#21 – Tom Dayspring, M.D., FACP, FNLA – Part II of V: Lipid metrics and cholesterol regulation

1. 0:00 – 0:04

   Intro

   1. PADr. Peter Attia0:00

      [upbeat music]

2. 0:04 – 6:15

   Lipids Travel in Lipoproteins: Gofman and the Ultracentrifuge

   1. PADr. Peter Attia0:04

      Hey, everyone. Welcome to The Peter Attia Drive. I'm your host, Peter Attia. The Drive is a result of my hunger for optimizing performance, health, longevity, critical thinking, along with a few other obsessions along the way. I've spent the last several years working with some of the most successful top-performing individuals in the world, and this podcast is my attempt to synthesize what I've learned along the way to help you live a higher quality, more fulfilling life. If you enjoy this podcast, you can find more information on today's episode and other topics at peterattiamd.com. [upbeat music] Hi, everybody. Welcome to episode two of five in the week of Dayspring. This episode, we cover lipoprotein basics, what's lipoproteins and lipids 101. We talk about Gofman and the ultracentrifuge and how we came up with these whole ideas of densities of lipoproteins. We get into very specifics around the lipoprotein structure, their function, and their metabolism. We talk about how to measure the lipoprotein and the cholesterol content and what NMR is and how it has changed the game a little bit. We get into the distinctions between LDL cholesterol, LDL particle number, and apoB. There is some confusion here amongst physicians and presumably amongst patients, so hopefully that will clear that up. We get into the biochemistry of lipids, and then we talk about sterols specifically as a more broad category. [upbeat music] Now, before we could measure anything to do with lipoproteins, i- if my memory serves me correctly, it would've been the v- late '40s, very early '50s when the first assays were developed, maybe it was 1951, that could actually just measure total cholesterol. So you would take plasma from a patient, you would presumably in an assay break down all of the lipoproteins and just aggregate the total amount of cholesterol, and you would yield that number, which still amazingly shows up on a panel today. You go and get a blood test, and it might say your total cholesterol is 200 milligrams per deciliter. So that, that was... Am I correct? That was the early '50s maybe?

   2. TDDr. Tom Dayspring2:10

      Uh, no, I think they were analyzing cholesterol long before that, 'cause that was... That's a molecule. You can take blood and dissolve whatever you gotta dissolve, and cholesterol appears. So they had cholesterol measurements for a long, long time. It's like the first lipid [chuckles] -

   3. PADr. Peter Attia2:24

      Yeah

   4. TDDr. Tom Dayspring2:24

      ... anybody could ever measure. What you're talking about in the '50s is where John Gofman discover that, "Hey, wait a minute, there are no lipids floating around in plasma," 'cause lipids are incredibly hydrophobic. Your plasma is water. You can't have lipids circulating in plasma. So lipids obviously have to be within what I call water-soluble lipid transportation vehicles, and that turns out, of course, to be a lipoprotein, a, a protein-wrapped collection of hydrophobic and amphipathic, uh, lipids that just wouldn't be in your plasma unless they're attached to a protein. Peter mentioned albumin. It's a protein, so lipids can attach to albumin and be circulated around. And o- other type proteins, but albumin's the most frequent protein in the blood, so it serves as a carry... I think an albumin can carry like 17 molecules of cholesterol. A few are phospholipids too. So it's, it's a player out there. We got a ton of albumin in our plasmas. You'd be shocked to find out how much cholesterol's in it. Not quite as much as in lipoproteins.

   5. PADr. Peter Attia3:24

      Albumin's kind of an amazing protein.

   6. TDDr. Tom Dayspring3:26

      Right.

   7. PADr. Peter Attia3:26

      It'll carry hormones.

   8. TDDr. Tom Dayspring3:28

      Yeah. [chuckles]

   9. PADr. Peter Attia3:28

      It'll carry just about anything.

   10. TDDr. Tom Dayspring3:29

       Yeah.

   11. PADr. Peter Attia3:29

       It's remarkable.

   12. TDDr. Tom Dayspring3:30

       And it has everything to do with osmotic pressures and things like that. Uh, so albumin is, uh, kind of an essential [chuckles] little protein to say the least, performing many, many functions. But when John Gofman, a physicist by the way, who had... Physicists had been playing with ultracentrifuges for a long time, separating nerve radioactive particles and stuff. He somehow wound up separating lipoproteins or saw things floating around in a centrifuge [chuckles] test tube that he then identified as the lipoproteins. So i- if you learn nothing else today, learn the, the first thing is lipids, for the most part, go nowhere in the human body unless they're a passenger inside a lipoprotein. So if you believe there are a lot of lipid-associated diseases, and I certainly believe atherosclerosis, it's... You cannot have atherosclerosis without a sterol, a lipid being in your arterial wall. And I know that artery- arterial wall didn't over-synthesize sterols, creating a sterol buildup. Somebody had to deliver those sterols there, and that h- of course, turns out to be a lipoprotein. And o- one of the places a lipoprotein should never deliver sterols to, to any serious degree, of course, is your arterial wall intima. So being a Jersey guy, one of my standard jokes on a lecture circuit was atherosclerosis is just the evidence of illegal dumping, where a lipoprotein, instead of bringing lipids to wherever it's supposed to be bringing it, was bringing sterols to the arterial wall. And over decades, you got a problem. Y- you know, it could do it for a few days, six months, you're not gonna die of atherosclerotic disease.

   13. PADr. Peter Attia5:14

       So, so when did it become clear... So Gofman figures out by first principles, basically, he imputes that there's got to be something that is transporting this very, very hydrophobic molecule through plasma. It doesn't, you know... I mean, it's in, it's easy in retrospect to make light of what an observation that is, but the next observation would be it would need to be spherical, right? I mean, it's, it's... To optimize the volume in which you could transport-

   14. TDDr. Tom Dayspring5:38

       Correct. Yeah

   15. PADr. Peter Attia5:39

       ... it would have to be spherical.

   16. TDDr. Tom Dayspring5:40

       You're a mathematician. A volume of a sphere-

   17. PADr. Peter Attia5:42

       Yeah

   18. TDDr. Tom Dayspring5:42

       ... the third power of the radius. So if you're gonna devise a transportation vehicle, a sphere-

   19. PADr. Peter Attia5:46

       That's by far the most-

   20. TDDr. Tom Dayspring5:47

       ... is better than a flatbed truck.

   21. PADr. Peter Attia5:48

       Yeah.

   22. TDDr. Tom Dayspring5:48

       You know?

   23. PADr. Peter Attia5:49

       So how long was it until- I mean, I know the answer to this question, but I just have to sort of tee it up. Who then went on to figure out these things occur in different densities? It's not just one. There's not just one spherical molecule that's transporting these things.

   24. TDDr. Tom Dayspring6:03

       It was-

   25. PADr. Peter Attia6:03

       'Cause this is a beautiful story, right?

   26. TDDr. Tom Dayspring6:04

       Yeah, it was Hoffman. He noticed that there... And they weren't calling them apoB and apoA-

   27. PADr. Peter Attia6:10

       Right, right

   28. TDDr. Tom Dayspring6:10

       ... one particles that today, but they were different densities. They were gigantic-

3. 6:15 – 15:58

   Density, Size and ApoB: Why Particles Differ

   1. PADr. Peter Attia6:15

      So explain what you mean by density. 'Cause this term, you know, we talk, everyone knows low density lipoprotein, high density lipoprotein, but w- tell me what, where that terminology actually came from.

   2. TDDr. Tom Dayspring6:24

      Well, I think it has to do with water has a certain density, so it's whether things float in water or sink in water. We know rocks sink if we throw it in a pond, so they're very dense things, whereas other things float on top of water. They obviously are less dense than water is. So everything is relative to water there. So if you establish what you think is the density of water, things that float. So when he separated these things in a centrifuge, the lipoproteins or these fat balls that didn't move at all were obviously very buoyant. Some sunk just a little bit, so they were less buoyant, but still pretty buoyant, and some went right to the bottom of the test tube, obviously incredibly dense. And it turns out what makes a, a lipoprotein buoyant is a ratio of its lipid fat content, 'cause I think we all know fat floats on water, or if proteins m- you check out the molecular weights of proteins, really heavy, they sink. So they're the rocks. So your density of a specific particle here, a lipoprotein particle, is gonna be related to its lipid content versus its protein content. So our big monsters that are delivering, as I told you, triglycerides, but have a lot of phospholipids on our thing, they have some proteins, but they have so much lipids they float. They're the buoyant ones. And as they lose the lipids, they become smaller. Now, they lo- might lose a few proteins as they shrink, but they're really using the, the lipids-

   3. PADr. Peter Attia7:59

      But they're fundamentally concentrating protein as they get s- I mean-

   4. TDDr. Tom Dayspring8:02

      Yes

   5. PADr. Peter Attia8:02

      ... 'cause when you look, when you go from chylomicron, even though they're not the same lineage, so I wanna be very careful. You'll explain this in detail. You do not go from a chylomicron to a VLDL, to an IDL, to an LDL, to an HDL.

   6. TDDr. Tom Dayspring8:13

      No.

   7. PADr. Peter Attia8:13

      They're three separate lineages I just described. But in size, they loosely track as the smaller they get, the more they've concentrated protein.

   8. TDDr. Tom Dayspring8:22

      Within every category of lipoproteins, be you talk chylomicrons, which intestinally produce VLDLs, hepatic produce, and the classic teaching is as VLDLs become smaller, you call them intermediate density and low density. We now know the liver can produce-

   9. PADr. Peter Attia8:38

      Make each of those

   10. TDDr. Tom Dayspring8:39

       ... an LDL-

   11. PADr. Peter Attia8:40

       Yeah

   12. TDDr. Tom Dayspring8:40

       ... without making a VLDL first. High densities which form themselves in the, uh, things sort of go the opposite way, whereas the VLDLs and chylomicrons come out as big fat monsters and lose lipids and become smaller and denser. The HDL, as it gathers lipids, becomes bigger and more buoyant. But within every class of lipoproteins, you're gonna have a heterogeneous range of densities, from big species to small species, and this is why to me, I like to tease because you always hear people talk about the small, dense LDL. Within every lipoprotein classification, the smaller particle is always more dense than the... So that's a redundancy.

