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

00:00:00.000 Hey, everyone. Welcome to the Peter Atiyah Drive. I'm your host, Peter Atiyah.

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00:00:41.300 Hi, everybody. Welcome to episode two of five in the week of Dayspring. This episode,

00:00:47.920 we cover lipoprotein basics, what's lipoproteins and lipids 101. We talk about Goffman and the

00:00:54.060 ultracentrifuge and how we came up with these whole ideas of densities of lipoproteins.

00:00:58.440 We get into very specifics around the lipoprotein structure, their function, and their metabolism.

00:01:03.880 We talk about how to measure the lipoprotein and the cholesterol content and what NMR is and how it

00:01:09.640 has changed the game a little bit. We get into the distinctions between LDL cholesterol, LDL particle

00:01:14.840 number, and ApoB. There is some confusion here amongst physicians and presumably amongst patients.

00:01:21.040 So hopefully that will clear that up. We get into the biochemistry of lipids,

00:01:25.300 and then we talk about sterols specifically as a more broad category.

00:01:32.280 Now, before we could measure anything to do with lipoproteins, if my memory serves me correctly,

00:01:38.060 it would have been the late 40s, very early 50s when the first assays were developed,

00:01:43.460 maybe it was 1951, that could actually just measure total cholesterol.

00:01:47.240 So you would take plasma from a patient, you would presumably in an assay break down

00:01:53.460 all of the lipoproteins and just aggregate the total amount of cholesterol, and you would yield

00:01:57.820 that number, which still amazingly shows up on a panel today. You go and get a blood test,

00:02:02.680 and it might say your total cholesterol is 200 milligrams per decilator. So that was,

00:02:08.400 am I correct? That was the early 50s, maybe?

00:02:10.200 No, I think they were analyzing cholesterol long before that, because that's a molecule. You can

00:02:15.300 take blood and dissolve whatever you've got to dissolve, and cholesterol appears. So they had

00:02:20.200 cholesterol measurements for a long, long time. It's like the first lipid anybody could ever

00:02:25.420 measure. What you're talking about in the 50s is where John Hoffman discovered that,

00:02:31.820 hey, wait a minute, there are no lipids floating around in plasma, because lipids are incredibly

00:02:36.000 hydrophobic. Your plasma is water. You can't have lipids circulating in plasma. So lipids obviously have

00:02:42.440 to be within what I call water-soluble lipid transportation vehicles, and that turns out,

00:02:47.840 of course, to be a lipoprotein, a protein-wrapped collection of hydrophobic and amphipathic lipids

00:02:55.620 that just wouldn't be in your plasma unless they're attached to a protein. Peter mentioned

00:02:59.820 albumin. It's a protein. So lipids can attach to albumin and be circulated around and other type

00:03:05.940 proteins, but albumin is the most frequent protein in the blood. So it serves as a carrier. I think an

00:03:10.940 albumin can carry like 17 molecules of cholesterol, a few of phospholipids too. So it's a player out

00:03:17.740 there. We've got a ton of albumin in our plasmas. You'd be shocked to find out how much cholesterol is

00:03:22.340 in it. Not quite as much as in life. Albumin's kind of an amazing protein. It'll carry hormones. It'll

00:03:28.220 carry just about anything. It's remarkable. Yeah, and it has everything to do with osmotic

00:03:33.940 pressures and things like that. So albumin is kind of an essential little protein, to say the least,

00:03:39.700 performing many, many functions. But when John Hoffman, a physicist, by the way, who had

00:03:46.840 physicists have been playing with ultracentrifuges for a long time, separating their radioactive

00:03:51.860 particles and stuff, he somehow wound up separating lipoproteins or saw things floating around in a

00:04:00.340 centrifuged test tube that he then identified as the lipoproteins. So if you learn nothing else today,

00:04:08.180 learn the first thing is lipids, for the most part, go nowhere in the human body unless they're a

00:04:14.100 passenger inside a lipoprotein. So if you believe there are a lot of lipid-associated diseases, and I

00:04:21.160 certainly believe atherosclerosis, you cannot have atherosclerosis without a sterol, a lipid being in

00:04:27.920 your arterial wall. And I know that arterial wall didn't oversynthesize sterols, creating a sterol

00:04:35.300 buildup. Somebody had to deliver those sterols there, and that, of course, turns out to be a

00:04:40.140 lipoprotein. And one of the places a lipoprotein should never deliver sterols to, to any serious

00:04:47.000 degree, of course, is your arterial wall intima. So being a Jersey guy, one of my standard jokes on a

00:04:53.220 lecture circuit was atherosclerosis is just an evidence of illegal dumping, where a lipoprotein,

00:05:00.380 instead of bringing lipids to whoever it's supposed to be bringing, it was bringing sterols to the

00:05:04.880 arterial wall. And over decades, you got a problem. You know, it could do it for a few days, six months,

00:05:12.040 you're not going to die of atherosclerotic disease.

00:05:14.120 So when did it become clear? So Hoffman figures out by first principles, basically, he imputes that

00:05:20.460 there's got to be something that is transporting this very, very hydrophobic molecule through plasma.

00:05:26.480 It doesn't, you know, I mean, it's, it's easy in retrospect to make light of what an observation

00:05:31.620 that is. But the next observation would be, it would lead to be spherical, right? I mean, it's,

00:05:35.820 it's to optimize the volume in which you could transport, it would have to be spherical.

00:05:40.400 You're a mathematician, a volume of the sphere, the third power to radius. So if you're going to

00:05:44.660 devise a transportation vehicle, a sphere is better than a flatbed truck, you know?

00:05:49.220 So how long was it until, I mean, I know the answer to this question, but I just have to sort of

00:05:54.780 tee it up who then went on to figure out these things occur in different densities. It's not

00:05:59.180 just one, there's not just one spherical molecule that's transporting these things. Cause this is a

00:06:03.820 beautiful story, right? It was Hoffman. He noticed that there, and they weren't calling them April B

00:06:09.960 and April A one particles at the day, but they were different densities. They were gigantic.

00:06:15.380 So explain what you mean by density. Cause this term, you know, we talk, everyone knows low density,

00:06:19.780 but tell me what, where that terminology actually came from.

00:06:24.340 Well, I think it has to do with water has a certain density. So it's whether things float

00:06:29.440 in water or sink in water. We know rocks sink if we throw it in a pond. So they're very dense

00:06:35.200 things. Whereas other things float on top of water, they obviously are less dense than water is. So

00:06:41.940 everything is relative to water there. So if you establish what you think is the density of water,

00:06:47.580 things that float. So when he separated these things in a centrifuge, the lipoproteins or these fat balls

00:06:54.320 that didn't move at all, were obviously very buoyant. Some sunk just a little bit. So they were less

00:07:03.060 buoyant, but still pretty buoyant. And some went right to the bottom of the test tube, obviously

00:07:07.260 incredibly dense. And it turns out what makes a lipoprotein buoyant is a ratio of its lipid fat content.

00:07:17.240 Because I think we all know fat floats on water. Or proteins, check out the molecular weights of

00:07:23.540 proteins. Really heavy, they sink. So they're the rocks. So your density of a specific particle here,

00:07:31.080 a lipoprotein particle, is going to be related to its lipid content versus its protein content.

00:07:37.020 So our big monsters that are delivering, as I told you, triglycerides, but have a lot of phospholipids

00:07:43.600 on our thing, they have some proteins, but they have so much lipids, they float. They're the buoyant

00:07:49.260 ones. And as they lose the lipids, they become smaller. Now they might lose a few proteins as they

00:07:56.620 shrink, but they're really using the lipids.

00:07:59.080 But they're fundamentally concentrating protein as they get. I mean, because when you go from

00:08:03.800 chylomicron, even though they're not the same lineage, so I want to be very careful, you'll

00:08:07.400 explain this in detail. You do not go from a chylomicron to a VLDL, to an IDL, to an LDL,

00:08:12.400 to an HDL. There are three separate lineages I just described. But in size, they loosely track

00:08:19.340 as the smaller they get, the more they've concentrated protein.

00:08:22.540 Within every category of lipoproteins, B, you talk chylomicrons, which intestinally produce,

00:08:28.300 VLDLs, hepatic produce, and the classic teaching is as VLDLs become smaller, you call them intermediate

00:08:35.340 density and low density. We now know the liver can produce an LDL without making a VLDL first.

00:08:43.340 High densities, which form themselves in the thing, sort of go the opposite way, whereas

00:08:48.660 the VLDLs and chylos come out as big fat monsters and lose lipids and become smaller and denser.

00:08:54.960 The HDL, as it gathers lipids, becomes bigger and more buoyant. But within every class of lipoproteins,

00:09:03.360 you're going to have a heterogeneous range of densities from big species to small species.

00:09:10.500 And this is why, to me, I like to tease because you always hear people talk about the small,

00:09:14.960 dense LDL. Within every lipoprotein classification, the smaller particle is always more dense than the,

00:09:21.920 so that's a redundancy.

00:09:22.980 It's a redundancy.

00:09:23.540 Just tell me dense LDL. Just say small LDL. I know it has to be dense, or if it's dense,

00:09:27.700 I know it has to be small compared to its sister particles within that family or so.

00:09:33.140 Somehow small has only been applied more frequently to LDLs, because that's the killer one,

00:09:39.600 or HDLs. Oh my God, you want to have the big HDLs. Another joke that's turned out, but for a

00:09:46.080 longest while, if you don't have big HDLs, you're in big trouble or so. And if you've got the small

00:09:51.360 LDLs, you're in the biggest trouble. That basically turns out to be because if you have small LDLs,

00:09:56.200 you need a ton of them to carry whatever your lipid load is. So you've got a super high LDL

00:10:01.680 particle concentration if you have small LDLs, and that's more related to its pathology per se than

00:10:07.920 the size. Not that that won't cause certain functional characteristics of the LDL. But the

00:10:14.880 VLDL, the chylos come out big and they shrink. Now the reason though that differentiate chylomicrons

00:10:22.560 and the VLDLs, IDLs, and LDLs is they have a lot of apoproteins on their surface, which they do lose

00:10:29.320 as they shrink. But there's one protein they never lose, and it's the one that has the most

00:10:34.420 massive molecular weight, apoprotein B. So that's why they are never going to be as dense as an HDL

00:10:41.760 particle because an HDL doesn't have this monstrosity high molecular weight apoprotein B on

00:10:46.800 it. It's got other things, far less lipids. But to some, the LDLs, IDLs, VLDs are always going to be

00:10:54.520 way more buoyant because of it, because they do have a little bit of an anchor on them, creating

00:11:00.040 to their densities that apoprotein B. And it's the only, as you study apoproteins, there are probably

00:11:06.300 up to 20 to 30 of them now, all of which have certain functions that it sort of directs a

00:11:12.440 lipoprotein down which path it's going, a catabolic path. The only apoprotein, by the way,

00:11:19.260 I get definitions out the way, apoprotein, apolipoprotein, lipoprotein. An apoprotein is

00:11:25.240 the protein your cell makes. Once it binds to lipids, it's called an apolipoprotein. And of

00:11:31.940 course, the whole particle itself is called the lipoprotein.

