Dimethylallyl pyrophosphate

Transcription

Kevin Ahern: Okay folks, let's get started. [class murmuring] Day before the exam. At least the class day before the exam, you know? Let's see. So I am doing a review session tonight at 7:30 and that will be at ALS 4001. I will videotape that and I will get the video posted as quickly as I can. That's one. Number two, the material for the second exam starts here. So everything I'll talk about today will be on the second exam, and since we're a little behind then the second exam's probably going to have more material on it than the first exam. So be aware of that. Think ahead. And, that's basically where we are. So, I want to spend some time now, we're going to go back and start talking about metabolism. Metabolism, of course, the biosynthetic pathways. We've seen now how all the energy considerations are done with respect to respiration and so now we're going to see how that energy is used to make molecules. And how we make them and how we break them down. For today's lecture almost everything I'll be talking about is how we make them. We don't spend a lot of time talking about breaking down of the molecules that you will see today. We've talked about glycerophospholipids and we've also talked about fat. And it's important to understand a bit of their metabolism. So if we think about, that's a little bit loud, glycerophospholipid biosynthesis, not surprisingly the starting molecule is a molecule of glycerols, specifically it's a molecule of glycerol-3-phosphate. And glycerol-3-phosphate gets two fatty acids put onto it. Usually the first fatty acid at the top is saturated and usually the second fatty acid is unsaturated although that's not an absolute thing, but that's a general tendency for the fatty acids. And the third position of course is occupied by the phosphate that we saw here. The molecule you see on the screen at the bottom is called phosphatidate, or as you're more likely to call it probably phosphatidic acid. Phosphatidic acid is an important intermediate in the synthesis of the phosphatidyl compounds which I'll show you in a minute, and also for making fat. So if we want to take phosphatidic acid and make fat we need to clip that phosphate off from this structure here. And then we put the third fatty acid onto there and that creates a fat. And that's actually shown here. Phosphatidate cleaves the phosphates off. We then have a hydroxyl here. That gives us diacylglycerol. You've seen that before. And we take that third fatty acid, put it on that position and we have a triacylglycerol. And a triacylglycerol is the same thing as fat. And by the way, I think I've said it before but I'll say it again. The difference between a fat and an oil is simply the fact that an oil is liquid at room temperature and a fat is solid at room temperature. So that's really the only characteristic difference between them. Student: [inaudible] Kevin Ahern: I'm sorry? Student: Do we need enzymes [inaudible] Kevin Ahern: I did not give you any enzymes and when I don't give you enzymes I'm not expecting you to know them. Now, I'm going to talk about the synthesis of some glycerophospholipids, some phosphatidyl compounds. And you'll see that there's a fair amount of information here. And again I want you to see big picture on these. The big picture is that we have starting molecules like phosphatidic acid and we attach various things out here to the phosphate on the side. As I noted earlier on the last one I'm not expecting you to know enzymes for this, but just big picture. If I were to make a CDP-diacylglycerol, for example, how would I make it? Well this guy right here turns out to be an important intermediate in the synthesis of glycerophospholipids because, and you might begin to see the pattern here, it is an activated intermediate. An activated intermediate you remember is a molecule that has a high energy bond and it uses the energy of that bond to give a part of itself to something else, or attach a part of itself to something else. So we're going to see this CDP-diacylglycerol is used to make the phosphatidyl compounds, and that's coming up. That's a nice structure. If we were to take CDP-diacylglycerol and swap out the CDP for inositol, we would make phosphatidylinositol. And then, again, here is that activated intermediate that is using the energy of this bond right here to transfer a part of itself, which is this black part over here to this green guy over here. The result of that is we're making a phosphatidylinositol and this is the root molecule we talked about. We talked about about PIP2, PIP3, and so forth. This is PIP. Actually it's not even PIP because it doesn't have a phosphate on it but it's phosphatidylinositol. If we put phosphates onto any of these OH's out here we would create PIP, phosphatidylinositol phosphate. And PIP, you may remember, was used for signalling. Now in the process of making this you'll notice that one of the phosphates of the CDP-diacylglycerol is left behind. That means that what clips off is actually