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Oct 08

Guesting on the Peter Attia Drive (3 of 5) – Remnant Cholesterol, Craig Moffitt, Fasting

 

This is a five part series covering my appearance on The Peter Attia Drive podcast. Please skip to the final post to comment. 

Part 1 of 5 – Lean Mass Hyper-responders, Oxidized LDL, All-Cause Mortality
Part 2 of 5 – Cholesterol Challenge, Lipid Metabolism, LDL Receptor
Part 3 of 5 – Remnant Cholesterol, Craig Moffitt, Fasting
Part 4 of 5 – Energy Status, Risk, Testing the Hypothesis
Part 5 of 5 – Comments and Featured Thoughts

In both this and Part 4, I’m going to “let the tape role” as it were. While I considered trying to summarize many of these parts, I quickly realized it’s too unrealistic here as the ongoing context is important to keep together.

Remnant Cholesterol

Dave Feldman

Let’s circle back to remnants real quick.

Peter Attia

Okay.

Dave Feldman

This is why I pause a little bit on the case study that you showed me where you had the triglycerides a bit higher. Now, as you know, what is the poor man’s version of remnants is you basically can just take your triglycerides divided by five. You probably actually …

Peter Attia

No, no, no. We got to be very clear on this stuff. We’re going to confuse the hell out of people.

Dave Feldman

Okay.

Peter Attia

That’s the poor man’s version for VLDL cholesterol.

Dave Feldman

Correct.

Peter Attia

Very important distinction.

Dave Feldman

Fair point. Yes.

Peter Attia

The poor man’s version, which should never be done because it is such an abomination is to take the triglyceride level divided by five, and that number would be an estimate of your VLDL cholesterol.

Dave Feldman

Now, what would you, Peter Attia recommend as the most effective means by which somebody could determine their remnant cholesterol?

Peter Attia

We can’t. It’s impossible. We have no way of knowing remnant cholesterol. Let me be clear. I think I know what you mean by remnant, which is why I’m asking that question. You’re asking pathologic remnant. You’re asking VLDLs that have shed their triglyceride and are now basically pathologic, small. Started out as big, triglyceride rich, and now have shed that through their ApoC-II II LPL pathway, and now have the potential for atherosclerosis, is that what you’re meaning about remnant?

Dave Feldman

No, I now think we may think of it differently. Straight up Wikipedia right now would define remnant cholesterol as basically all cholesterol that’s not in either an LDL particle or in a HDL particle. If you were to just subtract HDL cholesterol [crosstalk].

Peter Attia

If you directly measure total cholesterol, which you can and you can directly measure LDL cholesterol and you can directly measure HDL cholesterol, you subtract those two and you have the amount of cholesterol that is virtually all in a VLDL, and presumably some IDL, if it stick around.

Dave Feldman

Some IDL possibly chylomicrons remnants if you ate recently, but you shouldn’t have any chylomicrons remnants.

Peter Attia

Yeah, that’s very easy to exclude.

Dave Feldman

Right, but effectively, if you’ve had a fasted cholesterol test, pretty much all your remnant cholesterol, pretty much will be in VLDL has longest residence time relative to the IDLs.

Peter Attia

That’s correct, but that’s like telling me outside a very few pathologic states, like [inaudible 01:46:01] and type-III Bs, that’s as interesting to me as your eye color.

Dave Feldman

The remnant cholesterol?

Peter Attia

Yeah.

Dave Feldman

Really?

Peter Attia

Yeah. I mean it’s generally going to be very low. It tracks quite well with triglycerides, though there are lots of examples where it’s been … Actually, I think I brought a copy of one of my other goofy experiments. I don’t know. I probably won’t find it anytime soon, but there is an example of how mine was so far off. It was like a 700% delta between actual versus predicted in one of these studies, but now, the point is yeah, directionally speaking, I would love to see a VLDL cholesterol below 15 milligrams per deciliter as calculated by taking non-HDL cholesterol subtracting the LDL cholesterol, but if you have a direct LDL, cholesterol is your best measurement of that.

Whether it’s 10 milligrams per deciliter, 15 milligrams per deciliter, 20 milligrams per deciliter, that just tells me the sum of cholesterol in all of my VLDL remnants. It tells me nothing about the pathology of them. It tells me nothing about what they’ve done or where they’re going.

Dave Feldman

But, that said, the question then becomes even for as much as what you just qualified, does that become a more powerful predictor relative to something like say LDL cholesterol?

Peter Attia

Maybe, but that’s like saying is rubbing two stones together better than rubbing two logs together to start a fire? It’s like why not just use a Zippo lighter? It’s like we could split hairs on whether non-HDL cholesterol or remnant cholesterol is a better predictor of cardiovascular disease than LDL cholesterol, but again, given that LDL cholesterol is such a crappy predictor of cardiovascular disease, I prefer not to really even think about that.

Dave Feldman

We do have now a situation where this particular phenotype where lean mass hyper-responders will have very low levels of LDL or I’m sorry, of …

Peter Attia

VLDL cholesterol.