00:11:34.340 So let me re-synthesize that. The lipoprotein is the spherical structure whose membrane is made

00:11:40.960 up of mostly these phospholipids but also other lipids. The apoprotein is the thing that kind

00:11:47.300 of gives it its signature. So for example, the chylomicron has a B48, the IDL, VLDL, and LDL have

00:11:54.300 a B100, et cetera. That's just called the apoprotein. Once the apoprotein, and I assume

00:12:01.120 it's covalently bound to the lipoprotein, that becomes the apolipoprotein. And we abbreviate

00:12:07.680 that APO, fill in the blank.

00:12:10.260 Yeah. So if I took a VLDL particle and later on I'll tell you, boy, on a VLDL, you're going

00:12:15.680 to find APOC1, APOC2, APOC3, APOA5, and including APOB. But it's going to lose everything but

00:12:25.140 APOB as it's transferred, lose most of the other ones because they're transferable. They

00:12:30.100 can jump on different lipoprotein if they so desire. The APOB never does. For a bunch of

00:12:36.520 reasons, it provides the structural integrity to that particle throughout its existence.

00:12:41.160 But APOB turns out to be the ligand for receptors that internalize those particles when your body

00:12:49.420 don't need them anymore. So the LDL receptor that everybody knows about.

00:12:53.100 So the ligand, just for some people listening, it's like the key that fits into the lock. If

00:12:57.660 the receptor is the lock, the ligand is the key. And in biology, that's sort of how everything

00:13:02.500 works. The key has to fit the lock.

00:13:04.480 Correct. And if it didn't, then that lipoprotein is going to stay in your plasma and probably

00:13:08.880 wind up going somewhere where it's going to create a pathological state.

00:13:12.340 So when was it figured out that APO lipoproteins are going to come and go, but there's one of

00:13:19.040 these ones that not only always stays, but you have one? Because that's a big deal. The realization

00:13:24.460 that APOB100, if you knew that concentration, you had a proxy for how many particles you had.

00:13:32.320 Yeah. So Goffman certainly figured out there were proteins involved here, but he wasn't applying

00:13:36.720 that nomenclature to him and everything. It's guys who further, a few years further down the

00:13:41.840 road, Fredrickson, Levy, and Lees.

00:13:45.020 We've talked about those with Ron Krauss.

00:13:46.880 We realized there are some very important structural and functional proteins on these

00:13:54.140 particles that we better start investigating and giving names to. So their research led to the

00:13:59.920 identification of all of them. And ultimately, I mean, we know now the amino acid breakdown of every

00:14:07.040 darn APO protein that's in our body or on our particles and everything. So it just, when one

00:14:14.880 researcher invents a little bit of the story, other ones pick up the pieces and start further

00:14:21.500 elaborating on it with different studies and technology improves. And some of these things

00:14:26.320 that were not assayable at one point become that you can measure them and identify their

00:14:32.940 structure and everything. So it's one of these evolutionary things. And, and it just made such

00:14:38.680 perfect sense too, because we knew these particles are changing. So they're undergoing catabolic

00:14:44.320 processes. Why? What's doing that? And then all of a sudden you figure out that these ligands,

00:14:51.800 these APO proteins are keys to various receptors. Some of those receptors pull the particle next to

00:14:59.180 where there's an expression of a lipid dissolving enzyme, a lipase, and it starts to all make perfect

00:15:06.180 sense to you. So over time, we've identified numerous of these enzymes that can catabolize

00:15:12.260 lipoproteins, numerous of the receptors that temporarily bind these particles in place so they can

00:15:18.380 undergo this thing. Ligands that lipidate, fill the particles with the lipids or delipidate them.

00:15:25.940 So if you're listening to this and you're confused at this point, it's okay. One, there's going to be

00:15:31.340 killer show notes, but more importantly, we're going to take a step back now. I'm a guy listening to this.

00:15:36.720 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

00:15:43.060 and it spits out the following. Total cholesterol equals this. LDL, and they won't even, it'll be

00:15:49.020 worse. It'll say LDL equals this. HDL equals this. Triglyceride equals this. And maybe it will say

00:15:55.420 non-HDL equals this. What do those things mean in relation to everything you just said?

00:16:01.140 Yeah. First of all, the misinformation on labeling lipid metrics is one of the things

00:16:07.400 a miracle. Hasn't given me a stroke yet. I do a lot of peer review. I'm going to,

00:16:12.240 one of the associate editors. That's why we're fasting you, Tom.

00:16:14.820 Journal of clinical lipidology. And I will reject a paper instantly that uses improper lipid metrics.

00:16:21.720 Don't tell me the LDL is this because LDL is a low density lipoprotein. It's not a laboratory metric.

00:16:28.940 You want to tell me what the LDL cholesterol is, the LDL particle number is, the lipidomics of an LDL

00:16:34.600 is the LDL oxidized or not? Great. We do have assays that will measure that. So let's please

00:16:40.580 all you, don't identify yourself as an ignoramus. And like I've told this to many of the top

00:16:47.340 lipidologists in the country who lectures, stop telling people what's your LDL. Ask them,

00:16:52.580 what is your LDL cholesterol? What's your, if we don't all talk the talk, you're never going to

00:16:57.580 understand the process. So this patient almost assuredly is talking about total cholesterol,

00:17:03.200 LDL cholesterol, HDL cholesterol, and non-HDL cholesterol.

00:17:07.060 Yeah. So I'll give you a quick, and by the way, Peter did mention something very quickly before. I

00:17:11.780 just wanted to expound. He talked about, hey, ApoB 100, ApoB 48. ApoB is a giant structural,

00:17:18.500 non-transferable apoprotein that's on chylomicrons or VLDLs. The intestinal machinery that synthesizes

00:17:26.660 a chylomicron makes a certain type of ApoB and the ApoB that is made in the liver makes a much

00:17:33.560 bigger ApoB. It has a higher molecular weight. So they knew the ApoB that's being made in the

00:17:40.280 intestine is much smaller. So it turns out to be that the ApoB in the intestine is 48% of the

00:17:47.240 molecular weight of the hepatic produced ApoB. If you get into genetic ApoB, you'll see ApoB 31,

00:17:54.400 that has 31% of the molecular weight of what's considered a normal ApoB. So when you hear ApoB

00:18:00.500 48, that should identify it as an intestinally produced ApoB particle, and a liver would be an

00:18:07.620 ApoB 48. And LDLs that come out of the liver should have ApoB 100 on it, like the VLDL. Or a VLDL,

00:18:14.740 it becomes an LDL. The ApoB 100 is still there. So just keep, if you hear 100 or 48, what does that

00:18:21.980 mean? It sort of tells us the origin. We are going to be talking about nuclear magnetic resonance.

00:18:27.080 And one of the parameters that used to give you a lot on, less so nowadays, is VLDL particle

00:18:32.360 concentration. When you analyze a lipoprotein using nuclear magnetic resonance, it cannot tell

00:18:38.780 the difference between a chylomicron and a VLDL because NMR doesn't measure the proteins. It's,

00:18:44.740 hey, that's a very big particle. So it has to be a VLDL or chylos. Most of your big particles are

00:18:51.120 VLDLs. Yeah. And even in a postprandial state, condomicrons have half-lives in minutes. They're

00:18:56.560 gone. So the vast majority of VLDL particle number via NMR is still VLDL part of, but there could be

00:19:03.840 some problems.

00:19:04.180 All right. But I want to go back to our lady. So her total cholesterol is 190 milligrams per

00:19:09.400 deciliter.

00:19:09.760 So total cholesterol, remember my premise that lipids go nowhere in the body unless they're

00:19:15.200 within a lipoprotein. It's not exactly true, but for today's purposes, that is true. And certainly

00:19:20.980 understanding lipid metrics, that's true. So total cholesterol would be the laboratory has

00:19:27.240 separated all your lipoproteins from the serum and they're take how much cholesterol is in this serum

00:19:34.000 tube. So where would that cholesterol be that they're analyzing? Well, it would be found in,

00:19:39.760 if there were any chylomicrons there that were hanging around or maybe they didn't fast.

00:19:45.200 Some of it would be chylomicron cholesterol. Some of it would certainly be VLDL cholesterol,

00:19:51.700 a lesser amount because there's just so many, so fewer of them would be intermediate density

00:19:56.100 cholesterol particles. And the rest would be in either LDL particles, low density lipoproteins or

00:20:02.900 the high density lipoproteins. There are other types of LDL particles called LP little a, which

00:20:09.480 we'll talk about. So total cholesterol is all of the cholesterol. It is every single lipoprotein that's

00:20:15.220 in a deciliter of your plasma.

00:20:17.340 And that is directly measured. It is not imputed.

00:20:21.320 That is not a calculation. That is assayed. So it's, anyway, there's always a coefficient of

00:20:26.680 variability. That's inaccurate. And so if you want to use cholesterol for anything nowadays,

00:20:32.980 because let's face it, that was the first parameter looked at in the epidemia. And they

00:20:37.480 certainly correlated total cholesterol levels with the risk for heart disease. But think about what I

00:20:42.760 just told you. It's the cholesterol within all the lipoproteins. What is the, if you count it

00:20:49.600 particles, what is the most numerous particle in your bloodstream? The ApoB particles. Well,

00:20:55.660 actually the HDLs are more, but they're so small, they don't carry much cholesterol. So most of your,

00:21:01.620 if you want to put a parentheses around it, atherogenic cholesterol would be within your ApoB

00:21:06.980 particles. So if you want to ascribe any use to total cholesterol, it's a real poor man's ApoB

00:21:14.000 level. In general, most people with very high total cholesterol levels will have a very high

00:21:19.940 ApoB level on there. And that's the real reason they're at risk for atherosclerosis because those

00:21:24.680 are the particles. Yeah. I mean, the original epidemiology basically said, you know, you have

00:21:29.860 to sort of applaud them for doing the best they could with the tools they had, but let's take total

00:21:34.040 cholesterol, which is at the time, the only thing we could measure clinically. Let's take the patients

00:21:38.820 who were in the top 5% and the patients in the bottom 5%. Was there a difference in their risk of

00:21:45.700 MI? And the answer was yes. Now it would be another, at least decade until Framingham. It's kind

00:21:53.780 of an interesting story, right? How it got this, this part of the story got ignored in Framingham was

00:21:58.500 that low HDL cholesterol and high triglyceride turned out to be four times more predictive of MI

00:22:05.520 than high LDL cholesterol. And again, this is still crude measurements, but that sort of didn't come

00:22:12.160 back into, people didn't come back to try to explain why that might be the case until Jerry Riven had

00:22:17.260 sort of done his work on metabolic syndrome. But I also realize I'm going to get us off topic. I want

00:22:21.120 to go back to this other question. So we've just explained what 190 milligrams per deciliter means.

