Transcription
Welcome back to Dirty Medicine's Dirty Biochemistry series. In this video, we're going to cover the third and final part of lipid transport.
If you've been watching the first two parts of lipid transport, and I hope that you have because we're building upon each previous video, then you probably already have a great understanding of how lipid transport progresses through the body. Where we left off was on this slide. To briefly summarize, the chylomicron had moved from the intestine into the lymph. It had then moved from the lymph into the systemic circulation. HDL came along and loaded the chylomicron with Apo C2 and Apo E. The chylomicron already had Apo B48 on it, and in the previous video, we discussed the role of each of those apolipoproteins individually, and I gave you guys a really awesome mnemonic for each of them to help you remember their high-yield function. Then the chylomicron left the systemic circulation and went into the liver in the form of a chylomicron remnant, depicted on this slide. The big purple chylomicron turns into the small chylomicron remnant down here with that small purple circle. In the liver, that is a very quick and very rough summary of where we've left off so far in lipid transport. We're going to pick up the pathway from this point onward.
Part three in this video will discuss the important, high-yield, two remaining apolipoproteins, as well as where lipid transport goes once the chylomicron remnants into the liver. Now, as the chylomicrons turn into their remnants and go into the liver, there's this dynamic process. Since that this dynamic process that's taking place where additional lipoproteins are actually secreted by the liver. The first piece that's going to come out of the liver is called very low-density lipoprotein. This is referred to in question banks and review textbooks as VLDL. On this slide and in this series, VLDL will be depicted as a pink square. Now, inside a VLDL, you have triglycerides and cholesterol. So, this is another lipoprotein that's just carrying lipids. The VLDL has a unique apolipoprotein that sits on its shell, if you will, and that apolipoprotein is ApoB100. Now, I'm not going to tell you right now what ApoB100 does because I need to continue to show you the biochemical pathway here, and then we'll come back to ApoB100 and discuss its function, and of course, I'll give you an awesome mnemonic to help you memorize its high-yield function.
So, if I can sort of take the liver and the VLDL, we're going to start from this part of the pathway. So, forget everything that happened in the first two parts with the chylomicrons. What I want you to focus on now are the details of what happens when the liver secretes VLDL. So, again, VLDL comes out, it's got triglycerides and cholesterol inside of it, and it has ApoB100 on its shell. Now, as VLDL progresses through this pathway, HDL comes along once again. In the previous video, we saw that HDL is an extremely important part of this pathway, and the reason that it is so important, and the reason that it's referred to as the "quote good fat," is because it's loading different pieces of this lipid biochemistry with ApoE and ApoC2. I've discussed all of this in the previous video, so watch that again if you need a refresher. But just like it did this in the previous video, HDL is also going to load these apolipoproteins onto the VLDL. So, as you see here on this slide, ApoE shown in our mucus color and ApoC2 shown in the reddish color are going to be loaded by HDL onto VLDL. So, they're going to appear on VLDL.
Now, at this point, the VLDL has three apolipoproteins on it, right? It has the ApoB100, which I'm going to tell you about in a little bit, and it has ApoE and ApoC2. And recall from the previous video that the role of ApoC2 is to activate LPL to hydrolyze and convert triglycerides to fatty acids for absorption. So, that's going to be happening here, just like other pieces in this pathway that we've seen. The ApoC2 on the VLDL carries the same exact function. Now, once that's happening, VLDL is going to is going to convert itself into something called IDL. So, this is an intermediate-density lipoprotein. So, we had very low-density lipoprotein, VLDL, and now we have the intermediate-density lipoprotein. So, the only thing that's really changing in terms of the naming convention is the density of these different lipoproteins. So, now we have IDL. And an IDL retains the ApoE that was put onto its predecessor, VLDL, and it retains the ApoB100 that was already on its predecessor. The LDL and ApoC2 is doing its job by activating LPL and converting the triglycerides into fatty acids. So, for the purposes of this discussion and to simplify this pathway, VLDL turns into IDL, and now it has ApoE and ApoB100 on its shell.