Dave Feldman

VLDL cholesterol, have very high levels of LDL cholesterol, will have very low levels of remnant lipoproteins.

Peter Attia

But we don’t know that. There’s no way you’ve measured that. I’ve never measured that. That’s not measurable. In a commercial, I say that’s worth its salt. I think VAP does a vague ass version of that, but it’s bunk, but look at this. Look at Garvey’s studies. We’ll link to this as well. This is actually measuring the number of particles. This is an insulin sensitive person. Their a total LDL-P is about 1,200. Their VLDL-P is about 80. You go to someone whose insulin resistant, but not diabetic. Their LDL-P goes up to 1,435 on average. Their VLDL goes to 84. Their IDL is counted. It’s around area, and then you take the population with type 2 diabetes. Their LDL cholesterol’s up to 1,600 nanomole per liter and their VLDL goes up to 100.

You’re right, the VLDL is going up as you get more insulin resistant, but it does not appear very clinically relevant, because remember this is all the burden of disease, is from these ApoB bearing particles, and so the increase in VLDL particle number is not what’s driving the risk of the disease. You actually had a really nice graph in one of your figures that you titled that is remnant that was going up. You know the figure I’m talking about?

Dave Feldman

Yeah.

He’s referring to this one:

Peter Attia

We’ll link to that as well, but you had a graph that showed I think as people were becoming more insulin sensitive, their pool of remnants was growing. What you perceived as remnants.

Dave Feldman

Well, I actually want to qualify something real quick. If I think it’s the graph that you’re talking about, it was the one downside to that is it was non-fasted remnants, which I’ve been trained to find [crosstalk 01:50:02].

Peter Attia

Oh, got it. Got it. Okay, okay.

Dave Feldman

Which I have a problem [crosstalk].

Peter Attia

It was in one of your talks.

Dave Feldman

It was in one of my talks.

Peter Attia

But anyway, my point is what’s missing from that analysis is ApoB or LDL-P. In other words, the expansion of that … See this study, which is I mean the most elegant study of this ever done shows that if you only saw the top line, this to this to this, everyone would be like wow. The more insulin resistant you get, the more your total burden of ApoB goes up. What this is showing is where is that burden coming from. The VLDL only increased by 20 nanomole per liter, but the LDL-P increased by 400 nanomole per liter.

Dave Feldman

Right, and the point I’m coming to is this is where we’re in uncharted territory because I believe will apply to people who are ketogenic fat adapt. I don’t believe this will apply to people who are very ketogenic fat adapted, and particularly who have these phenotype.

Let me see if I can come at it this way, right now, if I were to be able to get the data set for Framingham Offspring, because that is one of the studies that I was showing out for before, and I could basically just do this basic calculation of remnant cholesterol the way they were talking about, and conceding the point of your time that you said earlier that’s there’s no way to truly know. Would I still come up with a more valuable metric for subtracting HDLC, particularly when associating to all-cause mortality? Relative to say …

Peter Attia

Let me make sure I understand what you’re saying. You’re saying if you could develop an [inaudible 01:56:54] to distinguish between the pathologic remnants of VLDL versus the physiologic remnants …

Dave Feldman

I’m not even developing that. Let’s say I’m not even developing. I’m just taking the existing HDLC and LDLC metrics as they’re recorded right now. I’m just grabbing the data says it is right now.

Peter Attia

Yeah.

Dave Feldman

Will the remnant cholesterol that I get from that subtraction, will that actually be more relevant to all-cause mortality than say LDLC?

Peter Attia

I don’t know, but it would certainly rival it. I mean, again, the data are probably more clearer on non-HDL cholesterol versus LDL cholesterol, that’s typically what the literature talks about, but as you can tell that non-HDL cholesterol and LDL cholesterol are two of the three variables you would need. There’s a strong correlation between non-HDL cholesterol and remnant cholesterol, and yes, I believe non-HDL cholesterol is more predictive than LDL cholesterol.

Dave Feldman

But there’s one problem with non-HDL cholesterol I definitely want to bring up for people who are on a low carb diet. If you’re going to be powered much more by triglycerides directly, literally triglycerides being brought to you in VLDLs, then that is going to be relevant. Now, again conceding Peter, what we talked about before, I can’t know if I can stake my flag on it just yet, but I’d be willing to bet if I’m right on the energy model that if fact you are being powered more by triglycerides found in VLDLs, then you can have a higher resulting LDL particles.

Peter Attia

But, wait. That’s a … sorry, I’ll let you finish, but I think your missing something. Go ahead.

Dave Feldman

No, no. Go ahead.

Peter Attia

No, no. I’ll remember it. I feel bad I interrupted you.

Dave Feldman

Okay. No worries. Effectively, the bigger question is, are particular lean mass hyper-responders show casing directly that they’re being powered much more by triglycerides brought on these VLDL boats, if you will, and therefore having more subsequent LDL particles.