   13. PADr. Peter Attia9:23

       It's a redundancy.

   14. TDDr. Tom Dayspring9:23

       Just tell me dense LDL. Just say small LDL. I know it has to be dense, or if it's dense, I know it has to be small compared to its sister particles within that family or so. Somehow small has only been applied more frequently to LDLs 'cause that's the killer one, or HDLs. Oh my God, you want to have the big HDLs. Another joke that's turned out, but for the longest while, if you don't have big HDLs, you're in big trouble or so. And if you got the small LDLs, you're in the biggest trouble. That basically turns out to be 'cause if you have small LDLs, you need a ton of them to carry whatever your lipid load is, so you got a super high LDL particle concentration if you have small LDLs, and that's more related to its pathology per se than the size. Not that that won't cause certain functional characteristics of the LDL. [laughs] But the VLDL, the chylomicrons come out big and they shrink. Now, the reason though that differentiate chylomicrons and the VLDLs, IDLs, and LDLs is they have a lot of apoproteins on their surface, which they do lose as they shrink. But there's one protein they never lose, and it's the one that has the most massive molecular weight, apolipoprotein B. So that's why they are never gonna be as dense as an HDL particle, 'cause an HDL has, doesn't have this monstrosity high molecular weight apoB on it. It's got other things, far less lipids. But to some, the, the LDLs, IDLs, VLDLs are always gonna be way more buoyant because of that, because they do have a little bit of an anchor on them creating to their densities, that apoB. And it's the only, as you study apoproteins, and we're probably up to 20 to 30 of them now, all of which have certain functions that it sort of directs a lipoprotein down which path it's going, a catabolic path. The only apoprotein... By the way, get definitions out the way. Apoprotein, apolipoprotein, lipoprotein. An apoprotein is the protein your cell makes. Once it binds to lipids, it's called an apolipoprotein, and of course, the whole particle itself is called the lipoprotein.

   15. PADr. Peter Attia11:34

       So let me resynthesize that. The lipoprotein is the spherical structure whose membrane is made up of mostly these phospholipids, but also other lipids. The apoprotein is the thing that kind of gives it its signature. So for example, the chylomicron has a B-48. The IDL, VLDL, and LDL have a B-100, et cetera. That's just called the apoprotein. It's once the apoprotein, and I assume it's covalently bound to the lipoprotein, that becomes the apolipoprotein and we short, we abbreviate that apo fill in the blank.

   16. TDDr. Tom Dayspring12:10

       Yeah. So if I took a VLDL particle and later on I'll tell you, boy, on a VLDL you're gonna find apoC1, apoC2, apoC3, apoA5 and a bunch, including apoB, but it's gonna lose everything but apoB as it's-

   17. PADr. Peter Attia12:26

       Mm-hmm

   18. TDDr. Tom Dayspring12:26

       ... transferred, lose most of the other ones 'cause they're transferable. They can jump on s- a different lipoprotein if they so desire. The apoB never does. For a bunch of reasons, it provides the structural integrity to that particle throughout its existence, but apoB turns out to be the ligand for receptors that internalize those particles when you, th- your body don't need them anymore. So the LDL receptor that everybody knows about-

   19. PADr. Peter Attia12:53

       So the ligand, just for, 'cause there's some, some people listening, it's like the key that fits into the lock. If the receptor is the lock, the ligand is the key, and in biology, that's sort of how everything works. The key has to fit the lock.

   20. TDDr. Tom Dayspring13:04

       Correct. And if it didn't, then that lipoprotein is gonna stay in your plasma and probably wind up going somewhere it's, where it's gonna create a pathological state.

   21. PADr. Peter Attia13:12

       So, so when was it figured out that apolipoproteins are gonna come and go, but there's one of these ones that not only always stays, but you have one? 'Cause that's a big deal, the realization that apoB 100, if you knew that concentration, you had a proxy for how many particles you had.

   22. TDDr. Tom Dayspring13:32

       Yeah. So Gofman certainly figured out there were proteins involved here, but he wasn't applying that nomenclature to them and everything. It's guys who furthered, a few years further down the road, Fredericks and Levy and Lees started to-

   23. PADr. Peter Attia13:45

       So we've, we've talked about those with Ron Krauss and yeah, yeah, yeah

   24. TDDr. Tom Dayspring13:47

       ... realized there were, these are really, there are some very important structural and functional proteins on these particles that we better start investigating and giving names to. So their research led to the identification of all them and ultimately, I mean, we know now the amino acid breakdown of every darn, uh, apoprotein that's in our body or on, on our particles and everything. So it just, when one researcher invents a little bit of the story, other ones pick up the pieces and start further elaborating on it with different studies and technology improves and some of these things that were not assayable at one point become that you can measure them and identify their structure and everything. So it's one of these evolutionary things and, and it just made such perfect sense too because we knew these particles are changing so they're undergoing catabolic processes. Why? What's doing that? And then all of a sudden you figure out that these ligands, these apoproteins, are keys to various receptors. Some of those receptors pull the particle next to where there's an expression of a lipid dissolving enzyme, a lipase, and it starts to all make perfect sense to you. So over time we've identified numerous of these enzymes that can catabolize lipoproteins, numerous of the receptors that temporarily bind these particles in place so they can undergo this thing, ligands that lipidate, fill the particles with the lipids or delipidate them so-

   25. PADr. Peter Attia15:26

       So if you're listening to this and you're confused at this point, it's okay. One, there's gonna be killer show notes, but more importantly, we're gonna take a step back now. I'm a guy listening to this, I'm a girl listening to this. All I know is every time I go to the doctor, he or she gets a blood test and it spits out the following. Total cholesterol equals this. LDL, and they won't even... L- let's, it'll be worse. It'll say LDL equals this, HDL equals this, triglyceride equals this, and maybe it will say non-HDL equals this.

4. 15:58 – 28:59

   Reading a Lipid Panel: Total Cholesterol, HDL-C and Friedewald LDL-C

   1. PADr. Peter Attia15:58

      What do those things mean in relation to everything you just said?

   2. TDDr. Tom Dayspring16:01

      Yeah. First of all, the misinformation on labeling lipid metrics is one of the things that miracle hasn't given me a stroke yet. I do a lot of peer review. I'm gonna, uh, one of the associate editors of the-

   3. PADr. Peter Attia16:13

      That's why we're fasting you, Tom

   4. TDDr. Tom Dayspring16:14

      ... Journal of Clinical Lipidology and I will reject a paper instantly that uses improper lipid metrics. Don't tell me your, the LDL is this because LDL is a low density lipoprotein. It's not a laboratory metric. You want to tell me what the LDL cholesterol is, the LDL particle number is, the lipidomics of an LDL is, the LDL oxidized or not, great. We do have assays that will measure that. So let's please all you, d- don't identify yourself as an ignoramus and like I've told this to many of the top lipidologists in the country who lecture, stop telling people, "What's your LDL?" Ask them, "What is your LDL cholesterol? What's your..." If we don't all talk the talk, you're never gonna understand the process.

   5. PADr. Peter Attia16:59

      So this patient almost assuredly is talking about total cholesterol, LDL cholesterol, HDL cholesterol and non-HDL cholesterol.

   6. TDDr. Tom Dayspring17:07

      Yeah. So I'll give you a quick de- and by the way, Peter did mention something very quickly before and I just wanted to expound and he talked about, hey, apoB 100, apoB 48. ApoB is a giant structural non-transferrable apoprotein that's on chylomicrons or VLDLs. The intestinal machinery that synthesizes a chylomicron makes a certain type of apoB and the apoB that is made in the liver makes a much bigger apoB. It has a higher molecular weight. So they knew the apoB that's being made in the intestine is much smaller. So it turns out to be that the apoB in the intestine is 48%-

   7. PADr. Peter Attia17:46

      48% the molecular weight

   8. TDDr. Tom Dayspring17:47

      ... of the molecular weight of the hepatic-produced apoB. If you get into genetic apoB dis- you'll see apoB 31 that has 31% of the molecular weight of what's considered a normal apoB. So when you hear apoB 48, that should identify it as an intestinally produced apoB particle and a liver would be an apoB 48 and LDLs that come out of the liver have, no excuse, have apoB 100 on it like the VLDL or a VLDL it becomes an LDL, the apoB 100 is still there. So, so just keep, if you hear 100 or 48, what does that mean? It sort of tells us the origin. We are gonna be talking about nuclear magnetic resonance and one of the parameters they used to give you a lot on, less so nowadays, is VLDL particle concentration. When you analyze a lipoprotein using nuclear magnetic resonance, it cannot tell the difference between a chylomicron and a VLDL 'cause NMR doesn't measure the proteins. It's, "Hey, that's a very big particle, so it has to be a VLDL or chylomicrons." Most of your big particles-

   9. PADr. Peter Attia18:50

      But if you're fasted-

   10. TDDr. Tom Dayspring18:51

       ... are VLDLs. Yeah, and even in a postprandial state, chylomicrons have half-lifes in minutes. They're gone. So the vast majority of VLDL particle number via NMR is still VLDL-

   11. PADr. Peter Attia19:02

       VLDL

   12. TDDr. Tom Dayspring19:02

       ... part of, but there could be some chylomicrons in there.

   13. PADr. Peter Attia19:04

       All right. But I want to go back to our lady.

   14. TDDr. Tom Dayspring19:06

       Yeah.

