In this video, Nick Norwitz explains a newly discovered gut‑derived hormone, cholecin, that mediates a feedback loop between dietary cholesterol intake and hepatic cholesterol synthesis. He walks through data from a recent Cell paper showing that dietary cholesterol binds the intestinal NPC1L1 transporter, triggering cholecin release from enterocytes. Cholecin travels to the liver, binds the G‑protein‑coupled receptor GPR146, and suppresses the PKA‑ERK1/2‑SREBP2 signaling cascade, thereby reducing expression of cholesterol‑synthesizing enzymes such as HMG‑CoA reductase. Human cohort analyses reveal that genetic variants that lower cholecin levels or impair GPR146 are associated with higher LDL and total cholesterol, confirming relevance to humans. Norwitz then discusses how existing lipid‑lowering drugs (statins, PCSK9 inhibitors, ezetimibe) intersect with this pathway, highlighting that ezetimibe’s blockade of NPC1L1 also prevents cholecin release, potentially blunting its efficacy. He speculates that co‑administration of cholecin with ezetimibe could provide a “double‑hit” by reducing both absorption and synthesis. Throughout, he emphasizes scientific curiosity, the novelty of the mechanism, and the broader lesson that many physiological processes remain incompletely understood.
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Eating eggs does not increase cholesterol. You may even know this. It's actually becoming common knowledge, which I think is a good thing. But ask yourself, how? Why? What's the mechanism? Now, while you might think that even if you don't know the mechanism, science must have it figured out, turns out we don't, or we didn't. What I wanna do in this video is go over data from a brand new paper in a top journal, Cell, that explains the mechanism by which eating cholesterol leads to downregulation of cholesterol production in the liver. And if you don't eat cholesterol, your liver will just make more. It focuses on a newly discovered hormone called wait for it, cholecin, which is named for cholesterol inhibitor, inhibits cholesterol production by the liver. So it's actually kind of a clever name. The paper was published in Cell. It's entitled A Gut-Derived Hormone Regulates Cholesterol Metabolism. I'm going to go through this paper in this video, and by the end of this video, you're going to understand better than any of your friends why eating eggs doesn't increase cholesterol. Welcome to my channel, stay curious. So I want to dig into the data and mechanisms straight away. In this paper, as I said, they identify a new hormone, cholecin, which stands for cholesterol inhibitor, cholesterol synthesis inhibitor, because it's inhibiting cholesterol synthesis at the liver. And cholecin is released in response to dietary cholesterol. So you see that here, B is mice and C is humans. And when you go from the fasted state to the re-fed state, re-fed being a diet including cholesterol, what you see is cholecin levels rise in response to the dietary cholesterol. And then it's going to the liver and inhibiting cholesterol synthesis in order to maintain a cholesterol homeostasis. And if you eat less cholesterol or eat no cholesterol, then cholecin levels will stay low and you won't inhibit synthesis of cholesterol in the liver, and again, in order to maintain a cholesterol homeostasis. Now I want to kind of skip to the end and just show you the overarching picture, the mechanism, because this is really the takeaway, and then we'll zoom back and talk about a medication and implications. So this is the summative diagram. What happens is cholesterol binds to what's called the Niemann-Pick type C1-like-1 transporter or sensor. This is a transporter for cholesterol. It's how you absorb cholesterol, and it's a sensor insofar as that when cholesterol binds to it and then gets absorbed, cholecin is released from the gut cells labeled enterocytes here. And then cholecin goes to liver cells and binds to a protein on the liver cell surface, the GPR146, shown here in pink, and that inhibits a pathway downstream that controls cholesterol synthesis, the PKA-ERK1/2-SREBP2 pathway. SREBP2 being master regulator of cholesterol synthesis. So by inhibiting SREBP2 activity, you're decreasing levels of things like HMG-CoA reductase and preventing cholesterol synthesis. So again, high level: cholesterol binds to the Niemann-Pick transporter sensor, cholecin is released, cholecin inhibits SREBP2 via this binding to this protein GPR146, and that decreases cholesterol synthesis enzymes. By contrast, if there isn't cholesterol, cholecin isn't released, and this cholesterol synthesis pathway in the liver is more upregulated, so you do synthesize and secrete cholesterol. And again, in order to maintain a cholesterol homeostasis. If that all sounded like mumbo jumbo, pause, rewind, and listen to it again, 'cause it all makes sense, but I realize there's a lot of abbreviations and jargon, but I did want to break down this diagram, this mechanism, because it's actually pretty linear and succinct and clearly shows how cholesterol absorption inhibits is cholesterol synthesis. So if you then eat less cholesterol and are absorbing less, you have more cholesterol synthesis, again maintaining a cholesterol homeostasis. That's the point. The body is smart. Eat more cholesterol, make less. Eat less cholesterol, make more in the liver, right? So what is the relevance to humans? Well, they already showed some human data showing that eating cholesterol increases cholecin, and data in mouse models to suggest that this is the mechanism. So it would presumably be relevant to humans. But they go a step further, doing some cohort genetic analyses, and actually look at, okay, are there variations in the cholecin gene or the cholecin encoding gene, and also the receptor, the GPR146. Are there variations in humans, and does that correlate with changes in cholesterol levels? And indeed it does. So what I'm showing you here is genetic variants in the cholecin encoding gene, GG versus