00:22:25.260 When it says HDL, it really means HDL cholesterol as evidenced by the units. So those will either be

00:22:31.460 measured in millimole or milligrams per deciliter. That's a direct assay or an indirect assay?

00:22:37.360 Yeah. So Framingham, of course, did measure total cholesterol, was easily available. They did it.

00:22:42.400 They measured triglycerides too, although they really had no clue what they, where they related to

00:22:47.620 it. But it was measurable. Glycerides, they called it glycerides back then. And they did have a

00:22:53.020 direct assay for HDL cholesterol. They, you know, you could also measure, you know,

00:22:59.980 you can centrifuge particles, you can take out the LDL fraction and analyze how much cholesterol is in

00:23:05.720 them. That's theoretically the gold standard. You can separate the HDL product, but that's too

00:23:10.500 time consuming. Nobody's got ultra centrifuges. So to have real world tests, chemists had to develop

00:23:17.940 direct assay. So HDL assays were developed real early on. So Framingham could not only measure

00:23:23.740 total cholesterol, they could measure, directly measure, not calculate HDL cholesterol. What they

00:23:29.860 could not measure, and it took a long time, was LDL cholesterol.

00:23:34.820 Without ultra centrifugation.

00:23:36.940 Without ultra centrifugation, correct. In the 70s, somebody came up with a formula that here's a way of

00:23:43.020 at least estimating or calculating LDL-C, which took fire, because by the 70s, they realized the

00:23:50.080 most numerous atherogenic lipoprotein were the low-density lipoprotein. So as Framingham started

00:23:57.200 calculating LDL cholesterol, they, whoa, this is the story here. So they calculated for a long time.

00:24:03.120 So just to be clear, what they're doing is they're directly measuring total cholesterol,

00:24:07.980 because you can just do that off serum. They precipitate out the HDL, right? So you could measure

00:24:12.760 the HDL without ultra centrifugation, and you could measure triglycerides. So now the formula

00:24:18.760 for estimating LDL cholesterol became total cholesterol minus HDL cholesterol minus triglycerides

00:24:27.080 over five. Why the triglycerides over five?

00:24:29.700 Yeah. So Frida Wall put two and two together and realized, hey, total cholesterol is in essence

00:24:35.700 VLDL cholesterol plus LDL cholesterol plus HDL cholesterol. A equals B plus C plus D. So if I

00:24:42.480 know parameter A and I know parameter D and I know parameters C, I can figure out what parameter

00:24:47.300 C is. And so what he did was he said, I'm going to ignore chylomicron and IDL and LP little

00:24:52.660 a. Well, LP little a was at that point probably being not even, it was being included in the

00:24:57.280 LDL. Yeah. They were basically counted as, the chylos are counted as VLDLs and the IDL is

00:25:03.540 counted as LDL. Yeah. Okay. So therefore, if I know the HDL cholesterol and I know the total

00:25:11.180 cholesterol, if I only knew VLDL cholesterol, I could easily calculate what your LDL cholesterol

00:25:18.300 was. So then it becomes, uh, you have to know what is a VLDL particle. And at least if you have

00:25:25.820 a physiologically normal VLDL particle, most of those lipids are in the core of the particle,

00:25:32.560 no triglycerides on the surface, no cholesterol ester on the surface. If I only knew the composition

00:25:39.020 of these particles, I could figure out. So they came to the realization that on average, a physio,

00:25:47.460 at least in the 1970s, a VLDL particle composition had five times more triglyceride than it did cholesterol.

00:25:54.220 And virtually in a fasting state, all of the triglycerides, they're not in an HDL. They're

00:26:00.160 not in an LDL. We're not measuring chylomicrons because they're in a VLDL. So cholesterol in a

00:26:06.980 VLDL has to be triglycerides divided by five because there's one fifth as much cholesterol in

00:26:12.000 a VLDL particle. So VLDL cholesterol is triglycerides divided by five. So now if I have HDL cholesterol,

00:26:19.220 VLDL cholesterol, total cholesterol, you do the math, you're a mathematician, Peter. It's

00:26:23.680 very easy to, aha, this is what your LDL cholesterol is. And as they calculated that and they applied it

00:26:29.760 to clinical trial data, correlations are very, very good. And they knew that's probably where

00:26:35.580 the money is because of our APOB particles, the particles that are the ones delivering these

00:26:41.300 sterols to the artery wall, the overwhelming majority of them, 95%, at the lowest end, 90% are

00:26:49.600 LDL particles. It's where the money is. We need a metric of LDL and the calculated LDL-C was

00:26:57.540 earliest introduction to that. Now, down the road, people have developed direct assays of

00:27:03.220 LDL cholesterol. But you know what? Turns out it's not that much more accurate than the calculated

00:27:09.820 VLDL cholesterol unless as you start to go up, up, up in triglycerides, that calculation

00:27:15.140 falters. Which is something we're seeing more and more of today than we saw in the original

00:27:20.300 Framingham. Dad, it was said, oh boy, if your triglycerides get above 400, don't use that

00:27:24.360 calculation. It's ridiculous. So they actually developed a direct LDL-C to give us an LDL

00:27:30.080 cholesterol metric in people with triglycerides of 800, 1200, 4000, where now you know what their

00:27:36.780 LDL cholesterol is, whereas the formula would be useless there. We now know that formula starts

00:27:42.520 to become kind of erroneous at somewhere between a trig of 150 and 200 and the higher you go above

00:27:49.280 200. Be careful with a calculated LDL cholesterol and rely on direct LDL-C. But, and here's what

00:27:58.700 nobody realizes, the only value that calculated or directly measured LDL cholesterol brings to the

00:28:06.440 table, is it's a better poor man's estimate of your LDL particle concentration than is total

00:28:13.180 cholesterol. So an LDL cholesterol would correlate better with ApoB or LDL particle concentration than

00:28:20.380 what a total cholesterol. Down the road a little bit, we've come to the realization that if we

00:28:25.400 get another calculation called non-HCl cholesterol, that even better correlates with ApoB or LDL particle

00:28:32.440 concentration than does LDL cholesterol. So that's why that's the new thing that's in vogue.

00:28:38.660 We also, thanks to your, I know you spent a little time down in Hopkins, some of the lipid guys down

00:28:44.260 there have invented a much better calculated LDL cholesterol, which they're trying to get

00:28:48.960 incorporated rather than the older calculation of the Friedewald that we've been using forever and

00:28:56.040 most labs entirely use nowadays or so. So NMR, which is, you know, my first exposure to NMR was in

00:29:04.040 high school when we were taking organic chemistry and you learned that we had these tests. I still

00:29:10.620 remember how fun these tests were, where they would show you an NMR spectroscopy and you had to figure

00:29:15.680 out what the molecule was by knowing where those spikes were. So was Jim Otvos the guy that first figured

00:29:22.560 out that you could use that stuff to actually count the number of these ApoBs? Yeah, I think

00:29:30.740 Otvos was certainly one of the early pioneers and over father time, the real pioneer who evaluated

00:29:38.360 lipids and lipoprotein using nuclear magnetic resonance spectroscopy. He knew that lipids would

00:29:44.480 emit specific spectral signals that he could analyze and through very complex mathematics, turn them into

00:29:52.120 a variety of lipoprotein metrics, including you can do an NMR LDL cholesterol level and LDL triglyceride

00:29:59.320 level. In the future, that's one of the ways we're going to be measuring phospholipids on various

00:30:04.100 lipoproteins is NMR spectroscopy. Because as Peter says, every lipid has a different spectral signal. And

00:30:10.260 if you know what you're doing, you can look at a spectral signal and know what its molecular composition

00:30:15.720 is and everything. So Jim turned it into, you know, as we had all these lipid metrics that we're talking

00:30:22.940 about cholesterol, even triglyceride metrics, deep down, the guys know these are just poor man's way, easily

00:30:29.380 assayable ways of quantifying lipoproteins. And it's the quantification that matters in many cases or so. So we

00:30:36.800 have to, it turns out in the long run, it's the number of ApoB particles that primarily is what

00:30:42.800 forces it into the artery wall. Very little L. I mean, there are other factors, but that's the

00:30:47.720 number. But when was that, when was that pathophysiology first stumbled upon that it even

00:30:53.520 mattered how many of these particles you have versus, so let's just take out the estimates and

00:30:58.640 let's assume that you have the ability to measure the total cholesterol concentration within an LDL

00:31:03.500 particle, which is what's showing up when someone gets a blood test and it says direct. When it says LDL-C

00:31:09.220 direct, that means they've actually measured it. So now it's better than Friederwald's estimation. But that's

00:31:16.380 different from if you have an NMR where it says LDL-P nanomole per liter, and that's counting the number of

00:31:24.340 those particles. So one is the number of particles, the other is the amount of cholesterol contained within

00:31:28.740 them. We'll get to what a revisiting of MESA and Framingham made unambiguously clear, which is one of those

00:31:36.380 predicts better than the other. But was that really the realization that it was a gradient driven process by

00:31:42.340 number? Or was that understood beforehand, or at least hypothesized beforehand, and then more verified by the

00:31:48.720 experimental evidence?

00:31:49.580 Early on, they discovered it was the ApoB particles going into the artery wall and delivering these sterols and

00:31:55.460 everything that set off this maladaptive inflammatory process that led to a whole other area of

00:32:01.980 investigation or so. So the particle number data came, once they sort of identified a way of assaying

00:32:11.020 particle numbers, and they almost evolved as this, maybe ApoB came a little bit first, but then Jim

00:32:17.460 Opfos' work on LDL particles came at the same time. And it clearly became evidence that ApoB is a better

00:32:25.340 risk factor. And remember, there is one ApoB on every VLDL, IDL, and LDL, but 95% of the ApoB particles

00:32:34.980 are LDL. So ApoB is just a way for the labs to report to you what an LDL particle concentration is.

00:32:42.120 Opfos identified an LDL particle concentration using these methyl signals coming out of the methyl groups

00:32:49.600 that are on cholesterol, ester and triglycerides and phospholipids and translated into a particle

00:32:55.320 number that, wow, either ApoB or LDL particle number correlates a lot better with clinical events

00:33:04.720 or the presence of atherosclerosis. You haven't had an event, but if we do some imaging, we see plaque

00:33:10.280 in your wall than does the cholesterol measurement per self. So it's not a surrogate of particle.