   15. PADr. Peter Attia19:06

       So her total cholesterol is 190 milligrams per deciliter.

   16. TDDr. Tom Dayspring19:10

       So total cholesterol, remember my premise that lipids go nowhere in the body unless they're within a lipoprotein. It's not exactly true, but for today's purposes [chuckles] that is true, and certainly understanding lipid metrics, that's true. So total cholesterol would be the laboratory has, uh, separated all your lipoproteins from the serum and they're take how much cholesterol is in this serum tube. So where would that cholesterol be that they're analyzing? Well, it would be found in, if there were any chylomicrons there that were hanging around or maybe they didn't fast, some of it would be chylomicron cholesterol. So, uh, uh, some of it would certainly be VLDL cholesterol, a lesser amount 'cause there's just so many, so fewer of them would be intermediate density cholesterol particles and the rest would be in either LDL particles, low density lipoproteins, or the high density lipoproteins. There are other types of LDL particles called LP little A which we'll talk about. So total cholesterol is all of the cholesterol that is in every single lipoprotein that's in a deciliter of your plasma.

   17. PADr. Peter Attia20:17

       And that is directly measured. It is not imputed.

   18. TDDr. Tom Dayspring20:20

       And that's an assay. That is not a calculation. That is assayed. So it's, any lab, there's always a coefficient of variability that's inaccurate. And so if you want to use cholesterol for anything nowadays, 'cause let's face it, that was the first parameter looked at in the epidemia and they certainly correlated total cholesterol levels with the risk for heart disease. But think about what I just told you. It's the cholesterol within all the lipoproteins. W- what is the... If you counted particles, what is the most numerous particle in your bloodstream? The apoB particles. Well, actually the HDLs are more, but they're so small they don't carry much cholesterol. So most of your, if you want to put a parentheses around it, atherogenic cholesterol would be within your apoB particle. So if you want to ascribe any use to total cholesterol, it's a real poor man's apoB level. In general, most people with very high total cholesterol levels will have a very high apoB level and they're... And that's the real reason they're at risk for atherosclerosis, 'cause those are the particles-

   19. PADr. Peter Attia21:25

       Yeah, I mean, the original epidemiology-

   20. TDDr. Tom Dayspring21:27

       Yeah

   21. PADr. Peter Attia21:27

       ... basically said, you know, you have to sort of applaud them for doing the best they could with the tools they had, but let's take total cholesterol, which was at the time the only thing we could measure clinically. Let's take the patients who were in the top 5% and the patients in the bottom 5%. Was there a difference in their risk of MI? And the answer was yes.

   22. TDDr. Tom Dayspring21:47

       Correct.

   23. PADr. Peter Attia21:48

       Now, it would be another at least decade until Framingham... This is kind of an interesting story, right? How it got... This, this part, part of the story got ignored in Framingham was that low HDL cholesterol and high triglyceride turned out to be four times more predictive of MI than high LDL cholesterol, and again, this is still crude measurements. But that, that sort of didn't come back into... People didn't come back to try to explain why that might be the case until Jerry Reaven had sort of done his work on metabolic syndrome. But I also realize I'm gonna get us off topic and I want to go back to this other question. So we've just explained what 190 milligrams per deciliter means. When it says HDL, it really means HDL cholesterol, as evidenced by the units, so those will either be, either be measured in millimole or milligrams per deciliter. That's a direct assay or an indirect assay?

   24. TDDr. Tom Dayspring22:37

       Yeah. So Framingham, who of course did measure total cholesterol, was easily available, they did it. They measured triglycerides too, although they really had no clue [chuckles] what they, were they related to this, but it was measurable. Glycerides, they called it glycerides back then. And they did have a direct assay for HDL cholesterol. They w- you know, you could also measure chyl... You know, you can centrifuge particles, you can take out the LDL fraction and analyze how much cholesterol is in them. That's theoretically the gold standard. You can separate the HDL product, but that's too time-consuming. Nobody's got ultracentrifuges. So to have real world tests, chemists had to develop direct assays. So HDL assays were developed real early on. So Framingham could not only measure total cholesterol, they could measure, directly measure, not calculate HDL cholesterol. What they could not measure, and it took a long time, was LDL cholesterol. There was-

   25. PADr. Peter Attia23:35

       Without centr- without ultracentrifugation.

   26. TDDr. Tom Dayspring23:37

       Without ultracentrifugation, correct. In the '70s, somebody came up with a formula that here's a way of at least estimating or calculating LDL-C, which took fire because by the '70s they realized the most numerous atherogenic lipoprotein were the low-density lipoprotein. So as Framingham started calculating LDL cholesterol, they, "Whoa, this is the story here." So they calculated for the longest while

   27. PADr. Peter Attia24:03

       So just to be clear, what they're doing is they're directly measuring total cholesterol, 'cause you can just do that off serum. They precipitate out the HDL, right?

   28. TDDr. Tom Dayspring24:12

       Yep.

   29. PADr. Peter Attia24:12

       So you could measure the HDL without intersu- ultracentrifugation, and you could measure triglycerides. So now the formula for estimating LDL cholesterol became total cholesterol minus HDL cholesterol minus triglycerides over five. Why the triglycerides over five?

   30. TDDr. Tom Dayspring24:29

       Yeah. So Friedewald put two and two together and realized, hey, total cholesterol is in essence VLDL cholesterol plus LDL cholesterol plus HDL cholesterol. A equals B plus C plus D. So if I know parameter A and I know parameter D and I know parameters C, I can figure out what parameter C is.
5. 28:59 – 36:05

   NMR, LDL-P and ApoB: Particle Number Versus Cholesterol

   1. TDDr. Tom Dayspring28:59

      so.

   2. PADr. Peter Attia28:59

      So NMR, which is, you know, my first exposure to NMR was in high school when we were taking organic chemistry and you learned that we had these tests. I still remember how fun these tests were, where they would show you an NMR spectroscopy and you had to figure out what the molecule was by knowing where those spikes were. So was Jim Otvos the guy that first figured out that you could use that stuff to actually count the number of these apoBs?

   3. TDDr. Tom Dayspring29:30

      Yeah, I think Otvos was certainly one of the early pioneers and over father time, the, the real pioneer who evaluated lipids and lipoprotein using nuclear magnetic resonance spectroscopy. He knew that lipids would emit specific spectral signals that he could analyze and, through very complex mathematics, turn them into a variety of lipoprotein metrics, including you can do an NMR l- LDL cholesterol level, an LDL triglyceride level. In the future, that's one of the ways we're going to be measuring phospholipids on various lipoproteins is NMR spectroscopy, because as Peter says, every lipid has a different spectral signal and if you know what you're doing, you can look at a spectral signal and know what it's molecular composition is and everything. So Jim turned it into, you know, as we had all these lipid metrics that we're talking about, cholesterol, even triglyceride metrics, deep down the guys know these are just poor man's way, easily assayable ways of quantifying lipoproteins, and it's the quantification that matters in many cases or so. So we have t- it turns out in the long run, it's the, the number of ApoB particles that primarily is what forces it into the artery wall. Very little L. I mean, there are other factors, but that's the number one factor.

   4. PADr. Peter Attia30:48

      But when was that, when was that pathophysiology first stumbled upon, that it even mattered how many of these particles you have versus... So let's just take out the estimates, and let's assume that you have the ability to measure the total cholesterol concentration within an LDL particle, which is what's showing up when someone gets a blood test and it says direct. When it says LDL-C direct, that means they've actually measured it, so now it's better than Friedewald's estimation. But that's different from if you have an NMR where it says LDL-P, nanomole per liter, and that's counting the number of those particles. So one is the number of particles, the other is the amount of cholesterol contained within them. We'll, we'll get to what a revisiting of Mesa and Framingham made unambiguously clear, which is one of those predicts better than the other. But was that really the realization that it was a gradient-driven process by number, or was that understood beforehand or at least hypothesized beforehand and then more, more verified by the experimental evidence?

   5. TDDr. Tom Dayspring31:49

      No. Early on, they discovered it was the ApoB particles going into the artery wall and delivering these sterols and everything that set off this maladaptive in- inflammatory process that led to a whole o- other area of investigation or so. So, uh, the particle number data came once they sort of id- identified a way of assaying particle numbers, and they almost evolved as this, maybe ApoB came a little bit first.

   6. PADr. Peter Attia32:16

      Mm-hmm.

   7. TDDr. Tom Dayspring32:16

      But then Jim Otvos' work on LDL particles came at the same time, and it clearly became evidence that ApoB is a better risk factor. And remember, there is one ApoB on every VLDL, IDL, and LDL, but 95% of the ApoB particles are LDLs, so ApoB is just a way for the labs to report to you what an LDL particle concentration is. Otvos identified an LDL particle concentration using these methyl signals coming out of the, the methyl groups that are on cholesterol ester and triglycerides and phospholipids and translated into a particle number that, wow, either ApoB or LDL particle number correlates a lot better with clinical events or the presence of atherosclerosis. You haven't had an event, but if we do some imaging, we see plaque in your wall, than does the cholesterol measurement itself. So it's not a surrogate of particle. They are particle measurements, ApoB or LDL-P. So ApoB is an LDL particle metric. What too many people get lost at, "Hey, VLDL particles are an ApoB particle, so VLDLs are par-" And there's no doubt that VLDLs can get in the artery wall and contribute to it, but it's like a minor... The number of VLDLs that get into the artery wall are infinitesimal. The number of chylomicrons that get in are infinitesimal compared to the number of LDL particles. So yeah, they're all bad guys. They... And a VLDL per particle have significantly more cholesterol molecules in it than an LDL, but there are just so many more LDLs that collectively the LDLs deliver more cholesterol to that artery wall.

   8. PADr. Peter Attia34:00

      Oh, I'm gonna go back and do one more.

