivering cholesterol to the adrenal glands in a period of, you know, because that's about the most physiologically stressful thing that an organism can respond to. Again, I don't know if that's been documented, but it seems to me pretty logical, but that would be at least the most plausible explanation

for why HDL could plummet in patients who are going through that degree of stress. Yes, and by the way, it's the reason you never do an allipid profile in an acute situation. Yeah, it's a complete reason. Because a lot of lipids are going to be transiently changed or so here. But, Peter's right, we know this for a lot of reasons.

Clearly the erythroideogenic tissues need cholesterol to make their steroid hormones be they reproductive organs or your adrenal cortex. In the situation, Peter's talking about cortisone is a pretty useful alharmonia have around or other mineralic corticoids and things like that are. So clearly those organs, those tissues are going to need a lot of cholesterol pools to make all that. So they turn up their synthesis rates, so they make a lot of cholesterol, but they would also tune up their synthesis rates, so they make a lot of cholesterol, but they would also tune up their, hey, let's gather some exogenous cholesterol, so to speak.

So those cells would upregulate LDL receptors. And that's a case where there's a tissue that might under certain circumstances pull in LDL particles full of cholesterol ester. They would de-astarify it and use it. But in a physiologic person who's not in one of these acute situations, the adrenal gland most of the time just makes all the cholesterol it needs, but if it needs a secondary source, that's why you have HDLs. HDLs have a half-life of five days.

One of the reasons they circulate for five days is it's a floating plasma reservoir of cholesterol for tissues that might actually need cholesterol. Now my nose cell that I talked about before doesn't need HDLs or anybody else to deliver cholesterol to it. No other cell does, except those steroidogenic tissues. In other words, to be really clear and specific, you're sloughing off endothelial cells in your nose every day, while you have to replace them. The lion's share of the cholesterol requirement is to make a cell membrane.

It's just, it has the machinery. It has the machinery within the nucleus to produce that just as it's producing other structural proteins. Right. So, and this is what people just translate low cholesterol plasma measurements to think you're screwing up cells throughout the body and you're not. Yeah, this is one of the challenges that I've never come up with a great way to explain this idea of flux, which is you do a lipid measurement at a moment in time.

You're getting a snapshot of what's in the plasma at a moment in time, which doesn't give you two pieces of information. How is it changing over time and what's the movement or the velocity? And secondly, it gives you no insight into what's happening in the cell or what's happening in the endothelium for that matter. And instead, that's the nature of lipidology as you have to be able to extrapolate to these other things by indirect measurements. It gives you zero insight. The only usability of plasma measurements are as surrogates of lipoprotein defining whether you have apob, apoei one particles, and we know too many apob particles. Your over time at increased risk for after a throschorotic disease or events. Otherwise, why even measuring

lipids in the plasma? It tells you nothing. And what we're talking about, you call it influx-y, flux, and that nails it down, but it's cholesterol-homiestasis, or sterile-homiestasis. And your body has evolved a lot of ways to do. Interesting, too too, say that a crisis is going on, a adrenal needs continued. It's not just, hey, you cured yourself in 12 hours overnight, you survived whatever. And if that catastrophic process was ongoing, HDLs eventually would run out of cholesterol.

You just said your HDL cholesterol level is plummeting, and that's been documented many times. So the HDL all of a sudden has to go back and start grabbing cholesterol molecules from some other tissue and get it to the sterodogenic tissue. And the number mega place where HDLs get most citrillipidation as it goes right back to the liver and gets lipidated or what is the biggest cholesterol storage organ in the body, not the liver, your adipocytes. Everybody thinks adipocytes are just throwing triglycerides. They're a massive storage organ. So, baby HDLs that are depleted, they run back to the adipocytes, which express this ABCA1 transported at pumps out all their cholesterol to an HDL, which boom right back to the adrenal

gland. Bounces back and forth like a ping pong ball. You can find all of this information and more at peteratiamd.com forward slash podcast. There you'll find the show notes, readings, and links related to this episode. You can also find my blog and the Nerd Safari at peteratiamd.com. What's a Nerd Safariafari you ask? Just click on the link at the top of the site to learn more. Maybe the simplest thing to do is to sign up for my subjectively non-lame once a week

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