Peter Attia

Okay. My hypothesis is that that is not the case.

Dave Feldman

That it’s the higher degree of synthesis, right?

Peter Attia

Yes.

Dave Feldman

Going on with the cholesterol.

Peter Attia

That’s correct. That it is the higher degree of synthesis, which may or may not also be matched by a higher degree of absorption.

Dave Feldman

How would, if you were wanting to, if you’re going to suggest a way that we could test this, how would you suggest that?

Peter Attia

Before I do that, let me unpack where I think energy is moving from. I think we all agree that someone who is very insulin sensitive on a low carbohydrate high fat diet is utilizing a lot of triglyceride. We agree on that, right?

Dave Feldman

Yes.

Peter Attia

Okay. Let’s take an artificial construct and separate endogenous from exogenous triglyceride. Meaning someone on a low carbohydrate diet is eating themselves, and they’re eating triglycerides from the outside world.

Dave Feldman

Right.

Peter Attia

Assuming they’re in the phase of getting leaner. They’re losing weight or even someone who’s weight’s static, they’re utilizing their own internal stores of triglyceride that they’re replenishing. If they’re staying weight stable, right?

Dave Feldman

100%.

Peter Attia

Okay. The exogenous triglycerides enter the body through chylomicrons that’s a pure lymphatic play through CTAP that’s rapid hydrolysis. I think we all get that. I think it’s this other endogenous pool that’s interesting.

Dave Feldman

And if I could just interject this one thing, because this is one thing we’re dancing around that we both know that probably somebody’s who’s not familiar with my work should be aware of. Chylomicrons, they drop off these triglycerides and they’re just gone. Almost like depending on who reading within minutes or hours [crosstalk 02:00:31]. If you’re taking a fast cholesterol test, Peter, we were talking about it earlier, you shouldn’t see any chylomicrons or chylomicron remnants, they should be gone, and the cholesterol payload on those chylomicrons should be gone.

Peter Attia

That’s correct.

Dave Feldman

With that in mind, go back to the endogenous triglycerides.

Peter Attia

Endogenous means we’re dealing with the pool of triglycerides that are coming out of you as the person. You have adipocytes, adipocytes stored triglycerides, and those triglycerides are hydrolyzed such that you have free fatty acids that will be transported. Where do they go? When they come out of the adipocyte, who picks them up? Albumin. Albumin then does two things. It can take it directly to the muscle, so that the muscle can use in the highly fat adapted athlete, or it can take it back to the liver, and it can be repackaged in VLDL or it could be turned into a keto, if we’re getting into an extreme state of someone who’s ketotic.

Let’s talk about, what’s the guy’s name you said, Moffitt?

Dave Feldman

Craig Moffitt, yes.

The Craig Moffitt Example

Peter Attia

Okay. I remember seeing this in your presentation. He looked like a runner, great athlete, super lean dude, right?

Dave Feldman

Mm-hmm (affirmative).

Peter Attia

Do you have Moffitt’s number handy? Can you give it to me?

Dave Feldman

You, know what? I probably can. Glad you mentioned that.

Peter Attia

Even just directionally. I mean, I remember seeing this a few weeks ago.

Dave Feldman

Got it. Okay, just one second. This is perfect.

Peter Attia

Okay. I’m going to read this off to everybody, so Craig Moffitt who looks like a super fit dude, who’s running around, has a total cholesterol of 457 milligrams per deciliter. His LDL cholesterol is 335. His HDL cholesterol 109, and his trig is 67. I’m assuming you did the math correctly. I’m not going to check it, but if that’s presumably the LDLs direct, his remnant cholesterol is 13 milligrams per deciliter, and by the way, that’s not terribly far off from what you would get by the trig by five formula. He’s not that far off. Okay, fine.

Where is he getting his energy. Let’s say he’s out for a run. He’s not eating anything and he’s fat adapted, and he’ll say he’s fasted, let’s make it even easier. He’s fasted going out for a run. His adipocytes are releasing free fatty acids to albumin. The albumin is taking some fraction of that to the muscle directly, and they’re undergoing beta oxidation there. The albumin’s also going back to the liver, and some amount of that is being converted into beta-Hydroxybutyric, which goes down its own metabolic pathway, and some amount of that is being packaged in either a VLDL or an IDL because remember there’s still de novo ILDL production in the liver, just as there’s the novo LDL production.

Those VLDLs and IDLs are leaving the liver and dropping off their payload of lipid to the tissue. The tissue’s basically getting ketones from the liver, triglyceride from albumin directly to the muscle and triglyceride through the VLDL and IDL directly to the muscle. Do we agree on that?

Dave Feldman

We do. I’m just going to expand a little bit on what you just said. So, yes, it’s full body lipolysis, and that he’s releasing the free fatty acids. In the literature they’re usually calling it, NEFA, non-esterified fatty acids, but we’ll just keep it to free fatty acids. It’s getting released from all [crossatlk 02:04:32].

Peter Attia

We usually measure them by the way as one.

