Welcome back, everybody, to the Building Lifelong Athletes podcast. Thanks so much for stopping by. I really appreciate it. It means the world to me that you're here. Today, we're talking all about two different papers, two ideas. So, the lipid energy model, and then another Oreo experiment, what they say. Kind of comparing the two. So the lipid energy model is the alternative hypothesis saying, hey, these people who are really, really lean, why does their LDL get so high? And this is the proposed counter mechanism.
They've published studies, and this is essentially what the low carbs is: hey, when these numbers skyrocket, this is this specific phenotype, these specific people, and this is why we think it's going on there. So, I'm going to break down the science and showing what it's all about. And on top of that, we'll talk about this Oreo experiment. So, the Oreo experiment, I'll get into there in a little bit, but it shows about it's trying to prove this lean mass hyperresponder phenotype. So, we'll dive into the video here and then we'll come back in a second and talk about it. I'll get a little additional breakdown. In our last video, we broke down the response to retention model of atherosclerosis. We traced how ApoB particles physically penetrate the arterial endothelium.
Get trapped in the extracellular protoglycamatrix and spark the inflammatory cascade that builds plaque. We established that you cannot build plaque without the particle. And that brings us directly to the most polarizing mechanistic debate in cardiovascular nutrition today. What happens when an otherwise lean, metabolically fit person adapts a carbohydrate-restricted or ketogenic diet, and their LDL cholesterol explodes in the stratosphere, hitting 300, 400, or even 500 milligrams per deciliter, while their blood sugar, insulin, and inflammatory markers remain virtually flawless. To conventional cardiology, an LDL above 200 or 300 milligrams per deciliter is a huge red flag, requiring immediate high-intensity statin therapy. But within the low-carb community, a curious clinical pattern began to emerge that didn't fit the standard disease paradigm.
In 2021, software engineer Dave Feldman, along with Nick Norowitz and Dr. David Lugwood, published a paper formally characterizing this group as, quote, lean mass hyperresponders, or LMHR. It's defined by a specific triad, an LDL of 200 mg per streliter or higher, an HGL of 80 mg per deciliter or higher, and fasting triglycerides of 70 mg per deciliter or lower. But what puzzled clinicians was not just the sheer magnitude of cholesterol spike, which was huge, right? It looked very similar to familial hypercholesterolemia, but it was who was getting that spike. When researchers examined these individuals, they found normal baseline cholesterol levels before starting the diet, and nobody was known to have a genetic mutation that causes high cholesterol. And more remarkably, their LDL rise had a strong inverse correlation with body mass index. In plain English, the leaner the person was, the higher their LDL climb when they cut carbohydrates.
Here's an image from the 2021 paper by Norowitz and colleagues explaining the LMHR phenotype. And this graph is showing that the lower the BMI, the greater their increase in LDL. And even more fascinating was its reversibility. If you had a genetic familial hypercholesterolemia, it doesn't matter what you eat, your LDL won't drop by hundreds of points. Yet, in the lean mass hyperresponders, reintroducing eating modest amounts of carbohydrates cracks their cholesterol back down towards the baseline within a few weeks. This hyper-responsiveness led to an interesting question. Why is the body doing this? Is it due to increased production of LDL or because LDL is not getting cleared fast enough? And to answer that question, proponents propose a radical paradigm shift called the lipid energy model.
Published in 2022, the model argues that lipoproteins aren't just carriers for moving structural cholesterol around to repair tissues. In a lean person who cuts carbohydrates, lipoproteins transform into the body's primary High throughput energy distribution system. Let's walk through their proposed five-step physiologic cascade. And step one begins in the liver. When a person adopts a strict ketogenic diet, glucose from the diet disappears and liver glycogen stores run low. With hepatic glycogen depleted, circulating basal insulin drops and leptin signaling falls. This hormonal shift communicates a critical message to the rest of the body. Carbohydrate fuels are offline, and the body must transition to almost entirely lipid oxidation.