CMP, cytosine monophosphate, and this pattern is very common that we use for synthesizing all of the various phosphatidyl compounds. Here is diphosphatidylglycerol. It's kind of an odd one. And we can see over here, here's that phosphatidyl part with a phosphate. Yet over here is also a phosphatidyl with a phosphate. That's the diphosphatidyl part. And in the middle is a glycerol. Now this is a rather unusual compound and it's also called cardiolipin which tells us a little bit about where we find it. This unusual glycerophospholipid is actually found predominantly in heart tissue. Now, there are other pathways that we can use to synthesize phosphatidyl compounds, and you can see some of them on the screen. For example, if I wanted to make a phosphatidylethanolamine I would do it by this pathway here. Again, don't sweat the details too much. We're simply making an activated intermediate here, phosphorylethanolamine, alright? And then we're taking that compound and combining it with CTP to make a CDP. And then, let's see here we go. I have a figure for that. So here's our ethanolamine. Here's phosphorylethanolamine, so we're making an activated intermediate. There's that high energy bond right here. This is CDP-ethanolamine. We swap out the CDP. In this case we're putting a diacylglycerol on it and making phosphatidylethanolamine. So we can do that activated intermediate in two ways. One is we can link the CDP to the phosphatidyl part and then transfer the phosphatidyl part to something else, or as you see here, we can take and link the thing that's going to be attached to the phosphatidyl part, in this case ethanolamine, and we create an activated intermediate that transfers the ethanolamine to the diacylglycerol. The net product is the same. Now I'm not expecting you're going to go say which ones go with the activated intermediate with CDP first, and which ones go with the other one first. That's not the important thing. The important thing is that we're using activated intermediates in the process of synthesizing phosphatidyl compounds, and for our purposes we will just think about them as we can link the CDP to the phosphatidyl compound or we can link it to the other one. The net result is we get a phosphatidyl compound. So this is how we making phosphatidylethanolamine. That's how we make phosphatidylserine. That's how we make phosphatidyl-you-name-it. There will always be an activated intermediate involved in that process. Now I'd also like to sort of stop and think at this point about some important considerations relative to nucleotides because you've now seen nucleotides being involved as activated intermediates in a couple of ways. You've seen it-UDP-glucose for example was an activated intermediate. You saw that, here, CDP is used as an activated intermediate. There are other places where ATP actually is used and some places where GTP is used. We're not going to go into those right now but I point out that two major categories of metabolism involve activated intermediates with nucleotides. What this means is that nucleotides are very much necessary and they're also used to measure the pulse of a cell. If we don't have enough CTP we're not going to make glycerophospholipids. If we have an abundance of CTP we very well may be making glycerophospholipids. And that's important because if a cell is to divide it's going to need glycerophospholipids. So just as we thought of the energy needs of a cell with respect to division, ATP for example, so too can we think of the other nucleotides as being necessary for a very important cellular function. When we talk about the phenomena of translation later in the term we'll see that GTP is actually the energy source for translation. So all four nucleotides have very, very intimate and intricate roles in metabolism apart from their being involved in DNA and RNA. So that's a very, very important point when we think about the overall metabolism. And there's phosphatidylcholine. This one's a little bit unusual in the sense that to synthesize phosphatidylcholine we actually start with phosphatidylethanolamine, and the difference between phosphatidylethanolamine and phosphatidylcholine are three methyl groups. You see them up here in green. And the three methyl groups are donated to the molecule by a methyl-donating molecule that's common in the cells known as S-adenosyl methionine or, as you're welcome to call it, SAM. S-A-M. S-adenosyl methionine is a very common donor of methyl groups in metabolic processes. We'll see other ones later. The product of that gives us the methyl groups onto the target molecule and the by-product of that is S-adenosyl homocysteine. If we want to take that S-adenosyl homocysteine and use it again then that means we need to recharge the methyl group back on there so it can be used as a S-adenosyl methionine for something else. So that's basically what I want to say about glycerophospholipid biosynthesis. I'm really not going to say much about glycerophospholipid degradation until I talk about fat metabolism