Dave Feldman

Yeah. It’s a little frustrating because a lot of these terminology gets interchanged, but the free fatty acids are ultimately making it back to its liver getting packaged into the VLDLs. What we’re talking about the target sites of the muscles for which are making use of triglycerides. I should emphasis that I believe that the primary purpose of the creation of those is to replete everything. It’s not just to fuel the muscles, it’s also to put it back into the adipocytes that just now released it as well.

In other words, Craig Moffitt like many people who are lean mass hyper-responders, if we could install a little turnstile into their adipocytes. We would see that turnstile just spinning like crazy. They barely park the triglycerides there before it’s heading right back out, and that’s because there’s less total adipose mass overall in Craig Moffitt compared to somebody who’s a lot heavier, and therefore there needs to be more global supply of VLDLs relative to somebody else who has a lot more fat mass.

Peter Attia

But this depends on his energy requirement?

Dave Feldman

Absolutely.

Peter Attia

I mean, of course while he’s running, and again, I wrote a blog post on this a lot time I ago, which I guess we ought to link to. It’s something about fat flux. I don’t remember the name of it exactly, but the gist of it was over simplifying a fat cell as having two input doors and one output door. The two input doors as being the de novo lipogenesis door, which is still an esterified entry door, but I separated as a different storage. Meaning it’s coming from a carbohydrate, not from a fat, and then you have the re-esterification door, which has the turnstile that allows fat to go right back in, and then you have the lipolysis door, which allows the fat to exist. A person who is in fat balance has a situation where L, lipolysis equals the sum of the esterified de novo lipogenesis plus the re-esterified fatty acids. Agreed? That’s just straight up math balance.

Dave Feldman

Yes, yeah.

Peter Attia

When Craig’s running, he’s in negative fat flux. Make no mistake about it. His de novo lipogenesis is zero at that moment. His esterification is something, and his lipolysis has to be something bigger.

Dave Feldman

Right.

Peter Attia

If he’s not depleting glycogen, which if he’s highly fat adapted, he’s not.

Dave Feldman

And maybe it’s worth putting on a distinction. I’m not talking about whether they were successfully at the moment that he’s running. Successfully re-esterifying these fatty acids back into the adipocytes.

Peter Attia

And they might be though. That’s my point, because we don’t know. What we know is that in, which goes back to the question …

Dave Feldman

But do we know that it’s the job of the liver to keep maintaining that buffet? To keep putting that energy back out there, and generally speaking, we do know that. It’s just to what degree?

Peter Attia

No, I mean my hypothesis is yes. My hypothesis is, which is not by the way, I don’t think is a commonly held view. I think a lot of people would disagree with me, but my view is that the liver is the an ergo stat of the body. I borrowed that term from Mark Friedman, who wrote an amazing chapter on this in 2008. That has been one of the most influential things in my thinking on appetite, but he described the liver as the an ergo stat. It was, an engineer will appreciate the nomenclature. It looks kludgy to someone who’s not an engineer to say why would he call it an ergo stat, but in engineering speak, that makes perfect sense, but that the liver is probably most susceptible to detecting some currency of circulating energy and circulating metabolites.

ATP would be the most logical thing for it to be sensing. Probably ratio the ATP to ADP, or ATP to AMP, or ADP to AMP, something like that, but yeah. I think the liver … I mean, I think most people appreciate how impressive the liver is in general. I was just talking to a patient this morning, and I said, “Look man, here’s the deal. Anything that goes wrong with you can be supported extracorporeally. You get into a coma, no problem. You need to go on a left ventricular assist device, okay it sucks, but it’s there. You need dialysis, you need a ventilator, all that stuff, we do not have extracorporeal support for the liver. It is too complicated.

Dave Feldman

Anybody who follows me knows just how much I’m loving this because you’re the preacher’s preaching to the choir by far. I’ve often referred to the liver as the straight laced partner, who always puts up with your crap. Whatever you’re giving it, it’s having to pour us out and figure out, and balance the ledgers, and get everything in.

Peter Attia

No, no. That’s a great point, and that was part of the other point I made to this patient, who was not in any way opposing that view. He was just asking if the elevation we’d seen in his liver function tests, which was mild could explain a synthetic issue to which the answer is not a chance in hell under normal circumstances because the liver has an enormous capacity to do its job under even the most ridiculous stress.

Yeah, but going back to Craig, at the moment that he is running, which is the same as saying if someone’s losing weight while they’re on a low car diet, they are in negative energy balance. They are in negative fat flux, and again, when I say losing weight, let’s ignore the water weight and stuff. I’m talking about legitimate weight loss or shedding of …

Dave Feldman

Metabolism exceeds.

Peter Attia

Yeah. Yeah, but that’s what it means, right? On a practical level, it means lipolysis, the amount of fat that is leaving the fat cell has to exceed that which is reentering it, and again, I don’t know that this is entirely relevant, but you’ve eluded to it, so worth reiterating. Not all of that is oxidized. Some of that free fatty acid leaves doesn’t get oxidized, and guess what? It’s mopped back up provided the hormonal mill you still permits it.