00:33:16.660 They are particle measurements, ApoB or LDL-P. So ApoB is an LDL particle metric. What too many

00:33:25.240 people get lost at, hey, VLDL particles are an ApoB particle. So VLDLs, there's no doubt that VLDLs can

00:33:32.940 get in the artery wall and contribute to it. But it's like a minor, the number of VLDLs that get into

00:33:39.380 the artery wall are infinitesimal. The number of chylos that get in are infinitesimal compared to

00:33:44.540 the number of LDL particles. So yeah, they're all bad guys. And a VLDL per particle have significantly

00:33:50.860 more cholesterol molecules in it than an LDL, but there are just so many more LDLs that collectively,

00:33:57.580 the LDLs deliver more cholesterol to that artery wall.

00:34:00.360 I'm going to go back and do one more.

00:34:01.440 But an ApoB, by the way, gives us no information on VLDLs. It's an LDL particle metric.

00:34:07.140 You can't use it for anything else. So don't call me up and say my ApoB is high because I got too

00:34:11.940 many VLDL particles. Unless you have a rare lipid disorder where there are no LDL particles,

00:34:18.020 the type 3, this beta-lipoproteinemia. That's the only time an ApoB is measuring. It's a VLDL

00:34:25.080 measurement or a remnant measurement. It's not an LDL measurement. But everybody else, ApoB,

00:34:30.840 LDL-P, those are the tests you need. Because although they correlate very well with LDL cholesterol,

00:34:37.680 if they're both high in a given person, that person's a terrible risk. But as you well know,

00:34:43.840 and probably because of the metabolic makeup of our existing humans, at least around throughout the

00:34:50.180 world now is some people have a very high ApoB LDL-P, very good LDL cholesterol. Some people

00:34:59.800 have high LDL cholesterol, perfect ApoB LDL particle counts. When those metrics agree,

00:35:06.980 they're said to be concordant. Hey, use them both. Either one will give you the same information.

00:35:13.000 But what happens if you get a patient where they don't agree these metrics in virtually every single

00:35:18.840 trial ever looked at, the risk follows the particle metric more than the cholesterol metric.

00:35:25.520 So the only way to know who is discordant with a cholesterol metric and an ApoB or an LDL particle

00:35:32.620 metric is to do both of them. You could also say, hey, if I'm just doing ApoB or an LDL particle count,

00:35:39.740 I don't even need lipids. And I'd agree with you, except I think there is value in knowing what a

00:35:43.940 triglyceride is for other reasons. So that's the real key. And if you ever go to a doctor and you're

00:35:50.560 told, I'm very happy because your LDL cholesterol is normal, say, well, so am I, doc. But by the way,

00:35:56.640 what was the ApoB or LDL particle count? And if the doctor didn't do it, you demand he do it instantly

00:36:02.420 because otherwise you don't know your lipid-related risk.

00:36:05.620 Yeah, we're going to upset a lot of doctors here because I've already, and you've already been in the

00:36:10.060 business of that where people will hear you talk or something or read something you've written or

00:36:14.780 something I've written, and they'll go to their doctor and say, hey, I want my LDL-P or my ApoB.

00:36:18.720 And the doctor says, that's nonsense. You know, fill in the blank, TBD, blah, blah, blah, blah, blah.

00:36:25.120 And it puts patients in an awkward position. I mean, I really feel bad about this because

00:36:28.540 especially on depending on what country they live in, at least in the United States, I think anybody

00:36:32.340 can go to LabCorp directly and get the assay without a physician's prescription. But it upsets me.

00:36:38.460 I think the patients even have to do that. It upsets me that something that is such an important

00:36:42.440 metric, I would list LDL-P as one of the five most important metrics. I've talked about this,

00:36:48.240 that every patient should know their LDL-P or ApoB, and that that wouldn't be sort of fundamentally a

00:36:56.080 part of screening somebody for disease. And that a patient would get into a position where they're

00:37:00.980 having to argue with their doc about that is disconcerting. And look, hopefully this is sort of

00:37:05.660 why I do these podcasts is I think it's just as much to help physicians say, look, just because I

00:37:11.200 didn't learn this in my training doesn't mean I don't need to sort of pick it up today.

00:37:15.260 Amen. And I'm sad there's so much what I consider inferior lipid care being administered by

00:37:22.440 healthcare professionals in the United States. But there's nothing I can do about that is try and

00:37:27.700 teach them one at a time or expose my writings and other people's writings and the data on this as

00:37:33.440 much as I can. And it's tragic with public health problem number one or number two that this has

00:37:41.060 lagged so far behind, in part retarded by guidelines and third party payers who just don't want to pay

00:37:48.740 for different metrics and stuff. So there's other reasons behind it. But a big part is they don't

00:37:53.880 understand it. You have had cardiologists call you up. I have had being recognized as maybe in

00:38:01.120 northern New Jersey. Hey, Tom, you know, you told my patient that, you know, what I said about LDL

00:38:08.420 cholesterol doesn't matter because you've done an LDL particle. You know, not everybody believes that

00:38:13.880 or they give you some horse shit like that. And I say, I mean, I say, hey, doctor, would you like

00:38:20.620 200 manuscripts delivered to your desktop tomorrow? I'll do it if you promise me you'll read them

00:38:26.940 every single one. So, you know, it is what it is. I think the internet is help people in certain ways.

00:38:33.960 I think the internet is confuse people in a lot of ways, too, because there are people out there who

00:38:39.300 what we just talked about, and it's pretty much fact, who become deniers of the particle concentrations

00:38:45.120 because whatever else they're exposing as their way to cure heart disease, somehow aggravates LDL

00:38:51.320 particle count, and they just choose to ignore it. And look, are there people with high LDL particle

00:38:56.700 counts who don't somehow? Yeah, they're out there. But the overwhelming amount of literature says the

00:39:02.180 odds, or if you keep this for 20, 30 years, you're going down. Until somebody does a serious study

00:39:09.660 showing there are people who can escape this for 20, you're playing with fire to ignore an elevated LDL

00:39:15.800 particle count, April B. I don't have a way of identifying who might have a high metric there is

00:39:20.780 somehow protected against atherosclerosis. Well, I have lots of thoughts on this myself,

00:39:25.620 and maybe we'll come back to it. And I think we've gone back and forth. We had this fun email

00:39:30.640 string a while ago with you, Ron, me, Alan, I think Josh Knowles was on it as well, where we just,

00:39:36.820 you guys were the first people to be exposed to my new model, which is the necessary but not

00:39:41.920 sufficient, sufficient but not necessary, neither necessary nor sufficient causalities, because you

00:39:47.400 can actually have causal metrics that fit each of those buckets. But we'll digress and come back

00:39:52.900 to that. I want to go back to one semantic thing. You use the word sterol a lot. I'm very comfortable

00:39:58.440 with it. I want to make sure the listener knows the difference between a sterol, a stanol, a zoosterol,

00:40:04.680 a phytosterol. I think we're going to touch on this later, so let's just hammer out the semantics.

00:40:08.660 Right. Well, cholesterol, of course, is the molecule we all fear, because it's been drummed

00:40:13.580 into our head that cholesterol in an arterial wall is what is plaque. It's a cholesterol core,

00:40:20.860 and that cholesterol can cause impaired vascular biology, resulting in clinical events. So

00:40:26.360 what is cholesterol? And we certainly, in Peter's notes here, you're going to have pictures of the

00:40:32.200 cholesterol structure. And it's got four rings. It's an aromatic compound. And off the fifth ring

00:40:39.120 is a little tail sticking out, which is a carbon chain. So the precursor molecule is called the

00:40:46.480 sterane. So you have the rings, the four rings, and you may or may not have this tail sticking off

00:40:55.260 of the 17th carbon in the fourth ring. So all of the bonds are saturated. That is called the

00:41:01.500 sterane. So if you unsaturate it, one double bond in that sterane, it's called the sterane.

00:41:11.440 And if you then stick a hydroxy group on the third carbon in the first ring, it's called the sterol.

00:41:18.820 It's an alcohol, because you got a hydroxy group now sticking out.

00:41:22.420 Hydroxy being OH.

00:41:23.800 OH is hydroxy, excuse me. Correct. So you'll see the pictures in my illustrated diagrams there.

00:41:31.500 And that little tail that sticks out on the other end of the molecule has a lot to do with

00:41:37.180 what exactly type of sterol that is and how it will function in a cell or in a cell membrane or so.

00:41:44.320 So cholesterol would be this four ring structure. Three of the rings have six carbons in it. The

00:41:50.980 fourth ring has five carbons in it. You have this tail sticking off of carbon 17 that goes out. And

00:41:57.320 cholesterol, that's a totally saturated tail. Every bond in it is a saturated fatty acid.

00:42:03.620 And then on the three position, you'd have this OH group, the hydroxy group. By the way,

00:42:08.920 since OH is sort of soluble in water, that part of the cholesterol molecule is soluble in water,

00:42:15.020 whereas that carbon chain sticking out, so pure lipid, that's all carbon, that's not soluble in water.

00:42:20.900 So when cholesterol does exist in a surface membrane, like a cell membrane or lipoprotein,

00:42:27.140 it's cholesterol. It orients itself. Yeah. So the hydroxy group is sticking out and that

00:42:31.940 allopathic tail is sticking into the core of the particle or so. Now the cholesterol,

00:42:36.840 it's in the middle of the particle. Oh, that hydroxy group can't be in the middle of the particle.

00:42:41.920 That's water. So they stick a really long chain fatty acid. They replace the hydroxy group with a

00:42:51.140 long chain or really any chain fatty acid, but mostly it's a long chain. So you esterify cholesterol.

00:42:57.500 Remember I told you attaching a fatty acid to something is called esterify. So cholesterol,

00:43:02.760 which is the active form of cholesterol that can be changed into a hormone of bile salt or

00:43:07.140 function in a cell membrane becomes a storage form of cholesterol or a lipid core transportable form

00:43:15.300 of cholesterol called cholesterol. Now it's YL, it's not OL, ester. And we abbreviate that as CE.