And step two occurs in the adipose tissue or your fat storage cells. Now normally circulating insulin acts like a padlock on these cells, keeping fat locked away for storage. But when insulin drops, that padlock comes off, activating an intracellular enzyme called hormone-sensitive white base or HSL. Think of HSL as a molecular scissors. It snips Stored triglycerides apart into glycerol and individual loose fatty acid chains. In biochemistry, these uncoupled chains are called non-esterified fatty acids or NIFAs simply because they're no longer chemically bonded to glycerol.
Because raw fat doesn't dissolve in the watery blood, these fatty acids hitch a ride on circulating albumin and stream directly into the liver and muscle. Step 3 takes place back in the liver. The liver takes up these incoming fatty acids, resynthesizes them into triglycerides, and packages them into large, buoyant cargo ships called very low-density lipoproteins, or VLDL. According to this model, because a lean person has high daily caloric demands and minimal internal fat reserves to pull from locally, the liver is forced to mass produce and export high volumes of these VLDL freight cars to deliver fuel to distant muscles and organs. Then step four happens in the peripheral capillary beds, especially inside skeletal muscle and heart tissue. Here, circulating VLDLs encounter the enzyme lipoprotein lipase or LPL. And they say that in a fat-adapted person, LPL is running in overdrive. It rapidly hydrolyzes the triglyceride core out of the VLDL particle, feeding those fatty acids into muscle cells to be burned for ATP.
This hyper-efficient peripheral fat extraction explains why the fats interglycerides could be potentially so low in the LMHR phenotype. And finally, step five: particle remodeling. As that VLDL cargo ship unloads its triglyceride cargo, the core deflates. What's left behind is a shrunken, cholesterol-rich remnant, an LDL particle. And because LDL particles have a significantly longer residence time in the blood than VLDLs, these remnants accumulate in circulation, sending LDLs soaring. Simultaneously, the collapsing particle sheds excess surface membranes, transferring its APOA1 to build mature HDL. Under this model, the entire triad, high LDL, high HDL, and low triglycerides is simply a metabolic footprint of efficient fat transport. And now, any legitimate scientific hypothesis has to make testable predictions, right? The lipid energy model made a very bold one. If this astronomical LDL is simply driven by empty liver glycogen, leading to increased VLDL to meet energy demands, Then refilling that glycogen should shut down the entire assembly line.
Proponents argued that the carbohydrate source wouldn't even matter. It wouldn't require clean, unrefined starches. Any simple carbohydrate should flip that metabolic switch. Enter Dr. Nick Norwitz. In early 2024, Dr. Nick Norwitz published a paper in the journal Metabolites that went viral across the international media, the Oreo Cookie Experiment. Norwitz himself is an extreme lean mass hyper responder whose LDL and keto hovers near 400 milligrams per escalator.
He designed a crossover self-trial pitting the standard of care high-intensity statin therapy directly against ultra-processed junk food for lowering your cholesterol. The protocol was simple. In phase one, he added 12 Oreo cookies per day to his regular ketogenic diet for 16 days, adding exactly 100 grams of carbs. To ensure his body stayed in nutritional ketosis during the cookie phase, he consumed exogenous ketones four times daily. After a three-month washout period, back on a pure keto diet, his LDL returned to its baseline, which was very elevated. Then he began Phase two, six weeks of daily twenty milligrams of resuvastatin, a common lipid-lowering medication used in clinical practice. And the headline numbers stunned social media. In just 16 days, eating twelve Oreoles a day dropped his LDL cholesterol from a 384 Down to 111 milligrams per deciliter, a massive 71% reduction.
By contrast, the lowest he got his LDL on the statin was 284 milligrams per deciliter at week four, which is only a 32. 5% reduction. In this specific individual, eating junk food cookies was more than twice as potent at lowering LDL as the gold standard of pharmacological lipid lowering. Now, let's be completely fair to Dr. Nurowitz. Here's a quote he actually said. It says, This dramatic metabolic demonstration, consistent with the lipid energy model, Should provoke further research and not be seen as health advice. So he was crystal clear that this paper was what he called, quote, legit bait. I legit heard him say that on a podcast.