Dave Feldman

Yes.

Peter Attia

We agree on the completely. I look at his remnant cholesterol of 13 milligrams per deciliter, and say okay, it doesn’t tell me anything. I apologize. Your question was looking at that, what could we infer?

Dave Feldman

Yes, actually, and this probably gets to just a larger problem that I feel like remnant cholesterol is helping us to address is why is it that anybody would have high triglycerides at all? Why aren’t all triglycerides making their way to either the tissue that’s using it immediately, the skeletal muscle or the cardiac tissue, or to the adipocytes if the body means to not have it sitting inside of lipoproteins part in your bloodstream.

Peter Attia

That’s a totally separate question. I want to come back to this remnant cholesterol question, though.

Dave Feldman

But this is why the original graph that we talked to, this is why I draw that dotted line. I draw a lot of people’s attention to it is …

The dotted line I’m referring to as shown in this graphic, which was up on the screen we were using.

Peter Attia

Can you go back to that?

Dave Feldman

I’m sorry. I’m trying to find another one. Okay, yeah. This is the core emphasis.

Peter Attia

This is the energy delivery support diagram for the person who’s going to be looking at this later?

Dave Feldman

Right.

Peter Attia

Okay.

Dave Feldman

I mean, if I’m going to way oversimplify it, but not by too much – chylomicrons’ job deliver fat-based energy.

Peter Attia

Yeah, and is so far gone that it’s not really entering the discussion we’re talking about outside a very, very rare diseases.

Dave Feldman

HDL, not to deliver energy will just say, things not related to delivering energy, but I just call it support, generally speaking. Operations not related to delivering energy.

Peter Attia

I agree with that.

Dave Feldman

Okay. Last line. Liver, this being the ApoB containing lipoprotein is the one lipoprotein that clearly is pulling double duty.

Peter Attia

No, no, but hang on. Remember this is where your diagram at which you acknowledge is over simplified. The over simplification is hurting you. The liver has three purple arrows coming out of it, the VDL, IDL, LDL.

Dave Feldman

Agreed, which is why earlier I was emphasizing that I believe there’s a higher secretion of VLDLs overall for those people with lean mass hyper-responders, which is very relevant to our discussion.

Peter Attia

How do we know that?

Dave Feldman

It’s a theory. I’m not saying that. What I’m saying is as if this area was fatter, if the VLDL secretion is at a greater degree, it would make sense why there would be more remodeled final LDL particles remaining, and why would we see the inversion pattern in the first place? Because it originated in order to deliver more of those triglycerides, which was brought about.

Peter Attia

Why the excess cholesterol? If that were the case, Dave, wouldn’t you hypothesize that the LDL particle would be very high because you have more VLDL particles, but they’re shedding all of their triglyceride in an effort to deliver their energy payload, but you shouldn’t have an increase LDL cholesterol. You should actually have a reverse discordance from what we see in the insulin resistant patient where we typically see the LDL particle number, being this proportionately higher than the LDL cholesterol by percentiles, of course, and absolutely members, that’s always the case. In other words, if I was buying your hypothesis I would say the LDL cholesterol should be very low. You should have very cholesterol depleted skeleton particles that were mostly used to shed triglyceride as VLDL.

Dave Feldman

But instead, we see the concordance. We see the LDLC and the LDL-p very concordant in people who don’t appear to have other types of diseases.

Peter Attia

Well, at that point they’re so high. It’s hard to know, but clearly not discordant in the direction that would make sense given your hypothesis. In other words, what I’m getting at is, why is there so much cholesterol in those LDLs.

Dave Feldman

Correct me if I’m wrong, but as far as the actual drop off rate, the LDLC is still going be relatively standard on a per particle basis in a healthy subject. How much variability is there typically in LDLC per LDL particle because again, correct me if I’m wrong, I thought that the secretion level tends to be fairly standard, like a spare tire is standard for a car.

Peter Attia

Yeah, it’s …

Dave Feldman

The triglyceride levels can be very variable.

Peter Attia

Yeah, but the cholesterol levels. I mean they have capacity to carry a lot, but think about it. If you have large and small particles that even for the same amount of triglyceride have different amounts of cholesterol, but the bigger point is, where is the cholesterol coming from? If we go back and look at my guy, or look Moffitt. Moffitt’s LDL cholesterol was 335 milligrams per deciliter.

Dave Feldman

Right, but that’s what’s in circulation in the blood at that time.

Peter Attia

Hang on. Just to be clear, Dave, is there any point during his 24 hour day when that number is 30 milligrams per deciliter of LDL cholesterol in his bloodstream.

Dave Feldman

I don’t believe so.

Peter Attia

In other words, if you take the area under the curve, if we could get real time LDL cholesterol number on Moffit, and integrate him over 24 hours, we could argue for argument’s sake, he’s going to be always over 300 milligrams per deciliter. Hus AUC would be very high.