GA versus AA, just different nucleotide combinations. And what you see is, yeah, so with variations, the GG leading to lower cholecin levels, there are higher total cholesterol and higher LDL levels. And if there are variations with higher cholecin levels, then LDL tends to be lower. Now, there wasn't an effect on HDL, just to have that be clear. But basically, variations in cholecin and the receptor do correlate to changes in total and LDL cholesterol, making a further case for the relevance in humans. But now I want to take it from genes to pharmacotherapy, because I think that's what a lot of people like to think about. Now, just to be clear, I'm not advocating for or against pharmacotherapy. This is just a mechanistic exercise, I think, for how we think about these pathways and how we can manipulate them to change levels of a marker. I'm not saying it's desirable, I'm just saying we can based on understanding of the physiology. So there are several classes of drugs for modulating LDL levels. You know, the statins— statins inhibit HMG-CoA reductase, the cholesterol synthesizing enzyme in the liver, and then there's a compensatory upregulation in the LDL receptor which pulls LDL out of the serum. PCSK9 inhibitors also ultimately work by increasing LDL receptors. Um, they inhibit a protein called PCSK9, and that causes an increase in LDL receptors, which again pull cholesterol out of the serum. And then there's another class, or another drug, ezetimibe— goes by Zetia— which you may have heard of. And the way that works is it blocks cholesterol absorption in the gut, either from dietary cholesterol or from cholesterol that your body actually released in the bile. So again, ezetimibe blocks cholesterol absorption. How does it do it? Well, it blocks the Niemann-Pick type C1-like 1 protein, the transporter that we already introduced as a sensor for cholesterol and the thing that absorbs cholesterol, and also the sensor that causes cholecin release. So pause for a second, you can literally pause the video and think about the consequences of that. If we understand this pathway whereby cholesterol binds the Niemann- protein, cholecin is released, and that causes an inhibition of cholesterol synthesis. If we don't have cholecin, then cholesterol synthesis is upregulated. What happens if you block the Niemann-Pick type C1-like 1 transporter? Well, you're going to get less cholesterol absorption, which is how ezetimibe works, but you're also going to get less cholecin released. So there's going to be a relatively increased level of cholesterol synthesis in the liver for whatever cholesterol you're absorbing because it's not being sensed by the Niemann-Pick type C1-like 1 transporter, the sensor. So this happens clinically and is one of the reasons, probably, why ezetimibe doesn't have that big an effect in most people. There are exceptions, we can talk about lean mass hyperresponders maybe in another video. I have other thoughts about that. But basically what happens is there's a compensation. Your body's trying to fight back against the medication. With medications causing decreased cholesterol absorption, but at the same time you're not getting the stimulus for cholesterin release. So you're not putting the brakes on synthesis of cholesterol in the liver. In fact, you're removing the brake off of it by not having cholecin release. So as a result, when you take ezetimibe, there can be compensatory increases in cholesterol synthesis in the liver, decreasing the effect size of that medication. But now think, with this new discovery, with the understanding of cholecin, what if— again, not saying desirable, undesirable, I'm just saying mechanistically— the consequence of giving a patient Zetia, giving a patient ezetimibe with cholecin, is interesting? Because then what you're doing is you're taking this medication, ezetimibe, which can decrease cholesterol absorption and ultimately lead to LDL lowering in the serum, and you are sweeping the legs from underneath the compensatory mechanism by giving cholecin. Because normally ezetimibe prevents cholesterol absorption, prevents cholecin release, so cholesterol synthesis in the liver is upregulated. But if you add that cholecin, then that is downregulated. Then you have decreased cholesterol absorption and decreased synthesis in the liver. So a one-two punch to cholesterol levels. Again, not saying desirable or undesirable, I'm just saying it would work. And as a scientist, I find understanding the physiology and even just speculating through this mental exercise about how we could affect biology, how we could intervene as humans onto biology, I find that really fascinating. I hope you do too. I know I'm gonna get a lot of trolly comments either way. Nick, why would you want to lower LDL? Nick, how dare you suggest that lowering LDL is not optimal? Look, I'm not here to give you life advice. I'm not your physician. I'm just here to explain the science. I found this interesting, and now you definitely do know better than all of your friends have how or why eating an egg does not increase your cholesterol. It's the hormone cholecin, and I find it pretty fascinating, just because I find it fascinating. And also I kind of find it fascinating that only now in 2024 are we really understanding thoroughly why eating cholesterol doesn't increase your cholesterol. So I think it's important to step back and appreciate a lot of those things we take for granted as lay individuals or individuals who just aren't expert in a certain area. I certainly thought before this paper came out, scientists must know how this works. I just actually haven't spent the time to dig into the exact mechanism upon reflecting. And then a paper comes out, I'm like, wow, actually we didn't really fully understand. And now we are completing the puzzle. There is so much in science that we don't understand. So, so much more than we do understand. And the more you learn, the more you appreciate that fact. And I think that's pretty cool. I hope you do too.