He knew what he was doing. But he was not telling patients to eat cookies to manage your cholesterol, but he knew this would garner attention, and he was right. His objective was to create an undeniable metabolic paradox and to, quote, provoke constructive discussion and inspire a larger scale crossover trial. And on the low-carbon community, this felt like an open and shut validation of the lipid energy model. So, how did mainstream lipidologists, cardiologists, and social media react to this? Well, to be blunt, they were completely unimpressed. Conventional researchers didn't dispute that as LDL drop. What they argue, though, is that the lipid energy model is biologically untenable. and that the Oreo experiment proves absolutely nothing about systemic energy transport. Let's look at their counterclaims.
The first major objection from conventional lipidology comes down to a fundamental question why would your body build more cargo ships when that isn't necessary? The core premise of the lipid energy model is that when carbs are restricted, the liver ramps up VLDL export to help fuel the rest of the body. To be fair, VLDL isn't a trivial fuel source. Researchers have tagged VLDL triglycerides with isotope tracers. And measured how much gets burned. After an overnight fast, it comes out to roughly 10% to 20% of energy burn at rest. During exercise, the share actually drops, though, to around 3% to 6% because working muscles lean more heavily on other fuels. And so, what are these other fuels?
The big one is the express highway. The fat cells release free fatty acids straight into the blood carried by albumin. Muscles also burn fat stored inside the muscle fibers themselves. And on a ketogenic diet, the liver exports ketones as yet another fuel. So the real question isn't whether VLDL carries fuel. It does. The question is whether moving more fuel through VLDL actually requires the liver to create more VLDL particles. Think of a shipping company with freight to move.
It can load each truck heavier or it can put more trucks on the road. And one more caveat, those tracer studies I talked about, those measurements were done in people eating normal mixed diets. Nobody has measured VLDL fuel delivery in a lean mass hyper responder yet, so this is all conjecture. And the second objection is this: why would your body make more VLDA particles when it can just pack more triglycerides onto each one? Kind of what I alluded to before. But there's real evidence the liver does exactly this. In people with fatty liver disease, the liver secretes far more VLDL triglyceride, but the number of VLDL particles it releases doesn't change.
The particles just get bigger. And in a study of more than 230 people, the number of VLDL particles secreted explained only about 30% of the variation in how much triglyceride was secreted. But it's not a one-way street. In one study, researchers acutely raise free fatty acid levels in healthy young men with an infusion. VLDL triglyceride production nearly tripled, and VLDL particle production roughly doubled. So it looks like the liver can actually do both. Which strategy wins out long term in a lean person on a ketogenic diet? Your guess is as good as mine. We don't know.
But this is exactly the kind of question the lipid energy model needs to answer. And remember from previous videos, each VLDL particle carries exactly one molecule of apolipoprotein B, right? So whether your liver responds by making bigger ships or more ships may matter a lot to your arterial health. So, this brings up another important question involving particle kinetics. So, the question of production versus clearance. And this is, I think, the main sticking point between LMHR supporters and conventional lipidology. Circulating ApoB is governed by a fundamental fraction, production rate divided by fractional catabolic rate, so which is the rate of clearance. And proponents claim extreme LDL is driven by the numerator, excessive BLDL production.
Mainstream lipidology argues, though, it's driven almost entirely by the denominator, a massive shutdown in the LDL receptor clearance. To be fair, though, both these stances are hypotheses, and neither are backed by studies in this specific population. And so, many people on a ketogenic diet also eat a lot more saturated fat, things like butter, cheese, fatty meats, coconut oil. These foods are rich in palmitic and myristic acid. Not everyone on keto eats this way, but it's very common. And here's how this could affect clearance. Your liver cells have a cholesterol sensor in a membrane called the endoplasmic reticulum. When cholesterol is low, the sensor releases a switch called SREBP2. SREBP2 travels to the nucleus and then turns on the LDL receptor gene so the liver pulls out more LDL from the blood.
When cholesterol there is high, though, the sensor holds SREBP2 locked in place and LDL receptor production goes way down. And saturated fat appears to push the liver towards that second state more. So normally, the liver stores excess cholesterol by attaching a fatty acid to it. And saturated fats are poor partners to that reaction. So, more cholesterol stays in the free signaling form. The sensor reads: we're full, sREBP2 stays off, and fewer LDL receptors reach the surface.