Dave Feldman

For the existing traffic of the LDL particle, I mean basically what we’re talking about is what’s, I almost want to say it in terms of birds in the air. You have so many ships that have left the dock, that are continuing in circulation, but I guess here’s a different question that I’ll pose back to you.

Peter Attia

But, wait. I’m actually asking this because I’m trying to understand it.

Dave Feldman

How much of this cholesterol has already made a lap? Are you thinking of this in terms of it all getting synthesized and then reabsorbed, and then recreated it again?

Peter Attia

Let’s go back and make sure we’re agreeing on the same conditions here. Notwithstanding the experiment where they eat a ton of fat and they go from having incredibly high LDL to very high LDL, but let’s just take Mofitt, over the course of a week. Assume you could do real-time LDL cholesterol sampling on him.

Dave Feldman

And specifically, LDL cholesterol?

Peter Attia

Yes.

Dave Feldman

Okay.

Peter Attia

Or everything. Everything that’s on your page. You could sample his total cholesterol, his HDL cholesterol, his LDL cholesterol, his VLDL cholesterol, and his LDL particle number. You could sample all of these things in every second for a week. I think we’re agreeing that he will always have a very high LDLP and a very high LDLC and a low VLDLC. Correct.

Dave Feldman

Unless he eats a lot of fat.

Peter Attia

Okay. Yeah. Let’s, we’ll come back to that after, but yes.

Dave Feldman

Sure.

Peter Attia

Okay. So, given that the half-life of his LDL is a day, where is that extra LDL cholesterol coming from?

Dave Feldman

I believe it’s being recycled.

Peter Attia

Well, it’s always being recycled. How is his being recycled? So, so where is his, where is he deficient in cholesterol that a person who has an LDL cholesterol of 100 is not?

Dave Feldman

I guess I don’t understand the question. Where is he deficient?

Peter Attia

Yeah, if he’s got 335 milligrams per deciliter of cholesterol in his LDL particles, are you telling me that he has less cholesterol in his cell membranes or less of it somewhere else?

Dave Feldman

No.

Peter Attia

So he has more cholesterol in his body.

Dave Feldman

Correct.

Peter Attia

Why?

Dave Feldman

For the same reason that we would have say, life rafts on a boat and once we have more boats, we have more life rafts. So, if we had a harbor just outside this window, right? And you had 100 boats and on those hundred boats, their main job is to deliver something unrelated to life rafts. They’re delivering cargo to the other island. Right? And they deliver, and 100 of them go out, 100 of them come back. And then demand on that island has changed. Now they need to deliver five times as many things as they were delivering before.

Peter Attia

But the problem with that analogy is it assumes a completely fixed number of life rafts per boat.

Dave Feldman

It definitely does.

Peter Attia

But that’s not how the lipids work.

Dave Feldman

How does it work?

Peter Attia

There’s much more flex in the system. And furthermore, you could ask the question in reverse, why isn’t it higher?

Dave Feldman

Why wouldn’t LDLC be higher per boat?

Peter Attia

No, why wouldn’t LDLC be higher in that patient? In other words, what’s regulating it? What’s regulating how much LDL cholesterol he has?

Dave Feldman

The demand for the boats themselves for LDL particles.

Peter Attia

But what’s driving that demand? This is, I think where we differ, right?

Dave Feldman

The demand of the delivery for the triglycerides. The demand is for the cargo, the originating cargo that is clearly getting used.

Peter Attia

Right, but we agree that the VLDL vanishes very quickly.

Dave Feldman

The VLDL remodels to LDL very quickly.

Peter Attia

Yes, but if you go through the kinetics of this, I can’t follow why he should still have that much LDL cholesterol unless he is making more cholesterol. In other words, I’ve tried to think of this 10 ways to Sunday, the only way on a mass balance that I can explain this hypothesis is if he’s making more cholesterol.

Dave Feldman

And not if he’s recycling the same cholesterol? Certainly he’s making more relative to someone who doesn’t.

Peter Attia

Only if he were depleting it in some other store. So in other words, I’m making this up, but if you could say, well, all of us … I mean you probably know this. Everyone loves to quote this fact, right? But red blood cells have more cholesterol in them than LDL particles, right?

Dave Feldman

Right, right.

Peter Attia

So the, the LDL denier loves to say, “Well, we don’t think red blood cells are causing atherosclerosis and yet they have more LDL.” Whatever. But my point is, unless you’ve depleted a pool of cholesterol elsewhere in his body, just on mass balance, you had to make more of it.

Dave Feldman

As far as I understand, the liver can recycle cholesterol as many times as it wants to.

Peter Attia

Again, that’s true, and the liver and the gut have a very clear pathway, which he described.

Dave Feldman

Correct me if I’m wrong, the liver is the only organ that can actually degrade cholesterol, right? Non hepatic tissues can’t degrade cholesterol.