   9. TDDr. Tom Dayspring34:00

      But an ApoB, by the way, gives us no information on VLDLs. It's an LDL particle metric. You can't use it for anything else. So don't call me up and say, "My ApoB is high 'cause I got too many VLDL particles," unless you have a rare lipid disorder where there are no LDL particles, the type III, this beta-lipoproteinemia. That's the only time an ApoB is measuring it's a VLDL measurement or a remnant measurement. It's not an LDL measurement. But in everybody else, ApoB, LDL-P, those are the tests you need because although they correlate very well with LDL cholesterol, if they're both high in a given person, that person's at terrible risk. But as you well know, and probably because of the metabolic makeup of our existing humans, at least throughout the world now, is some people have very high ApoB, LDL-P, very good LDL cholesterol. Some people have high LDL cholesterol, perfect ApoB, LDL particle counts. When those metrics agree, they're said to be concordant. Hey, use them both. Either one will give you the same information. But what happens if you get a patient where they don't agree these metrics? In virtually every single trial ever looked at, the risk follows the particle metric more than the cholesterol metric. So the only way to know who is discordant with a cholesterol metric and an ApoB or an LDL particle metric is to do both of them. You could also say, "Hey, if I'm just doing ApoB or an LDL particle count, I don't even need lipids." And I'd agree with you, except I think there is value in knowing what a triglyceride is for other reasons. So, uh, that's the real key, and if you ever go to a doctor and you're told, "I'm very happy 'cause your LDL cholesterol is normal," say, "Well, so am I, doc, but by the way, what was the ApoB or LDL particle count?" And if the doctor didn't do it, you demand he do it instantly, 'cause otherwise you don't know your lipid-related risk.

6. 36:05 – 39:53

   Physician Resistance and Denial of Particle Metrics

   1. PADr. Peter Attia36:05

      Yeah, we're gonna upset a lot of doctors here because I've already, and you've already been in the business of that, where people will hear you talk or something or read something you've written or something I've written, and they'll go to their doctor and say, "Hey, I want my LDL-P or my ApoB," and the doctor says, "That's nonsense." The, you know, fill in the blank, TBD, blah, blah, blah, blah, blah. And it puts patients in an awkward position. I mean, I really feel bad about this because especially on, depending on what country they live in, at least in the United States, I think anybody can go to LabCorp directly and get the assay without a physician's prescription, but it upsets me, I think, that patients even have to do that. It upsets me that something that is such an important metric, I would list LDL-P as one of the five most important metrics, I've talked about this, that every patient should know their LDL-P or apoB, and that that wouldn't be sort of fundamentally a part of screening somebody for disease, and that a patient would get into a position where they're having to argue with their doc about that is, is disconcerting. And look, hopefully this is sort of why I do these podcasts, is I think it's just as much to help physicians say, "Look, just because I didn't learn this in my training doesn't mean I don't need to sort of pick it up today."

   2. TDDr. Tom Dayspring37:15

      Amen. And I'm sad there's so much what I consider inferior lipid care being administered by, uh, healthcare professionals in the United States, but there's nothing I can do about that, is try and teach them one at a time or expose my writings and other people's writings and the data on this as much as I can. And, uh, it is tragic with public health problem number one or number two that this has lagged so far behind, in part retarded by guidelines and, uh, third-party payers who just don't want to pay for different metrics and stuff. So there's other reasons behind it, but a big part is they don't understand it. You have had cardiologists call you up. I have had c- n- being recognized as maybe in Northern New Jersey, one of the, "Hey, hey, hey Tom, you know, y- you told my patient that, uh, you know, what I said about LDL cholesterol doesn't matter 'cause you've done an LDL particle and you put... You know, not everybody believes that," or they give you some horseshit like that. And I say, I'm going to say, "Hey doctor, would you like 200 manuscripts delivered to your desktop tomorrow? I'll do it if you promise me you'll read them every single one."

   3. PADr. Peter Attia38:27

      [laughs]

   4. TDDr. Tom Dayspring38:28

      So, you know, it is what it is. I think the internet has helped people in certain ways, and I think the internet has confused people in a lot of ways, too, 'cause there are people out there who, what we just talked about, and it's pretty much fact, who become deniers of the particle concentrations because whatever else they're exposing as their way to cure heart disease somehow aggravates LDL particle count, and they just choose to ignore it. And look, are there people with high LDL particle counts who don't somehow... Yeah, they're out there, but the overwhelming amount of literature says the odds are if you keep this for 20, 30 years, you're going down. You, until somebody does a serious study showing there are people who can escape this for 20-- you're playing with fire to ignore an elevated LDL particle count apoB. I don't have a way of identifying who, who might have a high metric there is somehow protected against atherosclerosis.

   5. PADr. Peter Attia39:23

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

7. 39:53 – 54:09

   Sterol Chemistry: Sterols, Esters, Stanols and Phytosterols

   1. PADr. Peter Attia39:53

      I want to go back to one semantic thing. You use the word sterol a lot. I'm very comfortable with it. I want to make sure the listener knows the difference between a sterol, a stanol, a zoo sterol, a phytosterol. We're gonna, I think we're gonna touch on this later, so let's just hammer out the semantics.

   2. TDDr. Tom Dayspring40:09

      Right. Well, cholesterol, of course, is the molecule we all fear, 'cause it's been drummed into our head that cholesterol in a, an arterial wall is where what is plaque. It's a cholesterol core, and that cholesterol can cause impaired vascular biology resulting in clinical events. So what is cholesterol? And we certainly, in Peter's notes here, you're gonna have pictures of the cholesterol structure, and it's got four rings. It's an aromatic compound. And off the fifth ring is a little tail sticking out, which is a carbon chain. So the precursor molecule is called the sterane. So you have the, the rings, the four rings, and you may or may not have this tail sticking off of the 17th carbon in the fourth ring. So all of the bonds are saturated. That is called the sterane. So if you unsaturated one double bond in that sterane, it's called a sterene. And if you then stick a hydroxy group on the third carbon in the first ring, it's called a sterol. It's an alcohol, 'cause you got a hydroxy group now sticking out of-

   3. PADr. Peter Attia41:22

      Hydroxy being OH.

   4. TDDr. Tom Dayspring41:24

      OH is hydroxy.

   5. PADr. Peter Attia41:24

      Oxygen. Yeah.

   6. TDDr. Tom Dayspring41:25

      Excuse me. Correct. So you'll see the pictures in, uh, my illustrated diagrams there. And that little tail that sticks out on the other end of the molecule has a lot to do with what exactly type of sterol that is and w- how it will function in a cell or in a cell membrane or so. So cholesterol would be this four-ring structure. Three of the rings have six carbons in it. The fourth ring has five carbons in it. You have this tail sticking off of carbon 17 that goes out, and in cholesterol, that's a totally saturated tail. Every bond in it is a s- it's a saturated fatty acid. And then on the three position, you'd have this OH group, the hydroxy group. By the way, since OH is sort of soluble in water, that part of the cholesterol molecule is soluble in water, whereas that carbon chain sticking out, so pure lipid, that's all carb, that's not soluble in water. So when cholesterol does exist in a surface membrane, like a cell membrane or lipoprotein, it's cholesterol-

   7. PADr. Peter Attia42:28

      It orients itself such that-

   8. TDDr. Tom Dayspring42:29

      Yeah. So the hydroxy group is sticking out, and that aliphatic tail is sticking into the core of the particle or so. Now, the cholesterol that's in the middle of the particle Oh, that-- the hydroxy group can't be in the middle of the particle. That's water. So they stick a really long chain fatty acid. They replace the hydroxy group with a long chain or really any chain fatty acid, mostly it's a long chain. So you esterify cholesterol. Remember I told you attaching a fatty acid to something is called esterify. So cholesterol, which is the active form of cholesterol that can be changed into a hormone, a bile salt, or function in a cell membrane, becomes a storage form of cholesterol or a lipid core transportable form of cholesterol called cholesterol. Now it's Y-L, it's not O-L, ester, and we abbreviate that as CE. So free cholesterol is either gonna be abbreviated as a C or an FC and cholesterol ester, and it's very difficult. If I wanted to-- If I'm an adrenal gland and I got some cholesterol ester stored and I wanna make a hormone 'cause I need cholesterol, I have to de-esterify that cholesterol ester to free cholesterol. If the liver has cholesterol ester storage pools, and it does, and it wants to make a bile acid, it has to de-esterify cholesterol ester. Cholesterol is stored in huge quantities in fat cells as cholesterol ester, and it would have to be de-esterified to be utilized to do something else or so.

   9. PADr. Peter Attia43:57

      One little story I'll just tell before we get to the stanols and all the other stuff is one of my prouder moments in front of Bob Kaplan was when you sent an email, like this was a couple months ago, you sent us an email and you said, "See if you can spot the error in this figure." And it was like a figure that had a million things on it, and I was like, "Oh, I'm not getting up until I figure out where the mistake is." And sure enough, somewhere in there, it took me about 10 minutes, w-- the illustrator had written, 'cause this was out of a paper or something, they had written cholesterol, O-L, ester instead of cholesterol, Y-L, ester. And, and, and when I responded to you and you, uh, responded in the affirmative, I was like, "I've got my stripes."

   10. TDDr. Tom Dayspring44:38

       [chuckles] And that figure he's talking about came out of one of the productions for the company that I work for. We develop educational pieces for physicians, and I d- obviously drew it and labeled it. But you send it off to a medical illustrator who formats it for the PDF or whatever, and cholesterol's cholesterol, and they make the mistake. Even though I sent in the picture where it was properly labeled, of course, I had a heart attack the first time I saw it, and we've since changed that. But somehow Peter got a hold of an older version or something that probably even I sent out and didn't recognize initially. But yeah, so it is cholesterol ester. Anything that's esterified becomes a YL, so you'll see lipids.

