Tom Dayspring, M.D., FACP, FNLA – Part III of V: HDL, reverse cholesterol transport, CETP inhibitors, and apolipoproteins

**Peter Attia** (0:04)
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Welcome, everybody, to episode three of The Week of Dayspring. In this episode, we talk about reverse cholesterol transport, we talk about lipid transportation, we talk about apolipoproteins, and we talk about CTEP inhibitors and HDL. Of all the things we talk about here, the thing that I think is the most interesting is the discussion on HDL, which I think most people today would agree is far from being understood and is probably far more complicated than LDL biology. I would say that of all of the things that Tom and I discussed over this seven hours, I learned the most personally in our HDL discussion and our discussion of the CTEP inhibitors. I was very familiar with all of the trials here, but Tom brought a level of nuance to this that actually sharpened my understanding of this, and for that I am, of course, eternally grateful. So welcome to episode three.
Let's define now direct versus indirect RCT.

**Thomas Dayspring** (1:45)
So if we're talking about the cholesterol, it's in lipoproteins. So at the end of the day, if you have perfect cholesterol homeostasis, if for some reason there's some cholesterol excess in your body, it's gonna wind up in your artery wall, or if you're lucky, it's gonna wind up in your stool. That would be the preferent way. So the body clearly knows beyond a certain point, we don't want cholesterol. We've talked about that at a bit of length so far. So now how can the body get rid of cholesterol that's already inside? It's made by cells.
And everybody thinks the liver makes most of the cholesterol. Liver may, we're not talking about the brain now. That's separate. Of your, rest of your cholesterol in your body, the liver makes 20% of it. The rest is made in your peripheral cells. So the bulk of your cholesterol that's in your body, if your peripheral cells are making too much, it's gotta get out or that cell will die. So the cells through, even beyond ABCA1, E-flux that we've talked about, they can free the fuse out of there. There's another ABC transporter that can pump cholesterol out. And it gets in a lipoprotein or it binds to albumin or binds to a red blood cell and it can be taken elsewhere.
So classically, we were taught that the HDL particles are definitely a substrate that a cell can E-flux cholesterol out into, especially in empty HDL. APOA1, the protein itself, that's un-lipidated or a real baby HDL particle, very small HDL particle, is a great cholesterol acceptor. And we have membrane transporters that can give them free cholesterol.
All right, so now the HDL has cholesterol, and what were we taught? Well, of course, the HDL just brings it right back to the liver, and the liver then will, if it has a need for cholesterol, it will use it up, and then it will put it in your bile. It will go down, it will go right out your rear end.
Or your liver can actually change it to a bile cell, which it sends down the bile, and your bile cell could be excreted in the stool. So in fact, that's a way, it's a major way of getting rid of cholesterol. But Aurelium doesn't cooperate. Aurelium typically reabsorbs about 90 to 95% of the bile salts and reuses them, so it's not the best way unless you can make sure that bile salt is being excreted. And we have a drug, the bile ester sequestrin, that makes sure that happens, then you would deplete internal cholesterol. So that's so simple. So our VLDLs and LDLs and collomicrons bring cholesterol to the tissues, and if for some reason there's too much cholesterol, the HDLs bring it back to the liver, and it goes bye-bye.
If you're talking to a second grader or physician at one point in our careers, that made great sense. That's plausible, that's perfect. That's why HDLs are not delivering cholesterol to the artery wall. They're bringing it back to an organ that's going to get rid of it or use it properly. Perfect. And if the other, the VLDLs, Kylo's and LDLs are bringing cholesterol to the tissues, they never called it that, but I would say, well, that's forward cholesterol transport. And if the HDLs are bringing it back, that's reverse. Perfect. And if we have a great balance between forward and reverse cholesterol transport, that's good cholesterol homeostasis. You're not going to get in trouble.