00:43:23.040 So free cholesterol is either going to be abbreviated as a C or an FC and cholesterol ester. It's very

00:43:30.600 difficult. If I wanted to, if I'm an adrenal gland and I got some cholesterol ester stored and I want to

00:43:35.340 make a hormone because I need cholesterol, I have to de-esterify that cholesterol ester to free

00:43:39.980 cholesterol. If the liver has cholesterol ester storage pools and it does, and it wants to make a

00:43:44.960 bile acid, it has to de-esterify cholesterol ester. Cholesterol is stored in huge quantities in fat

00:43:51.080 cells as cholesterol ester, and it would have to be de-esterified to be utilized to do something else

00:43:56.780 or so. One little story I'll just tell before we get to the standalls and all the other stuff is

00:44:01.040 one of my prouder moments in front of Bob Kaplan was when you sent an email like this a couple months

00:44:06.760 ago. You sent us an email and you said, see if you can spot the error in this figure. And it was like

00:44:11.960 a figure that had a million things on it. And I was like, oh, I'm not getting up until I figure out

00:44:17.740 where the mistake is. And sure enough, somewhere in there, it took me about 10 minutes. The illustrator

00:44:24.340 had written, because this was out of a paper or something, they had written cholesterol O-L ester

00:44:29.920 instead of cholesterol Y-L ester. And when I responded to you and you responded in the affirmative,

00:44:35.460 I was like, I've got my stripes. And that figure he's talking about came out of one of the productions

00:44:41.860 for the company that I work for. We develop educational pieces for physicians. And I obviously drew

00:44:47.240 it and labeled it. But you send it off to a medical illustrator who formats it for the PDF or whatever,

00:44:52.980 and cholesterol is cholesterol. And they make the mistake, even though I sent in the picture where

00:44:58.780 it was properly labeled. Of course, I had a heart attack the first time I saw it. And we've

00:45:02.320 since changed that. But somehow Peter got a hold of an older version or something that probably even

00:45:07.440 I sent out and didn't recognize initially. But yeah, so it is cholesterol, ester. Anything that's

00:45:13.300 esterified becomes a YL. So you'll see lipids. This discussion illustrates one of the challenges of

00:45:19.020 lipidology, which is, I find this to be certainly among the two or three most complicated subject

00:45:25.800 matters I've ever tried to master. And again, no one masters anything in life. I mean, that's sort

00:45:30.220 of the beauty of this. You haven't mastered this. But this journey of trying to learn it, I am

00:45:36.320 constantly humbled by how hard it is. It's just so goddamn complicated.

00:45:42.440 Well, that's true, especially if you want to take it to the nth degree. But you need to invest

00:45:46.480 yourself in some degree of education to at least be competent in today's world or so. So you have to

00:45:52.840 know some of this stuff. Well, and that's the thing you have to be willing to learn some of this

00:45:58.240 chemistry. I mean, you have to steep yourself in biochemistry and understand the because the

00:46:03.920 significance becomes enormous. One double bond in one of these things completely changes its

00:46:10.400 properties. And not to say that that's not true in general in biochemistry, but it's much easier

00:46:16.160 to talk about blood pressure or to talk about elevated levels of uric acid or insulin or glucose

00:46:22.980 without getting into that level of minutiae. It is not possible to discuss lipids without that.

00:46:28.880 That is the problem when a lot of people are spouting off on the internet and elsewhere about

00:46:32.720 all these, you just don't have an understanding of the complexity of how this all works and fits

00:46:38.720 together and why what you just said is wrong because there's something going on stoichiometrically that

00:46:43.540 you haven't even considered or so. To finish the sterol. So a steroid is a sterol. It's got another

00:46:51.440 keto group stuck on it someplace. Look at all the hormones. You'll see a double bond with oxygen

00:46:55.820 attached. But a stanol is you take, and let's take cholesterol as a stanol or a sterol. And remember

00:47:04.120 cholesterol at the third carbons and OH group, there's a double bond at carbon five to six in the

00:47:09.680 first ring. And then there's that tail at carbon 17. If I desaturated cholesterol, the double bond at

00:47:16.700 C5 and six disappears. That's called cholestanol. It's a stanol. A stanol is essentially a saturated

00:47:25.260 sterol. Changes the characteristics of that cholesterol. Free cholesterol can be readily absorbed in your

00:47:33.780 intestinal wall. Stanols cannot be absorbed. And it's kind of funny. Our liver to get rid of, or our

00:47:40.980 body to get rid of cholesterol, but sends it to the liver. The liver sends it through the bile to the

00:47:46.420 intestinal pool is free cholesterol. And your intestines more than capable of just reabsorbing

00:47:53.000 that cholesterol that the liver is trying to evict. Except our little friendly microbes down there in the

00:47:59.440 gut, convert a ton of the biliary excreted cholesterol into a stanol called cholestanol,

00:48:07.280 or there's an isoform of it called coprostanol. It's a stanol, cannot be reabsorbed. So you poop it

00:48:13.960 away. And that's how the body gets rid of cholesterol. It changes a lot of it to a stanol. Anthropologists

00:48:21.060 have been measuring specimens for coprostanol. That tells them humans live there at one time because

00:48:26.540 they find that in certain specimens and that human had to excrete it. You know, so a stanol is simply a

00:48:34.660 saturate. And that adds other applications because, hey, if stanols cannot be absorbed, and I would like

00:48:41.160 to have a metric of whether you're absorbing cholesterol or not, if I measured cholesterol in

00:48:48.720 your blood, shouldn't be there to any appreciable degree because you can't absorb it. If it is elevated in

00:48:56.280 your blood, for whatever reason, and we now know why, your intestine just absorbed that cholesterol.

00:49:03.100 And if it's absorbing cholesterol, which it tends not to, what is it absorbing in humongous excess

00:49:11.320 cholesterol? So cholesterol serves as a biomarker of are you or are you not, or what degree of

00:49:18.800 cholesterol absorption is going on in your intestines. And the last thing Peter did mention,

00:49:24.340 he said phytosterols. He called it a zoosterol. I call it zoologies because I call it a zoosterol.

00:49:31.160 So I don't know who's right on that.

00:49:32.660 I'm going to go with your right. Yeah, yeah. I'm just going to give you that.

00:49:36.360 And I do have a degree in zoology when I went to college. It was one of my majors.

00:49:42.340 And you're wearing, just so everyone knows, you're wearing your Rutgers t-shirt right now as well

00:49:46.160 from college, which is perfect. All right.

00:49:47.840 I wouldn't be here without the Earl Rutgers. Medical school was inconsequential. I learned

00:49:52.240 everything in Rutgers pre-med, at least the biochemistry and the physiology anyway.

00:49:58.500 So phytosterols, what? Plants are full of sterols. Their cell membranes are not cholesterol.

00:50:04.720 There are some plants that do have cholesterol and most do not, but they have sterols that if I showed

00:50:09.700 you, here's cholesterol and here's what's in this plant, you would think you're showing me a lot of

00:50:13.640 cholesterol. But if you look closely, you'd see that tail that's coming out of carbon 17 is

00:50:18.860 constructed a little differently. Or wait a minute, there's another double bond in one of those

00:50:23.220 rings in there. So it looks like cholesterol, but it's close, but it's really not. And since it was

00:50:30.040 made in a plant, collectively, let's call them phytosterols. Well, we hopefully all eat a few

00:50:35.680 vegetables during the day. So you're eating phytosterols, unless you're a total non, don't eat

00:50:41.840 any vegetables. And they get in even in other things, even if you're eating shrimp and stuff,

00:50:46.020 fish eat phytoplankton and stuff. So there's phytosterols and a bunch of foods. But your body

00:50:53.840 knows the only sterol I need to function is cholesterol. I don't eat any plant sterols.

00:51:00.880 Why would I want a human to ever absorb the plant sterol? They would get in the way.

00:51:06.340 Could they even be toxic? So evolution must have figured out they were. So evolution made sure our

00:51:13.160 intestine did not absorb phytosterols. Why? To me, it tells me there's a certain level at which

00:51:19.700 phytosterols are toxic. Well, this becomes interesting because I had a disagreement with

00:51:24.540 a physician recently who jointly takes care of one of my patients because the physician wanted to put

00:51:30.500 this patient on phytosterol supplements because this physician became convinced that it was such an

00:51:35.880 elegant way to lower cholesterol. It turns out about 10 to 15% of people in whom you give massive doses

00:51:42.440 of phytosterols. You do indeed lower their cholesterol. This physician felt that was a

00:51:47.380 good idea. I felt otherwise for reasons you'll explain, I'm sure. And needless to say, after a

00:51:53.440 long discussion, we agreed to stop the phytosterols. Yes. And again, to me, the best argument with that

00:51:59.620 is if your evolution thought we needed phytosterols, your intestine would be encouraged to absorb

00:52:05.060 phytosterols. If somehow they brought some miraculous property to the human body that enhanced survival,

00:52:10.140 you'd want them in there. And everybody's saying, oh, plants carry a lot of great stuff. We're only

00:52:14.500 talking about the sterol that's in the plant, the phytosterol. Other ingredients in plants do get

00:52:19.600 absorbed and probably are good for you, but not phytosterols. Well, there's data to show that

00:52:24.300 phytosterols on a per molecule basis are probably more atherogenic than cholesterol. There certainly

00:52:30.000 is that data there. But again, the people who just so focused on lowering LDL cholesterol don't even

00:52:36.420 entertain it, won't even look at it, or they dismiss it as nonsense, you know. And it's never going to

00:52:41.660 be studied in the proper type of trial that you'd have to study it in, you know. So, and as Peter

00:52:46.780 just hinted, if you're not a hyperabsorber of sterols, probably giving a phytosterol supplement

00:52:51.300 is good because it does compete with cholesterol, so you will absorb less cholesterol. And maybe that's

00:52:57.020 one way of lowering LDL cholesterol, but I would say who cares. But you would get a little bit of

00:53:02.740 B-reduction in certain people with that. But if you're a hyperabsorber, I'm polluting your body

00:53:07.340 with something that evolution didn't want in your body. Why would I do that? So, I beg anybody who's

00:53:12.700 a big advocate of supplementing phytosterols, please monitor phytosterols in the bloodstream.

00:53:18.400 That's how you identify, oh my God, you're the one person I absolutely should not be giving this to.

00:53:23.720 And I can send you a lot of data Peter's talking about showing you phytosterol toxicity

00:53:27.900 in humans and stuff. So. And when we say someone's a hyperabsorber, I mean, you and I have both

00:53:33.580 written about this ad nauseum, so we'll link to it rather than get into a diatribe. But

00:53:38.160 we're basically talking about, and your analogy is my favorite. I've always borrowed it,

00:53:42.940 outright stole it. I, hopefully I've always given you credit. You got a ticket taker in the bar.

00:53:47.880 Neiman picks C1 like one transporter. He lets everybody in. If you can fit through the door.

00:53:52.280 Star rolling. Yeah. He lets any sterile in. If you can fit through the door, you're coming in.

00:53:56.160 But then you've got this ATP binding cassette, G5, G8, and that's the bouncer. That's the enforcer.

00:54:01.420 That's the one who, in theory, probably informed by LXR, is making some sort of decision about you're

00:54:06.820 a good guy, you're a bad guy, you got to go, you got to stay. When someone is genetically a

00:54:11.880 hyperabsorber, is the quote unquote defect more on the ticket taker or on the bouncer?

