LogSeqDB/pages/apob.sync-conflict-20250817-085621-UULL5XD.md

- Attia Interview {{video https://www.youtube.com/watch?v=-OxvLbjMP_o}} collapse:: true collapsed:: true - {{youtube-timestamp 0}} so let's talk about like the number so the LDL I sorry the apob number because like if most people go to a standard lab and they measure their apob there's a reference range and it says you know okay if you're less than 80 milligrams per deciliter you're excellent then you're okay yeah um where does that number come from and you know what like is has anyone measured apob levels across the lifespan do we know like is there a correlation with apob levels and the beginnings of atherosclerosis has someone done those studies you know that sort of thing yeah so the reference ranges are purely uh populationbased um distribution questions so every lab will have a different way of doing this but a general uh you know sort of philosophy for labs is you know let you know so for the lab we use and by the way we completely ignore these reference ranges they're but they're there we can't avoid them there and we explained to our patients that we're going to - {{youtube-timestamp 61}} editorialize on top of them but you know the Reference Lab we use we'll say APO B below 80 is wonderful well 80 just happens to be the 20th percentile of the population it will say 80 to 100 is intered or 80 to 120 it says is intermediate risk and above 120 is very high risk so in for the lab we use we know that 80 is the 20th percentile uh 120 is the 80th percentile or the 60th percentile I can't remember um so it's it's literally just putting you up against to population distribution and that's that's it now our philosophy on apob is completely different and um as you may recall I write I devote actually quite a bit of real estate to this in the book because I think it is such an important concept and it is in my opinion certainly top three failures of medicine 2.0 is in failing to appreciate the point I'm about to make um which is that once you understand the cause Al it of apob meaning once you understand that apob is not just associated with - {{youtube-timestamp 125}} cardiovascular disease but it's causally linked to it meaning it causes ascvd to get into this discussion about managing 10year risk thinking about being in this percent versus this percent makes no sense when you have causal things that cause disease you eliminate them and the analogy I use is cigarettes with lung cancer so no nobody disputes that cigarettes are causally linked to lung cancer they are it's as clear as you know Tuesday follows Monday but people forget that you know causality doesn't mean everybody who smokes will get lung cancer and it doesn't mean that every person with lung cancer um smoked so you you don't need to be necessary and sufficient necessary or sufficient to still be causal but our approach to patients who smoke is very clear which is Never Smoke and if you do smoke stop immediately do we look at people who smoke and say well once your 10-year risk of lung cancer reaches this threshold we're going to tell you to - {{youtube-timestamp 192}} stop smoking or once your pack year smoking is above the 50th percentile or the 80th percentile we're going to tell you to stop absolutely not you immediately eliminate smoking and so similarly it makes no sense that we would look at a causal driver of asbd in the case of apob and kind of take an approach of well being at the 20th percentile or the 30th percentile the 40th percentile is acceptable none of those things really make sense you have something that is causing the disease you should eliminate it as soon as possible because it is an area under the curve problem so atherosclerosis begins at Birth um when you do autopsies on people who are very young in fact I in the book include a photo of a a guy who you know a man I forget I think maybe 26 years old who was a victim of a homicide or something so an completely unrelated death um but you look at the autopsy sections of his coronary arteries I mean he already had very Advanced - {{youtube-timestamp 253}} atherosclerosis now it wasn't clinically relevant it wasn't going to kill him anytime soon but the point is this is a disease that takes decades to progress and one of the biggest drivers of it in addition to things like high blood pressure and smoking and insulin resistance is apop so to be able to take that off the table sooner rather than later is going to has has certainly has the potential to take um atherosclerosis off its pedestal at the top of the uh list of killing and so what do you um I mean take you obviously can't take it off the table completely right we need a be but what well so so you do so so let's think about it yeah so so let's start with what we know apob Rises with age right um we don't really know there are probably a lot of little reasons um so there are you know endocrine changes insulin resistance um sence that you know might involve the uh decreased uh life of LDL receptors there there's no clear reason actually what - {{youtube-timestamp 327}} about so you're talking about clearance versus synthesis and I remember our mutual friend Ron Krauss like I've had you know many conversations with him I did my postc down the hall from his lab right um and I remember him telling me that you know apob you're you're basically your liver is constantly producing it you're making vldl just just churning it out right no just going going and we also make LDL denovo by the way right yeah there's a denovo pathway plus the vldl to LDL pathway but that you know the the the thing is is that you know he was saying well from an evolutionary perspective um you're you're making this vldl because as you mentioned you know it's transporting things throughout the body to other organs right cholesterol Tri triglycerides fatty acids it's also transporting and this is where I was so intrigued inflammatory protein so cyto ctive protein also are being transported through vldl now that was important pre - {{youtube-timestamp 386}} antibiotics pre everything that we do now to combat you know infectious disease and viruses and bacteria parasites whatever um but before that time that vldl did serve that purpose too and that's why he thinks you know it's kind of a relic left over where the reason why we're constantly making is because it's a very large protein in size it's like tens of millions of like the the unit versus like 50,000 or something it's very big and so it takes time to make it um and so I was the you know I was thinking well like inflam also does make it go