Now, at this point, the IDL can enter the liver. And what doesn't enter the liver will be converted into the next lipoprotein, which is known as LDL. This is low-density lipoprotein. Now, LDL is also known as the "bad cholesterol" or the "bad fat," and you'll soon see why. In the Dirty Medicine Biochemistry, Dirty Biochemistry series, LDL will be depicted by this small green square. So, IDL can either enter the liver or be converted directly into LDL. And a little bit of the LDL can actually come out of the liver itself. In either scenario, the ApoB100 will still be on the LDL. Now, recall that that ApoB100 was on the IDL before it, and the VLDL before that. So, there's obviously an important role for this ApoB100 because it's being, you know, retained as VLDL converts to IDL, and it's IDL converts to LDL. So, what that B100 actually mediates is the attachment of LDL to the LDL receptor. And that LDL receptor is what allows the LDL to undergo endocytosis into peripheral cells.
So, if we can sort of clip LDL out of the slide and put it next to a peripheral cell, this is what I'm referring to. So, you have LDL, also known as the "bad cholesterol" or the "bad fat," and cholesterol is really not a problem until it gets into certain cells. So, if on the right, you have this circular peripheral cell, the only way that LDL can get into that cell is for it to interact with the LDL receptor, right? There has to be a receptor on the surface of the cell that binds to the LDL, hence the name LDL receptor. Now, the way that the LDL receptor recognizes the LDL is by recognizing ApoB100. So, ApoB100 is what is recognized by the LDL receptor. So, if these two parallel blue lines represent the LDL receptor, then it's ApoB100 that's sort of acting like the key that fits nicely into that LDL receptor and informs the peripheral cell, "Hey, my name is LDL, I'm here to be inside of you." Sounds funny, but that's exactly how it works. So, when this happens, you have endocytosis of LDL into this peripheral cell, and now LDL with its little ApoB100 hat is sitting inside of the peripheral cell. And this is the process whereby triglycerides and cholesterol arrive at peripheral cells from the liver. So, recall that the LDL came from the liver, where it was converted from IDL, which also went to the liver. So, really, these triglycerides and this cholesterol are coming from the liver, and they're going to peripheral cells because LDL, the carrier, is going undergoing endocytosis into the peripheral cells. So, that's the reason that LDL is the "bad fat" because it's taking triglycerides and cholesterol from the liver where they're stored, and it's putting them into the peripheral cells, and this is where LDL can be really harmful and cause disease.
Okay, so let's pause for a second and take a step back and appreciate the big picture. We talked about that VLDL is converted to IDL. IDL either enters the liver and then becomes LDL, or is directly converted to LDL. In either case, as this whole transformation of VLDL to IDL to the liver to LDL takes place, all of those products retain this ApoB100 hat. So, the high-yield summary here is that if you see ApoB100, you should know that it mediates the ultimate entry of LDL into peripheral cells. So, LDL comes from the liver and gets into peripheral cells and brings with it triglycerides, cholesterol, fat from the liver into peripheral cells because ApoB100 interacts with the LDL receptor. That is the big takeaway point here that you absolutely need to know. It's incredibly high-yield.
So, the way that you should remember this and the Dirty Medicine mnemonic is that ApoB100 makes you gain 100 pounds. Right? So, ApoB100 is what puts the fat from your liver into the peripheral cells and makes you fat, right? It puts cholesterol and triglycerides and lipids, etc., all those buzzwords that all mean fat. It goes from the liver into your peripheral cells, and that's what makes you gain 100 pounds. So, ApoB100, again, just to really hammer this home, is what interacts with the LDL receptor and causes endocytosis of LDL along with its stored lipid content into peripheral cells. So, ApoB100 makes you gain 100 pounds.
Here's the slide that we had in the previous video. We had already spoken about ApoB48, ApoC2, and ApoE. Their function is listed on this slide, as well as the Dirty Medicine mnemonic. See the previous video if you need more information or a brief refresher. But now let's update this slide and add ApoB100. So, again, the function of ApoB100 is that it binds the LDL receptor for endocytosis into the peripheral cells. And the mnemonic here, our Dirty Medicine awesome mnemonic, is that ApoB100 makes you gain 100 pounds. And the reason that it does this is because ApoB100 is what interacts with the LDL receptor to allow LDL and all of its associated fat content to get into the peripheral cells.
Now, there's one more apolipoprotein that we need to cover, which we'll fill in the last row on this slide. And in order to really appreciate the function of that next apolipoprotein, we have to talk about the activation of HDL. So, recall from the previous video and even the beginning of this video that HDL is known as the "good cholesterol." The reason that it's the "good cholesterol" is because it has ApoE and ApoC2 sitting on its shell, and what it does is it carries ApoE and ApoC2 and loads it onto different players in this pathway, allowing them to be re-uptaken. That's what ApoE does. And through ApoC2, to cleave triglycerides into fatty acids for absorption. Now, these functions are crucial to the normal physiology of our human bodies, and without them, we would have a ton of disease. So, HDL is very important.