00:54:17.920 It turns out that it's both because, now when we talk about absorption, let's face it,

00:54:24.320 there's a million molecules that can be absorbed by your intestine. We're talking about sterile

00:54:28.400 absorption right now. And cholesterol is a key ingredient for human life. So evolution not only

00:54:34.720 gave every cell in your body the wherewithal to synthesize cholesterol, it allowed your intestine to

00:54:40.740 absorb cholesterol because it certainly didn't want any cellular deficiency of cholesterol,

00:54:46.220 which has nothing to do with plasma cholesterol, by the way. You can have an LDL-C of three and have

00:54:52.120 perfect cellular cholesterol metrics. So people don't understand that.

00:54:56.640 As evidenced by the hypofunctioning PCSK9 patients.

00:55:00.860 So this Neiman-Pick C1-like protein in our proximal intestine recognizes sterols. And there's a

00:55:10.160 sterile domain on there that binds tightly to sterols, but it binds most tightly to cholesterol.

00:55:16.220 Because cholesterol has that structure. It has a less avid binding to a phytosterol,

00:55:21.640 and it has minimal binding to a stanol. Now, ultimately, it'll bind to all of them,

00:55:27.300 but cholesterol gets the first preference to be pulled into the enterocyte. Xenosterol,

00:55:32.740 as I call it, rather than a phytosterol, xeno meaning other sterol, a sterol other than cholesterol,

00:55:38.400 would get in secondarily. And a stanol, they get in, but at much less concentrations.

00:55:43.880 So now the enterocyte has this sterol you just absorbed. Now, the enterocyte's position is,

00:55:52.220 I got to get this to the rest of the body. So I have to take this sterol and put it in a

00:55:56.220 chylomicron that I'm going to make. Or I could also efflux any sterol out to a baby HDL that's

00:56:01.920 looking for sterols. I can lipidate an HDL. So that's how sterols get out of the intestine.

00:56:06.900 Or the intestine can say, we don't need any more sterols. I'm getting rid of you. And that's

00:56:13.320 where the bouncer comes in. So these ATP binding cassette transporters, ATP binding cassette

00:56:20.060 transporters are a sterol efflux membrane transporter. So-

00:56:25.300 And this is important to distinguish because, and again, it might be confusing,

00:56:28.440 but the diagrams will make it easier. There's two effluxes you've referred to. There's an

00:56:32.980 efflux on the luminal side, and then an efflux back into the body. Both of them are leaving an

00:56:38.880 enterocyte. One ends up leaving the body. If it goes out the ATP binding cassette, it's going into

00:56:43.560 the lumen. It's being excreted with stool. If you efflux on the other side of the cell into either

00:56:49.320 the chylomicron or into the HDL, you're actually putting it right back into circulation.

00:56:54.020 And that is such a crucial point, Pierre. I'm glad you elucidated on that more. So yeah,

00:56:58.460 remember, we're talking about the enterocyte. Like the liver and enterocytes have a lot of things

00:57:02.920 they can do with sterols. So they can get rid of it, or they can even use it. Remember,

00:57:07.940 enterocytes have cell membranes. They need some cholesterol for their own cell membranes and

00:57:11.820 everything. So they can ship it out. A body needs cholesterol in the chylomicron. They can

00:57:16.840 lipidate in HDL, or they can return it to the lumen of the gut, where it'll go out your rear end.

00:57:24.420 So these ABCG5 or GA transporters, as you're called, and it's a heterodimer,

00:57:29.800 so you have one of each, will efflux. And they also have different affinities.

00:57:35.220 So unlike the Neiman-Pick, which really wants cholesterol to come in less so phytosterols

00:57:40.260 and not so stanols, which tells me evolution didn't want those other products in your body,

00:57:45.760 the ABC transformer exporters, they, number one, evict phytosterols first. That's another

00:57:53.720 evolutionary happenstance to me that tells me the body evolution didn't want phytosterols in your

00:58:00.200 damn body, because why is it giving you a phytosterol efflux protein in your intestine?

00:58:05.140 And the liver has it too, just in case a phytosterol ever makes it as far as the liver.

00:58:09.460 It gets evicted back to the bile to go back to your intestine. So second in line for exportation

00:58:16.220 would be a stanol, and third would be cholesterol. So your ability to absorb cholesterol is a happy

00:58:25.300 working relationship between the expression of your Neiman-Pick C1-like protein and your ABCG5,

00:58:32.420 GA transporters. So technically, if you even had a good normal degree of absorption, but you couldn't

00:58:39.780 evict any steroids because you got a loss of function of an ABCG5 or GA, you're going to be a hyperabsorber,

00:58:45.640 because then the only way those sterols couldn't get out of the enterocyte is in a chylamicron or in

00:58:50.080 an HDL. And by the way, when you do measure these phytosterols in the blood, people, it's like when

00:58:56.840 you measure cholesterol in the blood. Do you understand? I've already told you where that

00:59:00.320 cholesterol is. It's the cholesterol within all the lipoproteins. So if I'm measuring cytosterol,

00:59:06.420 stigmasterol, campesterol, which are some of the names of the 50 phytosterols that are in our plant

00:59:12.860 products, what am I measuring? Well, since the vast majority of lipoproteins are LDLs, I'm measuring

00:59:19.120 LDL cytosterol, LDL cholesterol, like I'm measuring LDL cholesterol. So you're measuring there, but God

00:59:26.320 forbid that particle invades an artery wall, the sterols go with it. And one last intriguing part

00:59:33.300 of this story, which better put the fear of God of phytosterols into you, that evolution didn't want

00:59:38.260 it in. So it gave you a protein that will not absorb phytosterols if it's working right. It gave

00:59:42.940 you a protein that immediately evicts phytosterols. But for any sterol to go in a chylamicron, what does

00:59:49.560 it have to be? Asterified. How does the intestine esterify cholesterol into cholesterol ester, which is

00:59:56.620 what makes up a giant part of the core of a chylamicron? There's an esterifying enzyme,

01:00:02.360 acylcholesterol, acyltransferase, ACAT. Guess what is the favorite ligand for ACAT? Cholesterol.

01:00:10.720 Guess what is not a favorite ligand for ACAT? Phytosterols. So you just don't esterify phytosterols,

01:00:18.040 which retards them getting into your body. And you know the real way to get in? That ABCA1

01:00:24.000 efflux transporter, which is what lipidates a baby HDL parto. It's not ABCG5G8, which is ABCA1

01:00:32.100 exports sterols into baby HDL particles. And just for the listener, again, you're saying ABC.

01:00:37.680 What you're saying is ATP binding cassette. So when they hear you say ABC, that's what you're

01:00:42.480 referring to. It's an energy-driven process. So some of that phytosterols you're measuring in

01:00:47.240 the blood are on HDL particles also. So that's a way to get in. And I always make, and you'd have to

01:00:54.120 do a study and prove it. We're going to be talking about HDL dysfunction. Suppose I measured phytosterols

01:00:59.260 in your HDL and it's very high. It's probably a type of dysfunctional HDL particle, you know? So

01:01:05.080 there's all sorts of intriguing. It would also, you know, not to get too esoteric, but that would

01:01:09.360 also suggest enterocyte dysfunction. Because the enterocyte should also quote-unquote know better

01:01:14.480 that that's not the direction of efflux I want. It is. But it's relying on the ABCG5G8 to efflux it.

01:01:22.020 Then it wouldn't even get to an ABCA1 to efflux it on the other side. And ACAT is not going to

01:01:27.680 esterified if it's all being evicted. There would be very little that would wind up being

01:01:31.200 esterified. And the last part of this puzzle, as Peter told, you have a gut lumen side and you got

01:01:36.700 a plasma side or a lymphatic side, which is where chalomicrons exit. We probably talk about it

01:01:44.340 somewhere today is this crazy process they used to call reverse cholesterol transport,

01:01:49.600 which is another one of these idiotic terms that should have disappeared a long time ago,

01:01:53.820 at least if you think it's mediated solely by HDL, high-density lipoproteins. That's the part

01:01:59.540 that's got to change. A big pathway of how does the body get rid of cholesterol, we're all thought,

01:02:05.040 oh, it brought it back to the liver and the liver will get rid of it in a certain way.

01:02:09.800 Guess what? A ton of it is just brought directly right back to the intestine. And the cholesterol in

01:02:15.180 the particle or the particle itself finds its way into the enterocyte through. And then the enterocyte

01:02:21.080 has another supply of sterols all of a sudden that it didn't absorb. And so what? It then will do with

01:02:27.800 that sterol what it wants. It can efflux it through ABCG5G8 into your gut lumen and you can poop it

01:02:33.400 away. So the process of a lipoprotein or some other trafficker, albumin, red blood cells, bringing

01:02:41.820 cholesterol back to the small intestine, bypassing the liver, gets right out into your stool, is called

01:02:48.960 transintestinal cholesterol efflux, abbreviated as TICE. And it's a major reverse cholesterol

01:02:55.680 transport pathway now. Do we have a sense, because we're going to talk about direct and indirect

01:03:00.560 RCT in a moment, I think that might as well, this is as good a foray into that as any. Do you have a

01:03:05.780 sense of how much cholesterol is being reverse transported, so to speak, through TICE versus

01:03:12.000 the sum total of direct and non-direct reverse cholesterol transport?

01:03:16.780 Yeah, this has been studied in dynamically, but you know, they're real small studies and it

01:03:21.440 probably varies individually depending on the complexity of your lipid and lipoprotein

01:03:28.080 transportation systems or so. In some people, it's probably 20%, in other people, it's been reported

01:03:35.120 as high as 60%. Wow. So it varies a lot. But it's a major player. It's not this infinitesimal

01:03:41.320 minor baby pathway that's inconsequential, except in some rat in a laboratory or something. This has

01:03:47.680 been proven in humans now. It's part of the review process in a really cool article coming out in the

01:03:55.260 Journal of Clinical Lipidology, where because of some biliary surgery the guy had, the only way cholesterol

01:04:00.980 gets out of this person's body was through the intestine. So he shows you the body can get rid

01:04:07.420 of cholesterol without a biliary system. How many articles do you review a year?

01:04:11.820 There's two things. When you're an associate editor, the main editor will say, here's a submitted paper.

01:04:19.520 Do you think this is pretty good? If so, send it out to four or five reviewers. They will send their

01:04:24.220 review to you, and then you make your decision and send it to me, and I'll make the ultimate decision.

01:04:28.300 But then also, I'm also just a reviewer, where another associate editor would say, I think Tom knows a lot

01:04:34.820 about this subject. So I'll ask him, would he please review this article to me? So I don't know, I probably

01:04:40.920 get about 15 articles a year where I'm the associate editor, and probably double that, where-

01:04:46.560 You're one of the reviewers.

01:04:47.900 Or just one of several reviewers or so.

01:04:50.920 But that's still about 50 papers a year that are coming across your desk.