up even further at the level of synthesis I don't know exactly the the clearance you know how it it's regulating clearance but do you think the aging process is mostly affecting the clearance of it or my intuition is yes my intuition is that it's it's it's primarily impacted on the clearance level which is going to be again some facet of ldlr ldlr beating LDL receptor so is it we are making less - {{youtube-timestamp 445}} of them they are surviving less uh the proteins that you know and and that can basically done there there are many ways to regulate that process but that that's my intuition is it's less a confirmational change in the ldlr and more a number of them and or uh A reduced amount of time that they stay present one thing I'll add on The evolutionary front you know I had a guy named John kelin on my podcast uh a few months ago and he he proposed a really interesting idea which completely makes sense evolutionarily which you you could argue sort of like we don't really need apob like this is the other thing like most species don't have apob they don't require LDL but how I mean they have cholesterol but they don't they don't they don't require transporting all these you know you can do it with HDL you can transport everything with HDL yeah okay yeah they don't need the LDL but I thought HDL was always going in reverse like it was bringing everything back to no it's - {{youtube-timestamp 505}} actually much more complicated I mean in US LDL is doing the majority of what's called reverse cholesterol transport so RCT which is kind of like the good movement of cholesterol you sort of think of the bad movement as taking cholesterol into the arteries the good movement is taking it back to the liver in US LDL is doing the majority of that so hdls are typically transferring their cholesterol to ldls and ldls are bringing them back to the liver um but John made an interesting point right which is that you know in in sort of following up on what you said The evolutionary cost of making cholesterol is enormous uh I mean it's a very labor intensive step right I I can't remember the number of atps that are required to make a molecule of cholesterol but it's in the tens right like it could could be 40 or something to that effect and so we evolved to have a system that prioritized having a lot of cholesterol being able to keep a lot of it around um - {{youtube-timestamp 564}} because again this was an energy conserving system now this serves us no benefit today because to we can make plenty of it and we are we are in an energy abundant environment which we were not in you know hundreds of thousands of years ago and so this is a bit of an unfortunate vestage of our past much in the way that a lot of the things that lead to insulin resistance are a vestage to things that were once very valuable uh I mean the things that allowed us to LEAP up out of the swand with our swamp with big brains was our primarily our capacity to store excess energy in a way that even primates can um again served us really well until 150 years ago and I think the same is probably true of of cholesterol and apob so going back to your question how much apob is enough well it turns out you don't really need any of it to be perfectly fine so if you look at a child they're born with an LDL cholesterol or apob level typically below 20 milligrams - {{youtube-timestamp 620}} per deciliter so a kid if you think about it has the greatest need for growth right like so you think about the cholesterol demand of myelinating the entire central nervous system all of the enormous uh explosion of steroidal tissue all of these things are done with lipoprotein levels that are incredibly low again what we call physiologic levels of LDL cholesterol and apob are on the order of 10 to 30 milligrams per deciliter and yet there are no negative consequences to such low levels of that lipoprotein burden and it's only when we get you know we become teenagers and in our 20s that we start to see those numbers go up and again that's really just reflected by a reduction in clearance than some need for additional LDL we don't have it the majority of what we need is actually you know before the age of 20 do you think uh so like if you were to then estimate or speculate a level of apob that you could say safely well I guess there's two things - {{youtube-timestamp 686}} one you're not going to die of atherosclerosis if you have you if you maintain a level below yeah so Peter Libby um from the Brigham who's one of the authorities on this topic has has argued uh and I referen him in my book that if you had an apob level below about 30 milligrams per deciliter 20 to 30 milligrams per deciliter it wouldn't be possible to develop atherosclerosis what about not dying from AOS like what about like if it's the if it's the major cause of death globally yep and let's say like what it takes to get down to 30 probably is pretty aggressive yeah most people cannot get down to 30 without without a pharmacologic intervention yeah y do you think that you would would die of atheroslerosis if you had you know if you're at 60 60 well it comes down to a couple of other things so the first thing is how long are you at 60 so if you say I've never exceeded 60 that's very different from saying hey I showed up and I was at - {{youtube-timestamp 750}} 120 and you now lowered me to 60 so again I think of you know I imagine like everybody walks around and you've got a graph that on the x- axis is time and on the Y AIS is AP B and you have a curve and you want to figure out what the area under that curve is and that we want to minimize the area under that curve so if if if you took exactly so if you took so again very similar to smoking right we talk about risk in pack years of smoking so if a person smokes a pack a day for 20 years or two packs a day for you know 10 years you know you have a way of kind of comparing Apples to Apples on those things so to have a lifetime ceiling of 60 would also be a very very low-risk individual 60 milligrams per deciliter is about the fifth percentile at the adult population level so then that comes back to my question Sor one across the lifespan when like wait when do you start measuring this like people aren't measuring their apob in their you know - {{youtube-timestamp 814}} teenage or 20 yeah I mean I would argue we should be but I want to go back and say one other thing about your question um which I should have mentioned earlier which is it also depends on other risk factors so there are really four big things that are driving risk causally apob is one insulin