   11. PADr. Peter Attia45:16

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

   12. TDDr. Tom Dayspring45:42

       Well, that's true, especially if you want to take it to the Nth degree. But you need to invest yourself in some degree of education to at least be competent in today's, uh, world or so. So you have to know some of this stuff.

   13. PADr. Peter Attia45:54

       Well, and that's the thing. You have to be willing to learn some of this chemistry. I mean, you have to steep yourself in biochemistry and understand the-- 'cause the significance becomes enormous. One double bond in one of these things completely changes its properties. And not to say that that's not true in general in biochemistry, but it's much easier to talk about blood pressure or to talk about elevated levels of uric acid or insulin or glucose without getting into that level of minutia. It is not possible to discuss lipids without that.

   14. TDDr. Tom Dayspring46:28

       And that is the problem when a lot of people are spouting off on the internet and elsewhere about all these... They just don't have un- understanding of the complexity of all [chuckles] how this all works and fits together and why what you just said is wrong because there's something going on stoichiometrically that you haven't even considered or, or, or so. To finish the sterol. So a steroid is a sterol. It's got another keto group stuck on it someplace. Look at all the hormones.

   15. PADr. Peter Attia46:54

       Yeah.

   16. TDDr. Tom Dayspring46:54

       You'll see a double bond with oxygen attached. But a stanol is you take... And let's take cholesterol as a stanol or a sterol. And remember cholesterol at the third carbon's an OH group. There's a double bond at carbon five to six in the first ring, and then there's that tail at carbon 17. If I desaturated cholesterol, the double bond at C five and six disappears. That's called cholestanol. It's a stanol. A stanol essentially a saturated sterol. Changes the characteristics of that mo- cholesterol. Free cholesterol can be readily absorbed in your intestinal wall. Stanols cannot be absorbed. And it's kind of funny, our liver to get rid of-- or our body to get rid of cholesterol sends it to the liver. The liver sends it through the bile to the intestinal pool as free cholesterol, and your intestine's more than capable of just reabsorbing that cholesterol that the liver's trying to evict. Except our little friendly microbes down there in the gut convert a ton of the biliary excreted cholesterol into a stanol called cholestanol, or there's an isoform of it called coprostanol. It's a stanol, cannot be reabsorbed, so you poop it away, and that's how the body gets rid of cholesterol. It changes a lot of it to a stanol. Anthropologists have been measuring specimens for coprostanol. That tells them humans lived there at one time [chuckles] 'cause they find that in certain specimens, and that human had to excrete it. You know, so, uh, a stanol is simply a saturated... And that has other applications 'cause, hey, if stanols cannot be absorbed, and I would like to have a metric of whether you're absorbing cholesterol or not- If I measured cholesterol in your blood, shouldn't be there to any appreciable degree-

   17. PADr. Peter Attia48:52

       It te- it tells you I'm-

   18. TDDr. Tom Dayspring48:53

       ... because you can't absorb it.

   19. PADr. Peter Attia48:54

       Yeah.

   20. TDDr. Tom Dayspring48:55

       If it is elevated in your blood, for whatever reason, and we now know why, your intestine just absorbed that cholesterol. And if it's absorbing cholesterol, which it tends not to, what is it absorbing in humongous excess cholesterol? So cholesterol serves as a biomarker of are you or are you not, or what degree of cholesterol absorption is going on in your intestines. And the last thing Peter did mention, he said phytosterols. He called it a zoo sterol. I call it zoologies, so I call it a zoo sterol, so I don't know who's right on that. [laughs]

   21. PADr. Peter Attia49:32

       I, I'm gonna go with you're right.

   22. TDDr. Tom Dayspring49:34

       [laughs]

   23. PADr. Peter Attia49:34

       Yeah, yeah. I'm, I'm just gonna give you that.

   24. TDDr. Tom Dayspring49:36

       And I do have a degree in zoology when I went to college. You know, it was one of my, uh, majors.

   25. PADr. Peter Attia49:42

       And, and you're wearing, just so everyone knows, you're wearing your Rutgers T-shirt right now as well-

   26. TDDr. Tom Dayspring49:46

       I am

   27. PADr. Peter Attia49:46

       ... from college, which is perfect, all right.

   28. TDDr. Tom Dayspring49:47

       I wouldn't be here without the, the Earl Rutgers. That medical school was inconsequential. I learned everything in Rutgers pre-med, at least the biochemistry and the physiology anyway. So phytosterols, look, plants are full of sterols. Their cell membranes are not cholesterol. Those, there are some plants that do have cholesterol in them, most do not, but they have sterols that if I show you here's cholesterol and here's what's in this plant, you would think y- you're showing me a lot of cholesterol. But if you look closely, you'd see that tail that's coming out of carbon 17 is constructed a little differently or, wait a minute, there's another double bond in one of those rings in there. So it looks like cholesterol, but it's close, but it's really not. And since it was made in a plant, collectively let's call them phytosterols. But we hopefully all eat a few vegetables during the day, so you're eating phytosterols unless you're a total non, [laughs] don't eat any vegetables. And they get in even in other things, even you're eating shrimp and stuff, fish eat ph- ph- phytoplankton and stuff, so there's phytosterols in bunch of foods. But your body knows the only sterol I need to function is cholesterol. I don't need any plant sterols. Why would I want a human to ever absorb the plant sterol? They would get in the way. Could they even be toxic, you know? So evolution must have figured out they were. So evolution made sure our intestine did not absorb phytosterols. Why? To me, it tells me there's a certain level at which phytosterols are toxic.

   29. PADr. Peter Attia51:21

       Well, this becomes interesting because I had a disagreement with a physician recently who jointly takes care of one of my patients, because the physician wanted to put this patient on phytosterol supplements-

   30. TDDr. Tom Dayspring51:33

       Right
8. 54:09 – 1:04:09

   Intestinal Absorption: NPC1L1, ABCG5/G8, ACAT and TICE

   1. PADr. Peter Attia54:09

      When someone is genetically a hyperabsorber, is the, quote unquote, "defect" more on the, the ticket taker or on the bouncer?

   2. TDDr. Tom Dayspring54:18

      Turns out that it's both because... Now, when we talk about absorption, let's face it, there's a million molecules that can be absorbed by your intestine. We're talking about sterol absorption right now, and cholesterol is a key ingredient for human life. So evolution not only gave every cell in your body the wherewithal to synthesize cholesterol, it allowed your intestine to absorb cholesterol, 'cause it certainly didn't want any cellular deficiency of cholesterol, which has nothing to do with plasma cholesterol, by the way. You can have an LDL-C of three and have perfect cellular cholesterol metrics. So-

   3. PADr. Peter Attia54:55

      Well, as, as-

   4. TDDr. Tom Dayspring54:55

      ... people don't understand that

   5. PADr. Peter Attia54:56

      ... as, as evidenced by the hypofunctioning PCSK9 patients.

   6. TDDr. Tom Dayspring55:00

      Yes. [laughs] Where... So This Niemann-Pick C1-like protein in our proximal intestine recognizes sterols. And there's a sterol domain on there that binds tightly to sterols, but it binds most tightly to cholesterol, 'cause cholesterol has that structure. It has a less avid binding to a phytosterol, and it has minimal binding to a stanol. Now, ultimately it'll bind to all of them, but cholesterol gets the first preference to be pulled into the enterocyte. Xenosterol, as I call it, rather than a phytosterol, xeno meaning other sterol, a sterol other than cholesterol, uh, would get in secondarily. And a stanol, they get in, but at much less concentrations. So now the enterocyte has this sterol you just absorbed. Now the enterocyte's position is, "I gotta get this to the rest of the body, so I have to take this sterol and put it in a chylomicron that I'm gonna make, or I could also efflux any sterol out to a baby HDL that's looking for sterols. I can lipidate an HDL." So that's how sterols get out of the intestine. Or the intestine can say, "We don't need any more sterols. I'm getting rid of you," and that's where the bouncer comes in. So these ATP-binding cassette transporters, ATP-binding cassette transporters are a sterol efflux membrane transporter. So-

   7. PADr. Peter Attia56:25

      And this is important to distinguish because... And again, it might be confusing, but the diagrams will make it easier. There's two effluxes you've referred to. There's an efflux on the luminal side, and then an efflux back into the body. Both of them are leaving an enterocyte. One ends up leaving the body. If it goes out the ATP-binding cassette, it's going into the lumen, it's being excreted with stool. If you efflux on the other side of the cell into either the chylomicron or into the HDL, you're actually putting it right back into circulation.