later. Sphingolipids are, as you've seen before, interesting and odd structures. They look rather unusual but as I pointed out to you when I talked about their structure before, I pointed out to you that when we look at them, their shape overall, they don't look very different from a regular phospholipid once they've been made. One of the primary differences we saw in the sphingolipids was that the sphingolipids, A, will frequently have carbohydrates in them. So we saw that, for example, a cerebroside had a single molecule of sugar in it, might be glucose, usually glucose, where as a ganglioside would have a complex mixture of sugars connected to it in an oligosaccharide. And the other difference that we saw with the sphingolipids was that they were usually not present in a phosphorylated state. The prime exception to that was sphingomyelin which I said was a sphingolipid commonly found in neural membranes. Well sphingosine is what we sort of think of as a starting material. It's technically not a starting material but it looks like a starting material so for our purposes we will call it that. How do we get to sphingosine? Sphingosine actually, or at least the sphingolipids that we make, are actually made by combining two very common things that we find in cells. And the two common things that we combine are the amino acid serine and the fatty acid known as palmitic acid. So we put those two together and we can make a sphingosine. Now you'll notice if you look at this equation that we make dihydrosphingosine which is why I said we don't directly make sphingosine but sphingosine looks like it so there's the reaction if you want to go through all the reaction. There's palmitoyl CoA. That's palmitic acid. Plus serine gives us blah blah, blah blah, blah blah. There's the dihydrosphingosine. Again I'm not expecting you're going to know this or know this. If you know sphingosine I'm happy with that. But from sphingosine forward I think you should have an idea about what's happening in the synthesis of these sphingolipids. If I take a dihydrosphingosine or in our case sphingosine and I say, and I add to it a single fatty acid, I create something known as a ceramide, C-E-R-A-M-I-D-E. I think in the highlights from before I've mentioned ceramides but I didn't talk about them in class. Here I'm letting you know what they are and how we make them. So this guy here comes from palmitate-palmitoyl CoA and serine and we make a dihydrosphingosine which gains another fatty acid. When it gains that fatty acid we have a ceramide. A ceramide is really a branch point between the synthesis of a ceramide there, the ceramide here. I'm not speaking very coherently, am I? Ceramides are actually branch points for the synthesis of the other sphingolipids. We can make sphingomyelin from ceramide. We can make a ganglioside from ceramide. We can make a cerebroside from ceramide. So ceramide's a very important branch point for the synthesis of the other sphingolipids. Yes sir? Student: [inaudible] Kevin Ahern: I'm sorry? Student: Is that because the ceramides now have that more reactive carbonyl group? Kevin Ahern: They do have a more reactive carbonyl group that can play a role, yes. Now here's my ceramide. If I take and I put on a, basically a phosphocholine from this process here I make sphingomyelin. If I take the ceramide and I put a glucose on it from UDP-glucose I can make a cerebroside. And if I were to take that cerebroside and add some additional sugars onto that I can make a ganglioside. So again, no enzymes here. We're just talking very simple schematic type of biochemical reactions. This is a schematic representation of a ganglioside. There's our ceramide base. There is a complex oligosaccharide out there. That's glucose, that's galactose. That's neuraminic acid right there. That's galactose. That's N-acetyl galactose. And no I'm not expecting that you're going to be able to draw that so don't sweat it, but you should know obviously that a ganglioside has a complex oligosaccharide present on it. And it varies tremendously from one ganglioside to another. That's a nice picture of lipids in a lysosome. And I won't say more about that. The important thing that I like to point out at this point is that deficiencies in enzymes necessary for breaking down some of the complex sphingolipids that we have, enzymes deficient in breaking those down, so if we have a person who has a genetic disorder where they're missing an enzyme necessary for some of the breakdown of these can have some very severe neurological problems. Tay-Sachs disease is one disease where people who have it are lacking an enzyme that simply takes off, this guy off the end and makes this guy over here. And again I'm not worried if you know GM2 or GM3, that's not really the important thing. But very simple lack of enzymes lead to in some cases severe neurological symptoms. Remember that these are things that are commonly used in brain and neural tissue and so an inability to process them properly leads to abnormal function, or abnormal structure of