Peter Attia

Well, again, it depends what you mean by degrade. Remember, cholesterol has no caloric value. It’s not a metabolite. It’s not something that we metabolize, right? We turn it into-

Dave Feldman

If you were synthesizing more, you’re saying it’s going to go somewhere if it needs to be synthesized more.

Peter Attia

Right. If you’re synthesizing more, presumably you have a higher growth of the organism. You have more cells, you need more cells because obviously probably the highest demand for cholesterol is for cell membranes. So that’s what I’m trying to figure out. It’s like, where is all this extra cholesterol coming from? If it’s not being synthesized de Novo?

Dave Feldman

And that’s my larger point. The inversion pattern is part of what should bring this to light. Is, why then, when I have an enormous amount of fat over three days, I would see my LDLC dropped by 73. Why would I see my LDLP drop by 1,115 in three days from eating huge amounts of dietary fat? Why would that happen?

Peter Attia

I mean, it’s an interesting question. I’m just not sure. All it’s basically saying is you have a way to perturb those levels. I mean, I’ll give you another anecdote here. So, you know, I did a one week fast, I went Keto for a week and then ate nothing for a week and now I’m actually back on Keto for a week and I’m checking my blood every seven days. So that was my LDLP before I … That was just me. That’s my normal LDLP. So I’m walking around at 920 nanomoles per liter. This is after months and months of time restricted feeding with virtually no carbohydrate restriction other than just I don’t eat crappy carbohydrates.

Dave Feldman

Right.

Fasting Impact on Data

Peter Attia

So then I went Keto for a week and look, my LDLP actually went up. Now I don’t think I would meet criteria for being a “hyper responder” because it went up to 1380, which is not that high, but you know, that’s still a significant jump for me. Right? Okay. What should it have done when I fasted for a week? Shouldn’t it have gone up according to this model?

Dave Feldman

Well, here’s the catch. The catch is, I only know the three day window. I don’t have a lot of data from people who fasted for a week, as in just water fasting.

Peter Attia

I do.

Dave Feldman

Okay. You do? Good.

Peter Attia

Yeah. I’ve done this on multiple patients who have done three, five and seven day fasts.

Dave Feldman

Okay. Who are fully ketogenic and you’re saying it typically goes-

Peter Attia

Not always ketogenic. No. Sometimes they’re just, you know, fat adapted. Sometimes they’re not. Sometimes they’re actually insulin resistant and we use the fast to kick them into a state of Ketosis to make it easier. But, and again, I want to be very careful. This is simply just anecdote because I’ve only done this on maybe 30 people, but this is not uncommon. I mean, look, my LDL cholesterol went from 64 to 37 after the fast. I mean it went way down.

Dave Feldman

Wow. Fantastic.

Peter Attia

And that’s consistent with what I see. Now, that’s not the reason I’m fasting. To be clear. I’m not using a fast to manipulate lipid proteins. I’m doing it for a completely unrelated reason, but my point is I always see, and again I can say always because it’s a relatively small end. Obviously, at a large enough and you’re going to see counterexamples to anything and everything, but the general principle seems to be under caloric deprivation, LDL goes down and under fat deprivation LDL goes down.

Dave Feldman

I’ve got to put in the one footnote and it’s an annoying footnote that I keep putting in. I really need to. And this is why I’m dying to get these parts of the exercise. I need to look at a population that also is not getting any, particularly weight training or resistance training and so forth, because that seems to impact it. Whether it’s my theory or not, that seems to impact overall lowering LDLC numbers. I’d be very interested about this in fasting.

Peter Attia

I’ve got that in my patients. Not every one of my patients lift weights despite my best efforts. So, again, I think the more common thing that we see is that when you put people on a high fat diet, the ones that go on to have this hyper response, as you note, their trigs usually go down, their cholesterol goes through the roof and it’s driven by a doubling, tripling, or even greater output of synthetic biomarkers like desmosterol. Now, for reasons I don’t understand, you also tend to see at least two of their three phytosterols go up. Now, one thing we didn’t talk about though, I wrote about it, so I’m sure you know about this, is this seems reversible. If you eliminate the saturated fat.

Dave Feldman

It does seem to matter in this case, and you’ll like this, at least in our own data with ApoE4s, seems more likely if you’re an ApoE4, you will see a drop somewhat in saturated fats.

Peter Attia

So I don’t think I have a large enough sample size because I’ve only put seven patients through that protocol. Which is, and I wrote about the very, very first one. So that’s probably the only one that you’ve seen that I’ve talked about, but this was a young guy who went on a Ketogenic Diet, was crushing it, meaning like everything was going well. I mean he’d gone through the adoption period. His performance was exceptional, mentally never felt better. He was not an overweight, or metabolically ill guy to begin with. He was just kind of a normal software guy who just decided he wanted to take it to the next level. But then he showed up with labs, not unlike these. He was the first guy I ever saw where there was a greater than sign on the LDLP.

Dave Feldman

Right. It maxes out at 35.