   8. TDDr. Tom Dayspring56:54

      And that is such a crucial point, Peter. I'm glad you elucidated on that more. So yeah, remember, we're talking about the enterocyte. Like the liver and enterocytes have a lot of things they can do with sterols, so they can get rid of it or they can even use it. Remember, enterocytes have cell membranes. They need some cholesterol for their own cell membranes and everything. So they can ship it out, "Hey, body needs cholesterol in a chylomicron." They can lipidate an HDL or they can return it to the lumen of the gut, where it'll go out your rear end. So these ABC G5 or G8 transporters, as you're called, and it's a heterodimer, so you have one of each, will efflux. And they also have different affinities. So unlike the Niemann-Pick, which really wants cholesterol to come in, less so phytosterols and not so stanols, which tells me evolution didn't want those other products in your body, the ABC transformer or exporters, they, number one, evict phytosterols first. That's another evolutionary happenstance to me that tells me the body d- evolution didn't want phytosterols in your damn body, 'cause why is it giving you a phytosterol efflux protein in your intestine? And the liver has it too. Just in case a phytosterol ever makes it as far as the liver, it gets evicted back to the bile to go back to your intestine. So second in line for exportation would be a stanol, and third would be cholesterol. So your ability to absorb cholesterol is a happy working relationship between the expression of your Niemann-Pick C1-like protein and your ABC G5, G8 transporters. So technically, if you even had a good normal degree of absorption, but you couldn't evict any sterols 'cause you got a loss of function of an ABC G5 or G8, you're gonna be a hyperabsorber, 'cause then the only way those sterols can get out of the enterocyte is in a chylomicron or in an HDL. And by the way, when we-- you do measure these phytosterols in the blood, people, it's like when you measure cholesterol in the blood. Do you understand? I've already told you where that cholesterol me- It's the cholesterol within all the lipoproteins. So if I'm measuring sitosterol, stigmasterol, campesterol, which are some of the names of the 50 phytosterols that are in our plant products, what am I measuring? Well, since the vast majority of lipoproteins are LDLs, I'm measuring LDL sitosterol, LDL cholesterol, like I'm measuring LDL cholesterol. So you're measuring there, but God forbid that particle invades an artery wall, the sterols go with it. And one last intriguing part of this story, which better put the fear of God of phytosterols into you, that evolution didn't want it in, so it gave you a protein that will not absorb phytosterols if it's working right. It gave you a protein that immediately evicts phytosterols. But for any sterol to go in a chylomicron, what does it have to be? Esterified. How does the intestine esterify cholesterol into cholesterol ester, which is what makes up a giant part of the core of a chylomicron? There's an esterifying enzyme, acyl cholesterol acyltransferase, ACAT. Guess what is the favorite ligand for ACAT? Cholesterol. Guess what is not a favorite ligand for ACAT? Phytosterols. So they-- You just don't esterify phytosterol, which retards them getting into your body. And you know the real way to get in? That ABCA1 efflux transporter, which is what lipidates a baby HDL particle. It's not ABC G5, G8, which is-

   9. PADr. Peter Attia1:00:31

      Right

   10. TDDr. Tom Dayspring1:00:31

       ... ABCA1 exports sterols into baby HDL particles.

   11. PADr. Peter Attia1:00:35

       And just for the listener, again, you're saying ABC, what you're saying is ATP-binding cassette. So when they hear you say ABC, that's what you're referring to.

   12. TDDr. Tom Dayspring1:00:43

       Yeah. It, it, it's an energy-driven process, so some of that phytosterols you're measuring in the blood are in HDL particles also. So that's a way to get in. And I always make... And look, you'd have to do a study and prove it. We're gonna be talking about HDL dysfunction. Suppose I measured phytosterols in your HDL and it's very high, it's probably a type of dysfunctional HDL particle, you know? So there's all sorts of intriguing-

   13. PADr. Peter Attia1:01:07

       It would also, you know, not to get too esoteric, but that would also suggest enterocyte dysfunction, 'cause the enterocyte should also kn- quote, unquote, "know better" that that's not the direction of efflux I want.

   14. TDDr. Tom Dayspring1:01:17

       It is, but it's relying on the ABC G5, G8 to efflux it, then it wouldn't even get to an ABCA1 to efflux it on the other side, and ACAT is not gonna esterify it if it's all being evicted, or very little it would wind up being esterified. And the last part of this puzzle, as Peter thought, you have a gut lumen side and you got a plasma side or a lymphatic side, which is where chylomicrons exit. We probably talk about it somewhere today is this crazy process they used to call reverse cholesterol transport, which is another one of these idiotic terms that should have disappeared a long time ago, at least if you think it's mediated by solely by HDL, high density lipoproteins. That's the part that's got to change. A big pathway of how does the body get rid of cholesterol, we're all told, oh, it brought it back to the liver, and the liver will get rid of it in a certain way. Guess what? A ton of it is just brought directly right back to the intestine, and the cholesterol in the particle or the particle itself finds its way into the enterocyte through the... And then the enterocyte has another supply of sterols all of a s- sudden that it didn't absorb. And so what? It then will do with that sterol what it wants. It can efflux it through ABC G5/GA into your gut lumen and you can poop it away. So the process of a lipoprotein or some other trafficker, albumin, red blood cells, bringing cholesterol back to the small intestine, bypassing the liver, gets right out into your stool. It's called transintestinal cholesterol efflux, abbreviated as TICE, and it's a major reverse cholesterol transport pathway now.

   15. PADr. Peter Attia1:02:57

       Do we have a sense, 'cause we're gonna talk about direct and indirect RCT in a moment. I think that might as well... This is as good a, a foray into that as any. Do you have a sense of how much cholesterol is being reverse transported, so to speak, through TICE versus the t- sum total of direct and non-direct reverse cholesterol transport?

   16. TDDr. Tom Dayspring1:03:16

       Yeah. This has been studied in dynamically, but, you know, they're real small studies and it probably varies individually depending on all the complexity of your lipid and lipoprotein transportation systems or so. Some pe- in some people it's probably 20%, and in other people it's been reported as high as 60%.

   17. PADr. Peter Attia1:03:36

       Wow.

   18. TDDr. Tom Dayspring1:03:37

       So it varies a lot. But it's a major player. It's not this infinitesimal minor baby pathway that's inconsequential except in s- some rat in a laboratory or something. It's, this has been proven in humans now. There... I just re- as part of the review process on a really cool article coming out in the Journal of Clinical Lipidology, where because of some biliary surgery the guy had, the only way cholesterol gets out of this person's body was through the intestine, and they did these [laughs] ... So it shows you-

   19. PADr. Peter Attia1:04:06

       How many-

   20. TDDr. Tom Dayspring1:04:06

       ... the body can get rid of cholesterol without a biliary system.

9. 1:04:09 – 1:07:40

   Peer Review and Staying Current with Lipid Literature

   1. PADr. Peter Attia1:04:09

      How many articles do you review a year?

   2. TDDr. Tom Dayspring1:04:11

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

   3. PADr. Peter Attia1:04:31

      Yep.

   4. TDDr. Tom Dayspring1:04:31

      Where another associate editor would say, "I think Tom knows a lot about this subject, so I'll ask him would he please review this article to me." So, uh, I don't know, I probably get about 15 articles a year where I'm the associate editor and probably double that where-

   5. PADr. Peter Attia1:04:46

      You're one of the reviewers

   6. TDDr. Tom Dayspring1:04:47

      ... I am, uh, or just one of several reviewers or so.

   7. PADr. Peter Attia1:04:51

      But that's still about-

   8. TDDr. Tom Dayspring1:04:51

      And, and-

   9. PADr. Peter Attia1:04:51

      ... 50 papers a year that are coming-

   10. TDDr. Tom Dayspring1:04:53

       Yeah, it's a lot

   11. PADr. Peter Attia1:04:53

       ... across your desk.

   12. TDDr. Tom Dayspring1:04:54

       And I am blessed at my stage of the game to have a job where I do have... I don't have to see patients anymore. I'm not traveling throughout the United States 100 times a, a year on flights doing lectures here, there, and everywhere. So I am blessed in my current position or my True Health Diagnostic, uh, Peter, probably when you hear this the first time, you'll get a list of my, uh, who I work for and who I don't. That's the only company I work for nowadays, and I'm their, uh, scientific academic advisor. So my job is to stay on top of the literature, know all this stuff, and explain it. So I have the freedom every day to spend time reading and educating. And part of my education, anybody who's a reviewer or an editor with other, you'll learn a lot doing that because I am... I don't know everything that's sent to me for review, but I'll sure as heck know where to go and get it if I do a study.

   13. PADr. Peter Attia1:05:45

       Well, there's a small group of us that are very lucky. We're having dinner with Jamie Underberg tonight, but you know, Jamie said there's like this group of like 10 people that you always send out the most interesting papers to. And about a year ago, I had forwarded a number of these on to Bob Kaplan, and he was like, "Hey, can you put me on this email too?" And, uh, I, I mean, [chuckles] we'll have to think about a way to, for, for you to create a special group where... 'Cause, uh, uh, it strikes me that there's a broader group of people who would actually like to get the once a week email from Tom with the most interesting lipid paper I've read this week.

   14. TDDr. Tom Dayspring1:06:20

       Yeah. I think the best way of doing that is, uh, somehow contacting me at DrLipid or so, uh-

   15. PADr. Peter Attia1:06:27

       I mean, you put a lot of this stuff out on Twitter too.

   16. TDDr. Tom Dayspring1:06:28

       Yeah. I, I do, so you can research it and-

   17. PADr. Peter Attia1:06:31

       But you don't get the commentary because your emails are sometimes so great 'cause what you'll do is you'll say, "Look, I know all of you aren't gonna read this 12-page paper. Here's like a 300-word summary of what you would learn." And then that, like for me to read that then open the paper, it's like, it's quick.

   18. TDDr. Tom Dayspring1:06:48

       And it was just a c- number one, I really don't want to get... I don't know how many people listen to Peter's podcast, but it's immense. I don't want 4,000 emails tomorrow saying, "Put me on your email." [laughs] And there's two things as part of that email. One would be my interpretation of some, which is fine. That's Dayspring's opinion piece where-

   19. PADr. Peter Attia1:07:06

       No, but maybe we could, we can-

   20. TDDr. Tom Dayspring1:07:07

       I, I can't attach PDFs to it that I might to an isolated friend-

   21. PADr. Peter Attia1:07:11

       Yeah, yeah

   22. TDDr. Tom Dayspring1:07:12

       ... because of copyrights and things like that.

   23. PADr. Peter Attia1:07:13

       Yeah, yeah. That's, that's probably the bigger issue.

   24. TDDr. Tom Dayspring1:07:15

       So that, that's part of an issue also.

   25. PADr. Peter Attia1:07:17

       Yeah.