neurons in brain tissue and can cause some severe problems. So I know I'm moving fairly rapidly through that so I'll slow down a bit and first of all take questions and then move on to cholesterol biosynthesis. So, questions? Nobody wants to think about this until after the exam, right? So again, I want you to look at this as the big picture. I want you to think about it in very general terms and, yes sir? Student: [inaudible] Kevin Ahern: Ceramide, yeah. Student: [inaudible] Kevin Ahern: You don't need to know structures here. You don't need to show me where they're going on the molecule if that's the question. But you should know that to go from a ceramide to a cerebroside that I would need glucose. And I think it would be useful to know that glucose comes from UDP-glucose. But where that's going to be attached on the ceramide, that's not really necessary for our purposes. You like that? Student: [inaudible] Kevin Ahern: Okay, well we don't tend spend a lot of time in biochemistry talking about glycerophospholipid metabolism or sphingolipid metabolism, and they are important, especially as we look at sphingolipid metabolism because as I said there are some very severe neurological problems that are known for people lacking certain enzymes. So it's probably an unfortunate thing but it's not something that we have much time to spend on. What I want to spend some time on though is talking about the synthesis of cholesterol. And I also want to talk about the movement of cholesterol in the body because this, both of these are pretty interesting phenomena. Cholesterol biosynthesis is actually fairly simple. Cholesterol's a fairly complex molecule but what we discover is that in the synthesis of cholesterol we start with very very simple building blocks and we make bigger building blocks that we start assembling. And I'll show you how this goes and you'll see it's not really overly complicated. This shows us the structure of cholesterol. And one of the things that the figure is trying to show you by using the red and the blue is to show you the source of all of the carbons in this molecule. It turns out that all the carbons in this molecule can come from this acetyl group over here. Acetyl CoA is the precursor of the entire cholesterol molecule. We can trace every carbon back to whether it was a methyl carbon or a carbonyl carbon in the original acetyl CoA. So even though this looks pretty hairy, and it is sort of hairy I'll be honest with you, we have very neat and relatively simple ways of putting these together. So let's take a look at how this process occurs. Now we'll come back and we'll talk, you'll actually see this figure later in the term when I talk about the synthesis of ketone bodies because this path overlaps with ketone bodies, but we're going to focus right now on making cholesterol and that means we're going to focus on everything that happens in the top part. We're not going to delve into the stuff in yellow. So if we want to make a cholesterol, how do we get started in the process? The way that we get started is by starting with a four-carbon molecule known as acetoacetyl CoA. How do I get acetoacetyl CoA? Well if I take two acetyl CoA's and I put them together and kick out one of the CoA's I end up with acetoacetyl CoA. So this guy is made originally from two acetyl CoA molecules. So now you can see we're going to add a third acetyl CoA molecule, which is shown in red there, and when we do that we make something that has six carbons. This guy right here with six carbons has a mouthful of a name and you're much more likely to be like me to learn it by its abbreviation, HMG-CoA. Hydroxy-methylglutaryl CoA. Now, the enzyme that catalyzes this process, I'm getting ahead of myself, the enzyme that catalyzes this process is not really important for our purposes. But what is important for our purposes is the next enzyme in the process. The enzyme that converts HMG-CoA into mevalonate you'll notice is doing something kind of funky. There's two NADPH's and NADPH is used commonly to make molecules. It is a source of electrons. So we're going to have to do a reduction in going from HMG-CoA to mevalonate. It's going to take two reductions. That is a total of four electrons to make this happen. And in the process CoA's going to get kicked off. Now this enzyme that catalyzes this reaction is a critically important enzyme for human health consideration. This enzyme is known as HMG-CoA reductase. HMG-CoA reductase. That's one enzyme I definitely expect that you will know. Why do I expect that you will know it? Well for one thing, this enzyme is feedback inhibited. And it's feedback inhibited by the end product of this pathway which is cholesterol. So as your body is making cholesterol, and that's what we're starting here is the process of making cholesterol, if it gets too much and makes too much cholesterol, cholesterol will feedback and inhibit the enzyme and say, "Quit making so much cholesterol." Now this is very important because as we will see the pathway to make cholesterol is