Now, what happens here is that before HDL is formed in its final form that you see here on this slide, it's actually first secreted from the liver and the small intestine in what is called nascent HDL form. So, but this basically means is that it's like baby HDL, right? It's the precursor to HDL that's not yet activated into full-blown mature HDL. And when I use the word mature HDL, I'm really just referring to the HDL that we've already talked about, right? The final product that has the ApoE and ApoC2 on it, donating those apolipoproteins to players in this lipid transport pathway. So, when you see this slide and you see the small HDL, what that really means is mature HDL. But before you get mature HDL, you get nascent HDL, so immature or baby HDL. And there's a very high-yield enzyme that activates or converts nascent HDL into mature, regular HDL. And that enzyme is called lecithin-cholesterol acyltransferase, also known as LCAT.
Now, the final lipoprotein, apolipoprotein, that we need to talk about is what is known as ApoA1. And the reason that ApoA1 is so high-yield and so important to understand is because it is actually the apolipoprotein that activates LCAT. So, ApoA1 comes along and activates lecithin-cholesterol acyltransferase, also known as LCAT. Which is to say that ApoA1 is what mediates the conversion of immature HDL into mature HDL. So, without ApoA1, you never get HDL. So, you never get the "good cholesterol" that loads ApoE and ApoC2 onto the various players in this lipid transport pathway. So, as I'm sure you can see by looking at this slide, ApoA1 is really freakin' important, right? Without it, you cannot get the good cholesterol. You use ApoE and ApoC2 because without ApoA1, you would never form the mature HDL.
So, what is the Dirty Medicine mnemonic for remembering this important pathway? Well, the way that you should remember this is by looking at the letter A, because ApoA1 is the only Apo that has an A in the name. So, the way that I remember this is that ApoA1 activates awesome fat, which activates awesome fat. Awesome because HDL is that awesome or the good fat. So, A for activates, A for awesome. Remember that A for A1 activates awesome fat. So, it activates the fat that is the good fat, which is to say that it activates HDL by working on the LCAT. Okay, so that's what ApoA1 does. And if we fill in this chart for completeness' sake, we've now touched on the five high-yield apolipoproteins. Again, remember that ApoA1 activates LCAT to convert nascent HDL into mature HDL. In the Dirty Medicine mnemonic is that ApoA1 activates awesome fat. ApoB100, we already talked about in this video. ApoB100 makes you gain 100 pounds because ApoB100 is what mediates the endocytosis of LDL, or the "bad cholesterol," into peripheral cells. So, it makes you fatter.
The last thing that I want to touch on before we conclude this video is one really high-yield differentiating point that's really easy for medical students to mix up. So, it's incredibly important to understand that LDL is taking the cholesterol from the liver to the periphery, which is to say that it goes from the liver to the peripheral cells in the body. But HDL is taking the cholesterol from the peripheral cells and bringing it back to the liver. So, the HDL, in addition to loading ApoE and ApoC2 onto various players in this pathway, is actually sucking up some of the fat, some of the cholesterol that is existing in your peripheral cells and putting it in the liver so that it doesn't damage your cells. So, that's why HDL, in addition to all the reasons that we've already talked about, is the "good fat," and LDL is the "bad fat" because it's taking the fat out of the liver and putting it in the periphery where it really should not build up too much. The way that I remember this is that HDL is hepatic delivery. So, H delivers those fats to the liver. So, hepatic delivery, H and hepatic D and L and delivery. So, HDL is where the fat undergoes hepatic delivery. So, make sure you understand that HDL is from periphery to liver, and that LDL is from liver to periphery. That point can be confused very easily if you overlook some details here.
But guys and gals, that's it for lipid transport. We've now touched on a very high-yield pathway that's very complex and it's very confusing because it's got all these different apolipoproteins, it's got all of these different pieces that all sound the same, right? VLDL sounds like IDL, sounds like LDL, sounds like HDL. There's a lot of D's, a lot of L's. You know, you have to understand the fine points here. But if you conclude each video by looking at my summary slides, understanding some differences, keeping the big picture in mind, and remembering my Dirty Medicine mnemonics, I think that you'll get most of your points correct on test day.