01:04:54.360 I'm blessed at my stage of the game to have a job where I do have, I don't have to see patients

01:04:59.380 anymore. I'm not traveling throughout the United States a hundred times a year on flights, doing

01:05:05.540 lectures here, there, and everywhere. So I am blessed in my current position, or my true health

01:05:12.600 diagnostic. Peter, probably when you hear this the first time, you'll get a list of my, who I work for

01:05:19.560 and who I don't. That's the only company I work for nowadays, and I'm their scientific academic

01:05:24.480 advisor. So my job is to stay on top of the literature, know all this stuff, and explain it.

01:05:30.920 So I have the freedom every day to spend time reading and edging. And part of my education,

01:05:36.640 anybody who's a reviewer or an editor with other, you'll learn a lot doing that. Because I don't know

01:05:42.080 everything that's sent to me for review, but I'll sure as heck know where to go and get it.

01:05:45.780 Well, there's a small group of us that are very lucky. We're having dinner with Jamie Underberg

01:05:50.260 tonight, but you know, Jamie said, there's like this group of like 10 people that you always send

01:05:55.160 out the most interesting papers to. And about a year ago, I had forwarded a number of these on to Bob

01:06:01.160 Kaplan, and he was like, hey, can you put me on this email too? And I mean, we'll have to think

01:06:07.400 about a way for you to create a special group where, because it strikes me that there's a broader

01:06:12.960 group of people who would actually like to get the once a week email from Tom with the most

01:06:17.920 interesting lipid paper I've read this week. Yeah, I think the best way of doing that is

01:06:23.260 somehow contacting me at Dr. Lipid or so. I mean, you put a lot of this stuff out on Twitter.

01:06:29.240 Yeah, I do. So you can research it. But you don't get the commentary because your emails are sometimes

01:06:34.120 so great. Because what you'll do is you'll say, look, I know all of you aren't going to read this 12

01:06:38.640 page paper. Here's like a 300 word summary of what you would learn. And then that like for me to read

01:06:45.200 that, then open the paper. It's like, it's quick. And it was just the number one, I really don't want

01:06:51.220 to get. I don't know how many people listen to Peter's podcast, but it's immense. I don't want

01:06:55.240 4000 emails tomorrow. And there's two things as part of that email. One would be my interpretation of

01:07:03.940 which is fine. That's Day Springs opinion. No, but maybe we can, we can't attach PDFs to it that

01:07:09.300 I might to an isolated friend of copyrights. Yeah, yeah, that's, that's, that's probably the

01:07:14.520 bigger issue. That's part of an issue also. So if it's open access, great. And if it is,

01:07:19.960 I've probably tweeted it and your best bet. And look, people aren't afraid to ask me questions. I

01:07:26.580 mean, a lot of them are asinine. I ignore them, but I will answer it. My Twitter followers know

01:07:31.440 you're legitimate and I'll, you know, either direct message you. Yeah, yeah. All right.

01:07:36.640 So back to this. And if I don't, then there's a reason. Okay. So let's get back to the business

01:07:41.300 of, of lipids here. So we've done a pretty good job explaining one side of the equation

01:07:47.380 at how cholesterol is regulated. Oh, by the way, a zoosterol would be cholesterol. It's the

01:07:52.040 only sterol we, the animal kingdom produces. Yes. Yeah, yeah. Cholesterol is the zoosterol.

01:07:57.500 Yeah. Yeah. Okay. So the other end of this regulatory pathway, so we've described the

01:08:02.740 reabsorption side pretty well. There's a synthetic side, which you've alluded to, obviously, by

01:08:07.880 making the statements that, Hey, every cell in the body can make cholesterol. And most of the time

01:08:14.480 it's sufficient for its needs. Obviously exceptions. Well, I'll let you explain what the exceptions are

01:08:20.380 to that. There are a certain scenarios and certain cells where they actually do need cholesterol from

01:08:25.440 other tissues. But let's just go back to this synthetic stuff just briefly, because I don't

01:08:30.080 want to give anybody too much headache. How do we make cholesterol? Very complexly. It's a

01:08:37.220 multi-stage process, 20 to 30 individual steps where one molecule is changing into another,

01:08:43.980 into another. And at the end of the day, cholesterol is made.

01:08:47.480 And it starts very small. It's basically acetyl-CoA, acetyl-CoA. It's two carbon,

01:08:51.420 two carbon. It's a small carbon chain molecule that keeps growing in length because cholesterol

01:08:56.100 has 37 carbons in it. So it has to grow. Through much of that growth, it's just a linear structure.

01:09:03.840 And at a certain point, this linear structure is long enough that it bends and changes into a sterol

01:09:10.000 configuration. Lanosterol being the first sterol that appears in the cholesterol synthesis chain.

01:09:16.280 By the way, if I wanted a lab and labs with liquid chromatography and mass spec could give you a

01:09:23.220 lanosterol measurement. And if it was up, hey, you're oversynthesizing cholesterol. That's not the

01:09:30.340 one they focus on. They pick a more downstream cholesterol precursor to do that. But even you could

01:09:37.200 pick some of the earlier ones and they do serve as markers of cholesterol synthesis, you know.

01:09:42.200 Now, the cholesterol synthetic pathway is bifurcated. Tell me a little bit about that.

01:09:46.460 So once you go through squalene and then that bends into a ring structure, lanosterol has to become

01:09:54.020 cholesterol. So lanosterol, and there's crosstalk between the pathways, but it has one or two pathways

01:10:00.520 that it's going to go down. And at the end of the day, both pathways, you'll wind up with cholesterol.

01:10:06.680 And no good pathways don't come with names. So what are the names of these pathways?

01:10:11.360 Yeah. Mr. Facetious. Yes. Well, my favorite, of course, is the block pathway. Because if you

01:10:18.760 don't, and I put him, he was a Twitter picture I put up recently. He won the Nobel Prize for

01:10:25.140 discovering this pathway in cholesterol. So it's probably important. They give you a Nobel Prize

01:10:30.180 for discovering this pathway of cholesterol synthesis. So the block pathway would be lanosterol

01:10:35.640 goes through a lot of precursors and becomes something called desmosterol, D-E-S-M-O-S-T-E-R-O-L.

01:10:43.640 Desmosterol looks exactly like cholesterol, except in carbon 24, there's a double bond.

01:10:49.960 There's no double bonds in that tail that's on the cholesterol molecule. So if I just saturate that

01:10:56.400 double bond in desmosterol, I change it into cholesterol. And of course, there's a specific

01:11:01.400 enzyme that does that. If you inhibit it. Can I guess it? Yes. So this is just so people can

01:11:07.400 understand what these enzymes mean. So I remember learning this in college. All right. So, or med

01:11:11.360 school, not college. Enzymes always end in ACE, right? Now, you just told me it was carbon 24.

01:11:18.180 So it's probably going to have something to have. It's going to have a 24 in there.

01:11:21.460 It will. And we often throw deltas into these things because delta denotes the position of the bond.

01:11:27.280 And did you say that desmosterol has a double bond at 24 and it has to be saturated. So it would

01:11:34.440 probably be something like a delta 24 saturase or desaturase. Correct. All right. So that would be

01:11:40.740 the enzyme. So when you say that, when you rattle that off, it sounds crazy and intimidating,

01:11:44.420 but it's logical, right? It is. And this is why what you were talking about before,

01:11:47.660 you really have to notice stuff or you might not be. And the presence or the expression or the lack

01:11:54.680 of expression of that enzyme is going to, are you going to use that pathway? If you're using that

01:11:59.240 and you don't convert desmosterol into cholesterol, you're going to have a lot of desmosterol in your

01:12:03.840 system. Are there consequences to that? There's a human disease called desmosterolosis that if it

01:12:09.180 occurs in utero, that kid ain't coming out alive. Or if he does, he ain't living for more than a few

01:12:13.960 days. And is that disease a genetic deficiency in the enzyme, delta 2040 saturase? It is. Yeah.

01:12:18.560 Now there's another pathway, lanosterol doesn't. And what determines sort of that is if you've got

01:12:24.100 a double bond at that 24, it's going to go through that pathway. Now there's a, lanosterol has another

01:12:30.880 pathway that goes through that's going to wind up with cholesterol. And the pre-cholesterol,

01:12:36.440 the penultimate as we call it, the next to the last cholesterol molecule in that chain is something

01:12:41.420 called lethosterol. Some people call it lethosterol. I call it lethosterol, L-A-T-H-O-sterol.

01:12:48.220 And that is called the canned Dutch Russell pathway, obviously after the guys who discovered

01:12:55.040 that. By the way, they didn't get the Nobel prize for some reason, even though that was

01:12:58.660 I think the Nobel committee said we already gave one of these things out. And also that you can only

01:13:04.500 have three people receive a Nobel prize. Oh, so that would be two. So whatever. Everybody else,

01:13:11.060 I guess, who worked in blocks lab got no credit. So, but anyway, so it's the canned Dutch Russell

01:13:16.500 pathway. So, and it's kind of interesting because in most people, both pathways exist and there are

01:13:23.360 some ways of jumping from one pathway to another. So at the end of the day, you're going to make

01:13:28.220 cholesterol or so, but if you want to start interfering with these pathways, there are

01:13:32.500 specific enzymes in each pathway that maybe that's would be something you could play with. Or maybe if

01:13:38.000 you're building too much of something, there's a lack of expression of that enzyme in you,

01:13:42.280 which maybe has consequences, maybe it doesn't. So it's all important to know. But some of this may

01:13:49.140 be tissue specific. One of the things I know it's a big topic of yours and I hope we get into today is

01:13:55.120 the brain. Everything I've talked about cholesterol today that we're measuring in the blood has zero to

01:14:00.340 do with cholesterol in the brain. Cholesterol, lipidology in the brain is might as well be in another

01:14:06.320 different body. It has nothing to do with what the cholesterol is going on in the rest of your body.

01:14:12.180 The brain makes every cholesterol molecule it needs and therefore there are no LDL particles

01:14:20.440 delivering cholesterol to your brain. So again, if with a super aggressive therapy- And to be clear,

01:14:25.120 this is because the LDL particle just doesn't fit through the blood-brain barrier. Correct.

01:14:30.560 Even HDLs where a little bit of our cholesterol might get into, it's delipidated through these ABC

01:14:36.080 things. And some of that might work its way into inconsequential amount. The ApoB is I guess too

01:14:43.140 big. The brain doesn't make ApoB. So, but the central nervous system has to traffic lipids from

01:14:47.980 brain cells to peripheral nerve cells. ApoE is the protein transporter in the brain. So cholesterol

01:14:57.100 or any cholesterol is attached to ApoE in the brain. And that's how it traffics around there or so.