very long and it requires a hell of a lot of energy. So we don't want to be making cholesterol if we don't need it, and so as the cholesterol levels start to rise this enzyme gets shut down. Now this enzyme is also critical for another very important purpose, and as you might expect it's a very good target for a drug. So people who have high cholesterol levels that aren't manageable by other means such as diet, and I'll talk about that in a bit, take drugs known as statins, S-T-A-T-I-N-S. And statins inhibit this enzyme. Statins inhibit this enzyme. And they're very effective at turning off this enzyme. You can really change a person's cholesterol levels significantly by treating them with statins. The most commonly used one is called lovastatin, L-O-V-A-S-T-A-T-I-N, and what these drugs do is they mimic HMG-CoA. The enzyme binds to them but it can't do anything with them. If the enzyme gets occupied the enzyme therefore isn't catalyzing and cholesterol biosynthesis goes way down. So statins are competitive inhibitors of this enzyme. They resemble the normal substrate. Now, if we were to talk about this lower pathway, which we will later in the term, we'll see that this pathway going down below also comes from HMG-CoA, and it leads to the synthesis of ketone bodies, and ketones bodies are important energy sources for us when we're very low on glucose. But I'll remind you of that when we get back to that later on. Gesundheit. Now we've gotten to mevalonate. Mevalonate has six carbons. It turns out that the building blocks that are used to make cholesterol actually have five carbons. And schematically we call them isoprenes. Isoprene is not a real molecule, it's a category of molecules. It's a category of molecules that have five carbons that are used to make cholesterol. And by the way, when you hear about steroid synthesis and steroid hormones and that cholesterol is the precursor of those. So this pathway which are known as isoprenoid synthesis is important for making cholesterol and therefore also important for making steroid hormones. So isoprene is a category of molecules. We'll see that there are two isoprenes that are used to make cholesterol. One is isopentenyl pyrophosphate. And no I don't have a better name for that. Oh heck, let's call it IPP. Why not? [class giggling] Let's call it IPP. Did you like that? It sounds like I had a bathroom accident or something, right? [class laughing] It just occurred to me. So isopentenyl pyrophosphate. How do we get there? Well we don't care about how all of these reactions go. We're starting with a six-carbon mevalonate and we're going over here through a decarboxylation ultimately to yield isopentenyl pyrophosphate. Notice this pyrophosphate, PP. We might expect that that is a high energy bond and in fact it is. A lot of the assembly of these molecules involves high energy pyrophosphates that are needed energy sources for the overall process to occur. Look at this. Just to go from mevalonate to IPP we need one, two, three ATP's. And we've only made the first five-carbon intermediate. So making cholesterol costs a lot of energy. The other molecule that we use to make cholesterol is known as dimethylallyl pyrophosphate, and let's just call that DMAPP, D-M-A-P-P. How about that? Dimethylallyl pyrophosphate or DMAPP is made from isopentyl pyrophosphate. It's simply an isomerization that is performed. See we moved that double bond from here over to here. And no, you don't need to know their structures. You do need to know they have five carbons. So we have our two building blocks. These two guys are used to make cholesterol and ultimately all of the steroid hormones. So how do we do this? Here is a rather confusing way of showing this to people. I'm not totally keen on this but I will tell you. Basically what we're doing is we're taking two five-carbon intermediates. We take one IPP and we take one DMAPP, and when we join them together we make a ten-carbon molecule. The ten-carbon molecule is known as geranyl pyrophosphate. This says "either or" and that depends with what you start with. But in the simplest scheme we start with five, one isopentenyl pyrophosphate, one DMAPP, and we end up with one geranyl pyrophosphate. Five carbons plus five carbons gives ten carbons. If we add another five-carbon molecule to that, as shown here in a much better figure, so here's our starting process, a five plus a five giving us a ten. If we add another isopentenyl pyrophosphate to that, five, or ten plus five is going to give us fifteen, and fifteen gives us farnesyl pyrophosphate. If we take farnesyl pyrophosphate, we take two of those and put them together we make a thirty-carbon molecule called squalene. So everything that we have has come ultimately from acetyl CoA molecules and we've made a thirty-carbon linear intermediate. I call it linear because you don't see any rings there yet. You're going to see rings in just a minute. So we've made a thirty-carbon intermediate known as squalene. Squalene is what I describe as the last significant linear