So, fewer receptors means fewer LDL particles being brought in and higher LDL in the blood. But in fairness to the LMHR side, there are some studies where they say, hey, this can't be the whole story. Saturated fat can't account for everything. There's a published case report of a man whose LDL went from 95 to 545 on a ketogenic diet that was actually low in saturated fat. And in a small crossover study of 10 lean women on keto, saturated fat intake didn't predict how high their LDL got or how much it changed. Their body composition and their thyroid markers did more. Now, moving on to another counterpoint, let's reconsider the Oreo experiment through another lens. Proponents say eating cookies proved the energy model because refilling glycogen dropped LDL, but others point out other confounders. Carbohydrates trigger multiple mechanisms simultaneously.
Eating 100 grams of carbohydrates refills your glycogen. Yes, it does, no argument there. But it also causes an immediate spike in insulin. And insulin directly stimulates hepatic LDL receptor expression, meaning it's going to take in more LDL. And it also triggers the intracellular degradation of ApoB. So, both models actually predict that eating sugar will crash your LDL. The Orio experiment cannot distinguish between the two, unfortunately, though. So, it could be very true that an LMHR phenotype is real and that this is the mechanism, but we have absolutely no way of knowing that from this specific experiment. And now let's address one of the most overlooked details of the ore experiment, the ketone supplementation.
So adding 12 ores a day, about 100 grams of carbohydrates, would normally kick you out of ketosis, but Nick Noritz wanted to see whether carbohydrates could lower LDL. While he stayed in ketosis. So during the 16-day cookie phase, he took exogenous beta-hydroxybutrate four times a day. That kept his blood ketones at about the same level on his usual keto diet. And on paper, that's a smart attempt to isolate carbohydrates as the single variable. But ketones aren't necessarily just fuel, they can also be signaling molecules, right? So they could bind to a receptor on fat cells. They're similar to the ones where the cholesterol drug niacinaxon, right?
So when this is activated, it can potentially dampen lipolysis, and fat cells release fewer fatty acids into the blood. And the issue is: hey, if we're decreasing lipolysis, are we changing something else in the equation, right? We're looking at VLTL transport and looking at free fatty acid transport. And if we're artificially lowering it, then we're going to have a potentially higher response than actually the diet's creating, if that kind of makes sense. It's just one confounding factor that not a lot of people were talking about. And I don't know how important that last one was, but I've seen it mentioned, so I just want to mention it as well. But the more interesting problem is probably on the clearance side. In one study, in rats, a ketone ester lowered blood cholesterol by about 40% and raised LDL receptors on the liver cell membranes by about two-thirds.
So, if anything like that happens in humans, the supplement could have lowered LDL through clearance completely independent of the energy transport story. We can't tell because the experiment had no ketone-only phase for comparison. Another thing is that Norwitz ate those 12 cookies on top of his normal diet. So it's roughly 600 to 700 plus extra calories a day. He gained weight during the cookie phase as well and returned to his baseline weight afterwards. Why does it matter? Well, because eating more, especially eating more carbohydrates, can actually change thyroid hormone metabolism. In classic overfeeding studies, three weeks of extra calories raised production of the active thyroid hormone T3. by roughly about seventy percent to eighty percent, whether the extra calories came from carbs, fat or protein. Carbohydrates matter on its own, too.
On a zero carbohydrate diet that was almost hypocaloric, T three levels dropped by almost half, while including at least fifty grams of carbohydrates a day prevented that drop. And why does this matter? Because eating more and especially eating more carbohydrates, it changes thyroid hormone metabolism. In classic overfeeding studies, three weeks of extra calories raise production of active thyroid hormone T3. By roughly 70 to 80%, whether the extra calories came from carbs, fats, or protein. And carbohydrates matter specifically on their own, too. On a zero-carbohydrate diet that was hypocaloric, T3 levels dropped by almost half. While including at least 50 grams of carbs, though, it prevented that drop from happening. And T3 is a major regulator of LDL clearance.