Peter Attia

I was like, “Oh, I didn’t actually realize the assay stopped at 3,500. This guy is my guy.” He looked better on some of the other metrics. He didn’t actually have a lot of the inflammatory stuff. This was before the Ox LDL assay was commercially available. So I didn’t have that. But you know, his CRP and is LPPLA2 we’re okay. But we had the discussion, right, which is the discussion that at the end of the day I’m accountable for having, which is what are we going to do about it? And he was young. I mean the guy was 30, so it wasn’t like we had to do something tomorrow. This is not a guy who’s going to have a heart attack in a week.

Dave Feldman

Because I think when you originally writing about it, he actually pushed back a little bit. Like he wanted to come up with a-

Peter Attia

Well, what he pushed back on was, because I basically said, “Look man, I don’t think the Ketogenic diet’s right for you. These numbers are crazy.” And he was like, “Yeah, I don’t ever want to go back to what I was doing before.” I mean he basically said in not so many words, like I’d rather die of a heart attack and feel this good. And he’s not saying like, “I’m going to die of a heart attack tomorrow”, but he’s like, “Look, I’d rather live to 60 and feel this way, than live to 70 and not.” Which I say totally fair by the way. That’s a very reasonable trade off to make, but let’s also think about this a little more logically. So that was actually probably the first case I ever discussed with Tom and this was I think back in 2011 and it was actually this discussion I think that lead Tom to go on to write the lipidaholics case, even though it wasn’t the patient that he used in that case because he then went out and found others like them.

What we just decided was on biochemistry first principles, our hypothesis was it’s the saturated fat, more than the ketones. Because that was the other thing, this guy didn’t want to leave ketosis. My thought was, let’s just dial this back, get you out of Ketosis. So our hypothesis was both ketones and saturated fat can be readily converted into cholesterol, but if he’s adamant on staying in Ketosis, let’s at least get his SFA down to 25 grams per day. Which was hard. This is a guy that was eating about 100 grams of SFA a day, maybe 80 grams. I mean, it was a lot. We basically just made most of it MUFA. So I said to the patient, I said, “Look, the way we could do this just for no other reason as the purpose of a thought experiment is, you’re going to basically have to become a nonstop olive oil, Macadamia nut eater. Even even the avocado you can’t go hog wild on because eventually you’ll get too much carbohydrate out of it for this purpose.”

And sure enough, I think he came back at like 1300, after eight weeks or something like that. So six more patients have been so adamant about staying in Ketosis and not taking any medication but wanting to go through this experiment and all of them have had the same response. Which is, if you can get them to main line MUFA, you fix the whole problem. Without reducing or increasing to any measurable effect, how much fat they’re consuming.

Dave Feldman

Have you been keeping track of their PUFA levels too? Because it’s hard to add a lot of MUFAs-

Peter Attia

Their PUFA was going up.

Dave Feldman

And you know, the issue with that, with adding more PUFA, is the downside is there’s the potential that you’re actually adding more peroxidation on the particle basis.

Peter Attia

Yeah. Yeah. I mean, I think it depends. This is one of those areas where I’m trying to get a lot smarter and I want to make sure I’m not sitting in the echo chamber. I’ve historically, you know, measured RBC levels of arachidonic acid and all of those things and tried to keep track of the ratio of that to the EPA and the DHA, but ultimately I don’t really think I know the answer to this yet. And I also don’t think … My guess is PUFAs are not as bad as I have historically thought them to be, but they’re probably not as good as MUFA. So not withstanding that, I just want to talk about this from the level of the thought experiment, so to speak. My sample size of those people is too small to know if there’s a relationship to their ApoE gene. To your point, what I’m hearing you say is maybe that’s more … That’s something that you’re more likely to do in someone who’s an ApoE4 carrier.

Dave Feldman

It’s been a proportional kind of thing that we’ve sort of noticed.

Peter Attia

I don’t know, but what I do know is it seems to point back to this idea that the hyper responders … That the Occam’s razor here is that they’re making more cholesterol. Because that makes sense from a mass balance standpoint. Again, I’m still-

Dave Feldman

And I would have agreed with you were it not for this energy inversion that I see. If it were not … The very thing that I said from earlier that I could move my LDLC to where I want to move it. That would be based on me basically arranging for a few days to eat to a certain level and I’d be pushing down my LDLC by eating up to a certain-

Peter Attia

Notice you’re pushing up and down on LDLC within super physiologic levels. Meaning, if I recall seeing your data, do you mind showing me that again?

Dave Feldman

Unfortunately, the computer died. That’s why I’ve had it closed, but yes, what you’d see as an inversion graph and-

Peter Attia

I’m very familiar with it and we’ll obviously link to it, but it was, as I described it, you’re showing that you can move your LDL between the ranges of very high and stupidly high.

Dave Feldman

No, like I’ve, I’ve moved my-

Peter Attia

What’s the lowest you’ve ever got your LDL?

Dave Feldman

98, and I suspect-

Peter Attia

Okay.

Next part: Guesting on the Peter Attia Drive (4 of 5) – Energy Status, Risk, Testing the Hypothesis

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