resistance is one hypertension is one and smoking is one those are the Big Four so you have to take everything we're saying on the apob front and acknowledge that those other things are also causally linked to asbd so again it's it's a difficult situation to imagine but it's certainly at least theoretically plausible you have somebody whose apob is at 60 but they have uncontrolled hypertension type 2 diabetes and they smoke I mean you could certainly arrive at that situation pharmacologically you're probably not going to arrive at that situation naturally um would I say that that person is free clear no I wouldn't so we you know at the outset I - {{youtube-timestamp 873}} mentioned how the you know the downside of talking about asbd is the number one killer I mean it's you know in fact when you talk about it globally the gap between asbd and cancer is even bigger it's like 19 million people annually to 12 or 13 million for cancer I mean it's an enormous difference um but the good news is our understanding mechanistically of what drives this is so clear and our tools for prevention are some of the best and most benign okay so let's say that um a person is relatively healthy you know they're communed exerciser they're not insulin resist I do want to talk about hypertension and insulin resistance but okay healthy generalized quote unquote healthy person right um wants to lower their apob they want to try everything through diet through lifestyle and you mentioned there are some major lifesty dietary factors that can increase AP so let's talk about those what are the major so the big two are anything that - {{youtube-timestamp 933}} contributes to insulin resistance so we'll start with that and that does so um mostly through the vldl triglyceride pathway so we talked earlier about it how there are really two ways we make LDL we make LDL directly we but most of the LDL is made through vldl so if you're exporting a lot of vldl what you're doing is both making a lot of that lipoprotein but you also have a lot of triglyceride in it now something I didn't mention a moment ago that's worth restating or stating in the first place the LDL is C carrying around both cholesterol and triglyceride and the more cholesterol there is all things equal the more LDL you need but the same is true with triglyceride so the first mechanism in which we see a very clear relationship between diet and apob is the higher the burden of triglycerides the higher the burden of apob to State this another way if you take two people who have the exact same level of LDL cholesterol in the same total - {{youtube-timestamp 998}} cholesterol but one has very high triglycerides and one has very low triglycerides the former is going to have a much higher apob and therefore be at a much higher risk of atherosclerosis because they have more cargo and therefore require more ships in the analogy of cargo being cholesterol and triglycerides and the ships being the lipoproteins so step number one is lower the triglyceride as much as possible and the triglyceride being low is an enormous proxy for insulin sensitivity so this is one of the important ways in which managing insulin resistance uh is is a key to keeping apob in check and of course there are other issues as well so insulin and glucose by themselves when elevated also create problems at the endothelial level which becomes another mechanism by which this is problematic um it's pretty clearly observed from a dietary pattern perspective that carbohydrate restriction is the most effective tool of triglyceride reduction - {{youtube-timestamp 1061}} all carbohydrates I mean like vegetables fruits F yeah refined and starchy carbohydrates yeah so but that actually feeds really nicely into the next observation which is what's the next dietary pattern that impacts apob and that saturated fat consumption and the reasons for that are twofold so the first is that saturated fat directly impacts cholesterol synthesis now this is not true equally of all saturated fats but we don't really have great data on if certain saturated fats have a greater impact on cholesterol synthesis uh relative to others for example a c16 might be potentially more so than a c18 or a c19 but again what foods would you find a c16 version oh like a c16 would be more in I believe like a coconut oil or a palm oil or something like that also by the way that you would also see that more a c16 like a palmitate would be more of a synthes would be more of a saturated fat you see in response to insulin resistance so it actually be - {{youtube-timestamp 1122}} a denovo saturated fat synthesis so um perhaps so so I think that's a big part of it I think cholesterol synthesis big part of it I think a bigger part of it might be that excess saturated fat inhibits this sterile binding the sterile regulatory binding protein in the liver that results in fewer LDL uh receptors being made so saturated fat therefore has two things that it's doing that are driving up apob and the susceptibility of this varies from different individuals so um I was on a ketogenic diet for 3 years I was not one of the people who seemed to suffer from this so even on a ketogenic diet where I was getting 80% of my calories from fat and probably half of that was saturated fat I did not have any sort of obnoxious increase in my apob or ldlc or any of these metrics similarly we have some patients who are on you know very low carb very high fat diets some of them have completely normal levels of lipids and some of them have lipids that go - {{youtube-timestamp 1188}} absolutely Haywire so it's not entirely clear what the difference is but clearly there are different genes that will allow certain people to metabolize that saturated fat safely While others do not so I'm not in the camp that believes that um and there is an entire Camp of people who believe this that if you're on a low carb high fat diet and your apob and ldlc go through the roof it's it's not problematic I I don't believe that at all I think that that's a very bold claim and I would not be willing to play that game I think if your apob goes Haywire even if you're very insulin sensitive and even if you're in energy balance and all the other wonderful things that might come with your uh with your you know your enic diet I I think you have to pay very close attention to if your if your lipids get out of whack so those are basically your big manipulations dietary Wise It's the composition of fat the quantity and composition of fat and the dietary - {{youtube-timestamp 1243}} choices that that address insulin sensitivity