It switches on liver LDL receptors, which is why people with an underactive thyroid tend to have higher LDL. And to be fair, the LMHR researchers see this as well, and they recognize this, but they actually read it as support for their model. In a study of lean women on keto, free T3 was one of the strongest predictors of how much LDL changed. And in their cholesterol drop experiment, five days of eating far more on a keto diet, including more saturated fat, lowered LDL and APO B, while under eating raised them. Their argument is that thyroid hormone and calorie intake are signals of energy status, which is the lipid energy model's whole point. But when talking about T3, T3 works largely by increasing LDL clearance. And so, when we consider insulin from the carbohydrates, the possible clearance effects of ketone supplements, and the thyroid shift from extra calories from carbs.
It's kind of hard to tell what's going on. The cookie experiment contains several mechanisms that could potentially lower LDL through clearance, not just through less VLDL production. And so that doesn't prove the Lipid energy model is wrong. It just means with this experiment, we can't tell the two explanations apart. So, how do we actually resolve the debate between energy trafficking and receptor clearance? Well, there's one definitive scientific test we could do, and that's a stable isotope kinetic tracer. And we could do this by infusing labeled amino acids like leucine into LMHR individuals. And from here, researchers could directly calculate the true production rate of VLDL out of the liver and the exact fractional catabolic rate of LDL clearance from the blood. But until those tracer kinetics are compared, the lipid energy model remains an intriguing but unproven hypothesis. However, this is an incredibly expensive experiment to perform.
And there's not a lot of money in this outcome, right? It's just looking at a small group of people. So I'm not super hopeful that we'll ever get the study. I hope we do. That'd be amazing, but we probably won't, just to be honest. So, the most likely scenario, though, is that we're just going to continue to have arguments on the internet, as that seems to be everybody's favorite pastime. So, to wrap things up, let's go through what we learned from these two papers. Number one, the LMHR phenotype seems to be a distinct real metabolic presentation. However, it's worth noting that it seems like the cutoffs of triglyceride, HDL, and LDL seem to be a little bit arbitrary, as well. I should mention that.
Number two, it seems that carbohydrate flux can dynamically manipulate LDL in these individuals. And number three, however intriguing as it is, and it most certainly is intriguing, lowering LDL with carbohydrates does not necessarily prove the lipid energy model here. It offers potential theories and explanations, but nothing from the study has actually been proven. It's all theoretical in nature. It's still really cool, I enjoy it, but we can't get out ahead of ourselves here. And also, it's worth mentioning that the authors of these studies caution that diet-induced Apo-B elevation, quote, should not be assumed to be benign, close quote, which is a helpful statement given the excitement around these papers. However, that brings us to the ultimate clinical dilemma.
If your blood sugar is perfect, your systemic inflammation is rock bottom and your blood vessels appear healthy, does having an LDL of 400 mg per second liter accelerate coronary plaque over time? That question sits at the center of the most controversial cardiologist study in recent history, the keto-CTA trial. And that study is so complex and so fiercely contested that we'll be breaking it down from every angle in the next video. All right, that's going to do it for our podcast today. At least that's the video version of it here. You know, what do I think about all this? Well, you know, as I go, I'm kind of just trying to be a little neutral here, so I'm not saying too much.
I think the video kind of explained it that this is cool, I think it's interesting. Uh, but it doesn't prove a darn thing, unfortunately. You know, you'll see people online saying, Oh, this proves that. Like, no, it doesn't, man. It proves that the LDL went down, is what it proves. You know, with Oreos, it went down, and this Levin's hypersonter could be real, it could be, it could be, but we don't know. And you know, that's the thing.
Will we ever know? Because there's not a lot of money in this, and so it's going to be challenging. But yeah, that's kind of where it's at. But once again, thank you so much for listening. If you're on the audio version, you get a little extended take on the front and back, just because I think. People who are listening. They're just, you know, bigger nerds like me. And that's how I appreciate y'all. So I want to give you a little more insight into what my brain's thinking.
But that's going to do it for today. Thank you so much for stopping by. If you found this helpful with me in the world, if you share this with someone you know, but that's going to be it for today. Now get off your phone, get outside, and we'll see you next time.