   26. TDDr. Tom Dayspring1:07:17

       So if it's open access, great, and if it is, I've probably tweeted it and your best bet... And look-

   27. PADr. Peter Attia1:07:24

       Maybe, may-

   28. TDDr. Tom Dayspring1:07:25

       ... people aren't afraid to ask me questions. I mean, a lot of them are asinine, I ignore them. But I will answer if my Twitter followers know you're legitimate and I'll, I'll either direct message you or-

   29. PADr. Peter Attia1:07:34

       Yeah, yeah. All right. So back to this-

   30. TDDr. Tom Dayspring1:07:37

       And if I don't, then, uh, there's a reason.

10. 1:07:40 – 1:13:51

    Cholesterol Synthesis Pathways: Bloch and Kandutsch-Russell

    1. PADr. Peter Attia1:07:40

       Okay. So let's get back to the business of, of lipids here. So we've done a pretty good job explaining one side of the equation at how cholesterol is regulated

    2. TDDr. Tom Dayspring1:07:49

       Oh, by the way, the, a zoo sterol would be cholesterol. It's the only sterol we, the animal kingdom produces.

    3. PADr. Peter Attia1:07:55

       Yes. Yeah, yeah, yeah.

    4. TDDr. Tom Dayspring1:07:56

       So cholesterol is the zoo sterol.

    5. PADr. Peter Attia1:07:57

       Yeah, yeah. Okay, so the other end of this regulatory pathway, so we've described the reabsorption side pretty well. There's a synthetic side, which you've alluded to obviously by making the statements that, hey, every cell in the body can make cholesterol, and most of the time it's sufficient for its needs. Obviously, exceptions... Well, I'll, I'll let you explain what the exceptions are to that. There are a certain scenarios and certain cells where they actually do need cholesterol from other tissues. But let's just go back to the synthetic stuff, just briefly, 'cause I don't wanna give anybody too much headache. How do we make cholesterol?

    6. TDDr. Tom Dayspring1:08:35

       Uh, very complexly. It's a, uh, multi-stage process, 20 to 30 individual steps where one molecule is changing into another, into another, and at the end of the day, cholesterol is made.

    7. PADr. Peter Attia1:08:47

       And it starts very small. It's basically acetyl-CoA, acetyl-CoA.

    8. TDDr. Tom Dayspring1:08:50

       And it's a

    9. PADr. Peter Attia1:08:51

       It's two carbon, two carbon.

    10. TDDr. Tom Dayspring1:08:52

        It really is. It's a very small carbon, uh, chain molecule that keeps growing in length, 'cause cholesterol has 37 carbons in it. So it has to grow. Through much of that growth, it's just a linear structure, and at a certain point, this linear structure is long enough that it bends and changes into a sterol configuration, lanosterol being the first sterol that appears in the cholesterol synthesis chain. By the way, if I wanted a lab, and labs with liquid chromatography and mass spec could give you a lano- [laughs] a lano- uh, sterol measurement. And if it was up, hey, you're over-synthesizing cholesterol. That's not the one they focus on. They pick a more downstream, uh, cholesterol precursor to do that. But even you could pick some of the earlier ones, and they do serve as markers of cholesterol synthesis, you know.

    11. PADr. Peter Attia1:09:42

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

    12. TDDr. Tom Dayspring1:09:46

        Yeah, so once you go through squalene and then, and then that bends into a ring structure, lanosterol has to become cholesterol. So lanosterol... And there's crosstalk between the pathways, but it has one or two pathways that it's gonna go down. And at the end of the day, both pathways you'll wind up with cholesterol.

    13. PADr. Peter Attia1:10:06

        And no good pathways don't come with names. So these-

    14. TDDr. Tom Dayspring1:10:09

        They do. [laughs]

    15. PADr. Peter Attia1:10:10

        What are the names of these pathways?

    16. TDDr. Tom Dayspring1:10:11

        Oh, yeah. Mr. Facetious here. [laughs]

    17. PADr. Peter Attia1:10:14

        [laughs]

    18. TDDr. Tom Dayspring1:10:14

        Yes. Well, my favorite, of course, is the Bloch pathway.

    19. PADr. Peter Attia1:10:17

        [laughs]

    20. TDDr. Tom Dayspring1:10:18

        'Cause if you do- And I pulled... Uh, here's a Twitter picture I put up recently. He won the Nobel Prize for discovering this pathway in cholesterol, so it's probably important they give you a Nobel Prize for discovering this pathway of cholesterol synthesis. So the Bloch pathway would be lanosterol goes through a lot of precursors and becomes something called desmosterol, D-E-S-M-O-S-T-E-R-O-L. Desmosterol looks exactly like cholesterol except in carbon 24 there's a double bond. There's no double bonds in that tail that's on the cholesterol molecule. So if I just saturate that double bond in des- desmosterol, I change it into cholesterol. And of course, there's a specific enzyme that does that. If you inhibit it-

    21. PADr. Peter Attia1:11:04

        Can I guess it?

    22. TDDr. Tom Dayspring1:11:04

        [laughs] Yes.

    23. PADr. Peter Attia1:11:06

        If it's... So this is just so people can understand what these enzymes mean. So the... I remember learning this in, in college. All right, so... Or med school, not college. Enzymes always end in ase, right? Now, you just told me it was carbon 24, so it's, it's probably gonna have something to do, have... It's gonna have a 24 in there.

    24. TDDr. Tom Dayspring1:11:21

        It will.

    25. PADr. Peter Attia1:11:22

        And we often throw deltas into these things because delta denotes the position of the bond. And did you say that desmosterol has a double bond at 24?

    26. TDDr. Tom Dayspring1:11:31

        Right.

    27. PADr. Peter Attia1:11:31

        And it has to be...

    28. TDDr. Tom Dayspring1:11:32

        Saturated

    29. PADr. Peter Attia1:11:33

        ... saturated. So it would probably be something like a delta 24 saturase or desaturase.

    30. TDDr. Tom Dayspring1:11:39

        Correct.
11. 1:13:51 – 1:15:22

    Brain Cholesterol Is Separate from Plasma Cholesterol

    1. TDDr. Tom Dayspring1:13:51

       One of the things I know it's a big topic of yours, and I hope we get into today, is the brain. Everything I've talked about cholesterol today that we're measuring in the blood has zero to do with cholesterol in the brain. Cholesterol lipidology in the brain is, might as well be in another different body. It has nothing to do with what the cholesterol is going on in the rest of your body. The brain makes every cholesterol molecule it needs, and therefore there are no LDL particles delivering cholesterol to your brain. So again, if with super aggressive therapies-

    2. PADr. Peter Attia1:14:24

       And, and, and to be clear, this is because the LDL particle just doesn't fit through the blood-brain barrier.

    3. TDDr. Tom Dayspring1:14:30

       Correct. Even HDLs where a little bit of their cholesterol might get into, it's delipidated through these ABC things, and some of that might work its way in, inconsequential amount. The apoB is, I guess, too big. The brain doesn't make apoB, so but the central nervous system has to traffic lipids from brain cells to peripheral nerve cells. ApoE is the l- uh, protein transporter in the brain. So cholesterol or any sterol is attached to apoE in the brain, and that's how it tr- it traffics around there or so. And again, it hasn't got nothing to do with the apoE that's involved with whatever lipoproteins are doing in your, the rest of your body also. So just understand it. But obviously-

    4. PADr. Peter Attia1:15:13

       I, I wanna come... This is such an important topic that I absolutely wanna come back to it, so I'm glad you brought it up. But that said, at the moment I would love to go back to the synthetic stuff.

    5. TDDr. Tom Dayspring1:15:22

       Correct.

12. 1:15:22 – 1:18:49

    Uses of Cholesterol: Membranes, Hormones, Bile Acids and Not Energy

    1. PADr. Peter Attia1:15:22

       So you've got each cell in the body can basically start with the most simple carbon subunit, which is a two carbon subunit, acetyl-CoA, and through a process of carbon fixation, go on to make these very complicated four carb- four-ringed structures. They... First and foremost, the cell uses these things. They make-

    2. TDDr. Tom Dayspring1:15:44

       Yeah

    3. PADr. Peter Attia1:15:44

       ... the, the b- the important part of the cell membrane. If, if anyone-

    4. TDDr. Tom Dayspring1:15:47

       And organelle membranes and depositing. Yeah.

    5. PADr. Peter Attia1:15:49

       That's right.

    6. TDDr. Tom Dayspring1:15:49

       Yeah.

    7. PADr. Peter Attia1:15:49

       So everything from the Golgi apparatus to the ER to the smooth ER, rough ER, et cetera. You also... You don't have to be, I think, a biochemist to look at a picture of a molecule like cortisol, estrogen, testosterone, and I think you could show a four-year-old a mol- picture of those and then a molecule of cholesterol, and they would be like, "Hey, those look similar."

    8. TDDr. Tom Dayspring1:16:11

       Yeah. It's like, maybe I look like my mother and father. Or do they... Did they have a, an origin or did they come from an ant cell? Sure. So certain cells can certainly transform cholesterol into reproductive hormones or adrenocortical hormones. Certain cells, hepatocytes, can transform cholesterol into a bile acid. I don't think there's any other cell that can change cholesterol into anything else. So when people talk about cholesterol metabolism, there is no cholesterol metabolism. It can be converted into something in specific tissues, but it can be excreted. That's it. There's no other way your body can handle the cholesterol.

    9. PADr. Peter Attia1:16:48

       So do we... Is there any evidence that we use cholesterol for energy?

    10. TDDr. Tom Dayspring1:16:52

        Zero. Why? There's no... Energy is really coming out of the saturated, the fats that have the mo- no double bonds. That's the most, they're carrying the most ATP. Cholesterol is not producing energy. Cholesterol cannot be metabolized and produce ATP in the process. [laughs]

    11. PADr. Peter Attia1:17:11

        I mean, to me, that's the bigger issue, right?

    12. TDDr. Tom Dayspring1:17:13

        Yeah.