01:15:03.300 And again, it's got nothing to do with the ApoE that's involved with whatever lipoproteins are

01:15:08.980 doing in your, the rest of your body also. So just understand it. But obviously-

01:15:13.980 I want to come, this is such an important topic that I absolutely want to come back to. So I'm glad

01:15:17.380 you brought it up. But that said, at the moment, I would love to go back to the synthetic stuff.

01:15:22.400 So you've got each cell in the body can basically start with the most simple carbon subunit,

01:15:28.880 which is a two carbon subunit, acetyl-CoA. And through a process of carbon fixation, go on to

01:15:34.320 make these very complicated four ringed structures. They, first and foremost, the cell uses these

01:15:42.540 things. They make the important part of the cell membrane.

01:15:46.040 And organelle membranes endopositorium.

01:15:49.420 That's right. So everything from the Golgi apparatus to the ER to the smooth ER, rough ER,

01:15:53.460 et cetera. You also, you don't have to be, I think, a biochemist to look at a picture of a molecule

01:15:58.760 like cortisol, estrogen, testosterone. And I think you could show a four-year-old picture of those and

01:16:07.820 then a molecule of cholesterol. And they would be like, hey, those look similar.

01:16:11.100 Yeah. It's like, maybe I look like my mother and father. Did they have an origin or did they come

01:16:16.840 from that? So, sure. So certain cells can certainly transform cholesterol into reproductive hormones

01:16:23.860 or adrenocortical hormones. Certain cells, hepatocytes, can transform cholesterol into a bile acid.

01:16:31.520 I don't think there's any other cell that can change cholesterol into anything else. So when people

01:16:36.020 talk about cholesterol metabolism, there is no cholesterol metabolism. It can be converted

01:16:40.860 into something in specific tissues, but it can be excreted. That's it. There's no other way your

01:16:47.200 body can handle cholesterol. So do we, is there any evidence that we use cholesterol for energy?

01:16:52.340 Zero. Why? There's no, energy is really coming out of the saturated, the fats that have the most,

01:17:00.680 no double bonds. That's the most, they're carrying the most ATP. Cholesterol is not producing energy.

01:17:06.800 Cholesterol cannot be metabolized and produce ATP in the process.

01:17:11.760 I mean, to me, that's the bigger issue, right? I think some people get confused about this.

01:17:15.400 It's not that there isn't energy in a carbon carbon bond or a carbon hydrogen bond,

01:17:19.040 because that's exactly what's being liberated in the metabolism of a fatty acid. The point is we

01:17:23.500 don't have the enzymatic machinery to undergo the chemical process of breaking down those bonds and

01:17:29.940 liberating the chemical energy into electrical energy.

01:17:32.440 You can't metabolize cholesterol. Cholesterol ester, which carries that fat as can be

01:17:37.420 de-esterified, but your cells aren't making cholesterol ester. The liver is, the intestine

01:17:42.640 is, but the adipocytes are. My hypothesis for why that's the case, which could be entirely bullshit,

01:17:48.340 and I'm just making it up, but that's what hypotheses are. They're guesses, is that it would

01:17:53.360 have been evolutionarily dangerous if we could have metabolized cholesterol. Because in periods of

01:17:58.940 fasting, which we all did evolutionarily, the last thing you want your body doing is going after cell

01:18:05.220 membranes and hormones as a source of energy. So I think it's actually a very deliberate design,

01:18:10.920 quote, I use design in quotes, to say, hey, no matter what, your cholesterol and your hormones are

01:18:16.580 off limits during starvation. And instead, we evolved this other remarkable pathway of ketosis,

01:18:21.740 which takes an ample substrate of fats and goes down the path of metabolizing those,

01:18:26.660 and actually saving our muscle from the catabolic destruction that we would undergo if we couldn't

01:18:32.500 undergo ketosis. This is the brilliance of Peter Atiyah to me, that he can come up with what sounds

01:18:38.480 like a super plausible thing. See, I'm not smart enough to give that. It could be entirely bullshit.

01:18:42.020 I can tell you how to sell God cholesterol, what it can do with it, but he's figured out

01:18:45.480 what sounds like a really plausible reason. And everybody's so worried about depleting cholesterol

01:18:51.340 in the plasma as measured by LDL cholesterol, which has nothing to do with anything, because actually,

01:18:55.980 there's more cholesterol in your red blood cells than there are in lipoproteins, and you're not

01:18:59.860 making that zero by any means by using lipid drugs or something. But you can't deplete a cell of

01:19:06.960 cholesterol beyond a certain amount, so you're going to scrub cellular function. And you can't put too

01:19:11.180 much cholesterol in that cell because it'll crystallize and kill that cell. So that's why it's

01:19:16.360 so tightly regulated, synthesis, influx, and efflux. Now, are there cells under certain circumstances,

01:19:23.920 for whatever reason, can't make enough cholesterol? Yeah, there are pediatric disorders where if you

01:19:30.080 don't synthesize cholesterol, things happen to you in utero.

01:19:33.260 Well, the other thing we see this in, and I don't even know why I started noticing this, but

01:19:37.060 this is one of the things I used to do in residency that used to kind of piss off some of the attendings

01:19:41.200 is I would do little experiments. And it was always a measurement experiment. So it wasn't like I was

01:19:45.780 putting a patient at risk other than a few more milliliters of blood were being drawn. But I remember

01:19:50.100 once happening on a finding, which was maybe by accident, I had checked a lipid panel on a patient

01:19:57.020 in the ICU. And I saw something interesting, and I kept rechecking it in other patients over and over

01:20:02.060 again. And I kept seeing this, which was anytime a patient was having a SIRS response, that's capital

01:20:07.100 S-I-R-S, systemic inflammatory response syndrome. So this is the vasometabolic response to sepsis,

01:20:15.080 infection, trauma, you name it. Enormous drop in HDL cholesterol. And I think we could look at that

01:20:22.980 today and say it's very likely that what we were seeing was in that period of profound physiologic

01:20:28.340 stress, the body is greatly ramping up its hormone production, leukocorticoids, and others.

01:20:35.380 And that would be one of the situations where cells were actually, you know, HDL was now delivering

01:20:39.900 cholesterol to the adrenal glands in a period of, you know, because that's about the most

01:20:43.300 physiologically stressful thing that an organism can respond to. Again, I don't know if that's

01:20:47.520 been documented, but it seems to me pretty logical that that would be at least the most

01:20:51.600 plausible explanation for why HDL could plummet in patients who are going through that degree of

01:20:56.880 stress. Yes. And by the way, it's the reason you never do a lipid profile in an acute situation

01:21:03.500 because a lot of lipids are going to be transiently changed or so here. But Peter's right. We know this

01:21:10.740 for a lot of reasons. Clearly, the steroidogenic tissues need cholesterol to make their steroid

01:21:17.200 hormones, be they reproductive organs or your adrenal cortex. And in the situations Peter's

01:21:23.040 talking about, cortisone is a pretty useful hormone to have around or other mineralocorticoids

01:21:29.720 and things like that are. So clearly, those organs, those tissues are going to need a lot of

01:21:36.740 cholesterol pools to make all that. So they turn up their synthesis rates. So they make a lot of

01:21:42.940 cholesterol. But they would also tune up their, hey, let's gather some exogenous cholesterol,

01:21:50.540 so to speak. So those cells would upregulate LDL receptors. And that's a case where there's a tissue

01:21:57.220 that might, under certain circumstances, pull in LDL particles full of cholesterol ester. They would

01:22:03.460 de-esterify it and use it. But in a physiologic person who's not in one of these acute situations,

01:22:10.580 the adrenal gland most of the time just makes all the cholesterol it needs. But if it needs a secondary

01:22:15.600 source, that's why you have HDLs. HDLs have a half-life of five days. One of the reasons they

01:22:22.620 circulate for five days is it's a floating plasma reservoir of cholesterol for tissues that might

01:22:28.580 actually need cholesterol. Now, my nose cell that I talked about before doesn't need HDLs or anybody

01:22:35.200 else to deliver cholesterol to it. No other cell does except those steroidogenic tissues.

01:22:41.320 In other words, to be really clear and specific, you're sloughing off endothelial cells in your nose

01:22:46.240 every day. Well, you have to replace them. The lion's share of the cholesterol requirement is to

01:22:52.540 make a cell membrane. It has the machinery. It has the machinery within the nucleus to produce that

01:22:59.740 just as it's producing other structural proteins. Right. And this is what people just translate

01:23:05.720 low cholesterol plasma measurements to think you're screwing up cells throughout the body,

01:23:10.920 and you're not. Yeah. This is one of the challenges that I've never come up with a great

01:23:15.060 way to explain this idea of flux, which is you do a lipid measurement at a moment in time,

01:23:20.600 you're getting a snapshot of what's in the plasma at a moment in time, which doesn't give you two

01:23:26.220 pieces of information. How is it changing over time and what's the movement or the velocity?

01:23:30.280 And secondly, it gives you no insight into what's happening in the cell or what's happening in the

01:23:35.460 endothelium for that matter. And instead, that's the nature of lipidology is you have to be able to

01:23:40.600 extrapolate to these other things by indirect measurements. It gives you zero insight. The only

01:23:46.200 usability of plasma measurements are as surrogates of lipoprotein defining whether you have APOB,

01:23:54.220 APOA1 particles, and we know too many APOB particles. You're over time at big risk,

01:24:00.800 at increased risk for atherosclerotic disease or events. Otherwise, why even measuring lipids in the

01:24:08.420 plasma tells you nothing. And what we're talking about, you call it influxy flux, and that nails it down,

01:24:15.520 but it's cholesterol homeostasis or sterile homeostasis. And your body has evolved a lot

01:24:21.880 of ways to do. Interesting too, and say that a crisis is going on, adrenal needs continued. It's

01:24:29.680 not just, hey, you cured yourself in 12 hours overnight, you survived whatever. And if that

01:24:35.700 catastrophic process was ongoing, HDLs eventually would run out of cholesterol. You just said your HDL

01:24:41.340 cholesterol level is plummeting, and that's been documented many times. So the HDL all of a sudden

01:24:47.500 has to go back and start grabbing cholesterol molecules from some other tissue and get it to

01:24:52.780 the steroidogenic tissue. And the number mega place where HDLs get most of their lipidation is it goes

01:25:00.480 right back to the liver and gets lipidated, or what is the biggest cholesterol storage organ in the

01:25:05.740 body, not the liver, your adipocytes. Everybody thinks adipocytes are just stirring triglycerides.

01:25:11.360 They're a massive storage organ. So baby HDLs that are depleted, they run back to the adipocytes,

01:25:17.640 which express this ABCA1 transporter that pumps out all their cholesterol to an HDL, which boom,

01:25:24.140 right back to the adrenal gland, bounces back and forth like a ping pong ball.

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The Peter Attia Drive - October 16, 2018

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

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