    13. PADr. Peter Attia1:17:13

        I think... So, so some people get confused about this. It's not that there isn't energy in a carbon-carbon bond or a carbon-hydrogen bond, because that's exactly what's being liberated in the metabolism of a fatty acid. The point is, we don't have the enzymatic machinery to undergo the chemical process of breaking down those bonds and liberating the chemical energy into electrical energy.

    14. TDDr. Tom Dayspring1:17:32

        Can't metabolize cholesterol. Cholesterol ester, which carries that fat s can be de-esterified, but your cells aren't making cholesterol ester. The liver is, the intestine is, but, the adipocytes are, but-

    15. PADr. Peter Attia1:17:45

        My hypothesis for why that's the case, which could be entirely bullshit and I'm just making it up, but it, that's, that's what hypotheses are, they're guesses, is that it would've been evolutionarily dangerous if we could have metabolized cholesterol. Because in periods of fasting, which we all did evolutionarily, the last thing you want your body doing is going after cell membranes and hormones as a source of energy. So I think it's actually a very deliberate design, quote, I use "design" in quotes, to say, "Hey, no matter what, your cholesterol and your hormones are off limits during starvation." And instead, we evolve this other remarkable pathway of ketosis, which takes an ample substrate of fats and goes down the path of metabolizing those and actually saving our muscle from the catabolic destruction that we would undergo if we couldn't undergo ketosis.

    16. TDDr. Tom Dayspring1:18:34

        This is the brilliance of Peter Attia to me, that he can come up with what sounds like a super plausible thing.

    17. PADr. Peter Attia1:18:40

        I, uh... [laughs]

    18. TDDr. Tom Dayspring1:18:40

        See, I'm not smart enough to do that.

    19. PADr. Peter Attia1:18:40

        It could be entirely bullshit, so.

    20. TDDr. Tom Dayspring1:18:42

        I can tell you how to sell gut cholesterol, what it can do with it, but he's figured out what sounds like a really plausible reason.

13. 1:18:49 – 1:27:02

    Cellular Cholesterol Homeostasis, Stress and HDL

    1. TDDr. Tom Dayspring1:18:49

       And everybody's so worried about depleting cholesterol in the plasma as measured by LDL cholesterol, which has nothing to do with anything, 'cause actually there's more cholesterol in your red blood cells than there are in lipoproteins.

    2. PADr. Peter Attia1:18:59

       Yes.

    3. TDDr. Tom Dayspring1:18:59

       And you're not making that zero by any means by using lipid drugs or something. So but you can't deplete a cell of cholesterol beyond a certain amount or you're gonna screw up cellular function. And you can't put too much cholesterol in that cell 'cause it'll crystallize and kill that cell. So that's why it's so tightly regulated, synthesis, i- influx and efflux. Now, are there cells under certain circumstances for whatever reason can't make enough cholesterol? Yeah, there, there are pediatric disorders where if you don't synthesize cholesterol, things happen to you in utero and-

    4. PADr. Peter Attia1:19:33

       Well, the other thing we see this in, and I didn't, I don't even know why I started noticing this, but this is one of the things I used to do in residency that used to kind of piss off some of the attendings, is I would do little experiments. And it was always a measurement experiment, so it wasn't like I was putting a patient at risk other than they, a few more milliliters of blood were being drawn. But I remember once happening on an, on a finding which was maybe by accident I had checked a c- a lipid panel on a patient in the ICU and I saw something interesting and I kept rechecking it in other patients over and over again and I kept seeing this, which was any time a patient was having a SIRS response, that's capital S-I-R-S, systemic inflammatory response syndrome, so this is the vaso, you know, metabolic response to sepsis, infection-

    5. TDDr. Tom Dayspring1:20:16

       Whatever

    6. PADr. Peter Attia1:20:16

       ... trauma, you name it, enormous drop in HDL cholesterol. And I think we could look at that today and say it's very likely that what we were seeing was in that period of profound physiologic stress, the body is greatly ramping up its hormone production, glucocorticoids and o- it's, and others. And that would be one of the situations where cells were actually... You know, HDL was now delivering cholesterol to the adrenal glands in a period of... You know, 'cause that's about the most physiologically stressful thing that an organism can respond to. Again, I don't know if that's been documented, but it seems to me pretty logical that that would be a, at least the most plausible explanation for why HDL could plummet in patients who are going through that degree of stress.

    7. TDDr. Tom Dayspring1:20:57

       Yes. And it, by the way, it's the reason you never do a lipid profile in an acute s-

    8. PADr. Peter Attia1:21:02

       Yeah, it's just completely-

    9. TDDr. Tom Dayspring1:21:03

       ... situation.

    10. PADr. Peter Attia1:21:04

        Yeah.

    11. TDDr. Tom Dayspring1:21:04

        Because a lot of lipids are gonna be transiently changed or so here. But Peter's right, we know this for a lot of reasons. Clearly, the, your steroidogenic tissues need cholesterol to make their steroid hormones, be they reproductive organs or your adrenal cortex. And in the situations Peter's talking about, uh, cortisol [laughs] is a pretty useful hormone to have around or other mineralocorticoids and things like that are so. So clearly the, those organs, those tissues are gonna need a lot of cholesterol pools to make all that. So they, they turn up their synthesis rates so they make a lot of cholesterol, but they would also tune up their, hey, let's gather some exogenous cholesterol, so to speak. So those cells would upregulate LDL receptors, and that's a case where there's a tissue that might under certain circumstances pull in LDL particles full of cholesterol ester. They would de-esterify it and use it. But in a physiologic person who's not in one of these acute situations, the adrenal gland most of the time just makes all the cholesterol it needs. But if it needs a secondary source, that's why you have HDLs. HDLs have a half-life of five days. One of the reasons they circulate for five days is it's a floating plasma reservoir of cholesterol for tissues that might actually need cholesterol. Now, my nose cell that I talked about before doesn't need HDLs or anybody else to deliver cholesterol to it. No other cell does except those steroidogenic tissues or so.

    12. PADr. Peter Attia1:22:41

        In other words, to be really clear and specific, you're sloughing off endothelial cells in your nose every day. Well, you have to replace them. The lion's share of the cholesterol requirement is to make a cell membrane. It's just, it has the machinery, it has the machinery within the nucleus to produce that just as it's producing other structural proteins.

    13. TDDr. Tom Dayspring1:23:01

        Right. So, uh, and this is what p- people just translate low cholesterol plasma measurements to think you're screwing up cells throughout the body, and you're not. [laughs]

    14. PADr. Peter Attia1:23:12

        Yeah. This is one of the challenges that I've never come up with a great way to explain this idea of flux, which is you do a lipid measurement at a moment in time. You're getting a snapshot of what's in the plasma at a moment in time, which doesn't give you two pieces of information. How is it changing over time, and what's the movement or the velocity?

    15. TDDr. Tom Dayspring1:23:30

        Hmm.

    16. PADr. Peter Attia1:23:30

        And secondly, it gives you no insight into what's happening in the cell or what's happening in the endothelium, for that matter. And instead, that's the nature of lipidology, is you have to be able to extrapolate to these other things by indirect measurements.

    17. TDDr. Tom Dayspring1:23:44

        It gives you zero insight. The only usability of plasma measurements are as surrogates of a lipoprotein defining whether you have apoB, apoA1 particles, and we know too many apoB particles, you're over time at big risk, at increased risk for atherosclerotic disease or events. Otherwise, why are you even measuring lipids in the plasma? [laughs] It tells you nothing. And what we're talking about, you call it influx, efflux, and that nails it down, but it's cholesterol homeostasis or sterol homeostasis, and your body has evolved a lot of ways to do... Interesting, too, and say that a crisis is going on and adrenal needs continued. It's not just, hey, you're, you cured yourself in 12 hours overnight. You survived whatever. And if that catastrophic process was g- ongoing, HDLs eventually would run out of cholesterol. You just said your HDL cholesterol level is plummeting, and that's been documented many times. So the HDL all of a sudden has to go back and start grabbing cholesterol molecules from some other tissue and get it to the steroidogenic tissue. And the number m- mega place where HDLs get most of their lipidation is it goes right back to the liver and gets lipidated or what is the biggest cholesterol storage organ in the body? Not the liver, your adipocytes. Everybody thinks adipocytes are just storing triglycerides. They're a massive storage organ. So baby HDLs that are depleted, they run back to the adipocytes, which express this ABCA1 transporter that pumps out all their cholesterol to an HDL, which boom, right back to the adrenal gland and bounces back and forth like a ping pong ball. [upbeat music]

    18. PADr. Peter Attia1:25:30

        You can find all of this information and more at peterattiamd.com/podcast. There you'll find the show notes, readings, and links related to this episode. You can also find my blog and the Nerd Safari at peterattiamd.com. What's a Nerd Safari, you ask? Just click on the link at the top of the site to learn more. Maybe the simplest thing to do is to sign up for my subjectively non-lame once-a-week email where I'll update you on what I've been up to, the most interesting papers I've read, and all things related to longevity, science, performance, sleep, et cetera. On social, you can find me on Twitter, Instagram, and Facebook, all with the ID peterattiamd. But usually Twitter is the best way to reach me to share your questions and comments. Now for the obligatory disclaimer, this podcast is for general informational purposes only and does not constitute the practice of medicine, nursing, or other professional healthcare services, including the giving of medical advice. And note, no doctor-patient relationship is formed. The use of this information and the materials linked to the podcast is at the user's own risk. The content of this podcast is not intended to be a substitute for professional medical advice, diagnoses, or treatment. Users should not disregard or delay in obtaining medical advice for any medical condition they have and should seek the assistance of their healthcare professionals for any such conditions. Lastly, and perhaps most importantly, I take conflicts of interest very seriously. For all of my disclosures, the companies I invest in and/or advise, please visit peterattiamd.com/about. [upbeat music]

Episode duration: 1:27:02