intermediate. As we look at that, we convert squalene, now this is kind of cool. Once we've got that guy made we discover that these bonds can be rotated into a form that looks not unlike what cholesterol looks like. We add some reducing power of NADPH again and we make an intermediate that starts to look more like cholesterol. Ultimately it flips into this configuration down here known as lanosterol. Lanosterol is what I describe as the first cyclic intermediate. So squalene is the last linear intermediate, squalene is the first cyclic. These guys are sort of transient in the process. Now lanosterol looks a heck of a lot like cholesterol. It looks a heck of lot like cholesterol and you might think that in fact it would be a very simple case to get to cholesterol, but in fact it takes nineteen steps. Would you like to go through those today? No. We've done enough already today, right? Nineteen steps. So we're going from this guy above to this guy below and you can see some changes. You can see these methyl groups, for example, disappear. You can see there's some changes in the ring out here. There's also a change in the location of this double bond. But for the most part they're relatively structural simple changes but it takes nineteen steps in order to get to that final product of cholesterol. Now that's the synthesis of cholesterol. Questions about that? Everybody's tired, right? A lot of material today? Student: [inaudible] Kevin Ahern: Yeah, why was [inaudible] Was that a comment or question? Oh, your hand was just going like that. Okay how about a song? [class murmuring] I've got a song that covers this process that may help you to learn it. So, it's to the tune of When Johnny Comes Marching Home. It's called To Make a Cholesterol. Lyrics: Some things that you can build with acetyl CoAs Are joined together partly thanks to thiolase They come together 1-2-3 Six carbons known as H-M-G And you're on your way to make a cholesterol. To synthesize a mevalonate in the cell Requires reducing HMG-CoA, as well The enzyme is a reductase Controlled in allosteric ways When the cell's impelled to make a cholesterol. The mevalonate made in metabolic schemes Get decarboxylated down to isoprenes They're built together willy-nil To build a PP-geranyl In the cells' routines to make a cholesterol. A single step links farnesyls but that's not all The squalene rearranges to lanosterol From that there's nineteen steps to go Before the sterol's apropos Which you must recall to make a cholesterol. The regulation of the scheme's complex in ways Inhibited by feedback of the reductase And statins mimic so they say The look of HMG-CoA So we sing their praise and not make cholesterol. Woo. So that's how we make cholesterol. What's that? Student: [inaudible] Kevin Ahern: No. The synthesis of cholesterol is regulated in the cell. Actually I'll tell you what. Let me come back to that next time. I'm going to come back to that next time. We're not going to leave early. I would rather spend our remaining time talking about the movement of cholesterol in the body. So next time I'll talk about the other regulation that's done because there are other important regulation considerations for cholesterol. Let's think about a very important consideration in our body. And the very important consideration in our body is we eat a lot of fat. We eat too much fat. But even when we eat too much fat or even when we eat just a little bit of fat, we've got a problem, and the problem is that fat is not soluble in water. Fat is not soluble in water. We eat plenty of glucose, not a problem. Digestive system dumps it into the bloodstream. Glucose is soluble in water. It moves in the bloodstream very rapidly and very easily. Fat does not do that. So fat actually takes, and fat compounds include things like cholesterol, so anything that's water-insoluble, cholesterol, fat, fat-soluble vitamins, all of these have to be packaged up so that they can move in the body. So that's what is the subject of the rest of what I'm going to say today. So these evolve some interesting complexes that are called lipoprotein complexes. So I want to take you through these. Let's imagine I've eaten that giant Big Mac double cheeseburger loaded, dripping with grease. So it's loaded with fat. Or maybe I'm eating a veggie burger that I dumped a whole bunch of butter onto, I don't know. Yum yum, right? We're going to follow those water-insoluble compounds in their movement through our body. So when I eat that, the first thing that happens is these compounds hit my digestive system and that digestive system has the very first thing it has to do to make them soluble, and it does. It solubilizes water-insoluble compounds using detergent. Just like you use detergent to clean your clothes, your stomach uses detergent to solubilize water-insoluble things. The detergents have a name and they're known as bile acids. Bile acids. B-I-L-E. Bile acids are derivatives of cholesterol that have some charged groups that have been placed onto them. We'll see their metabolism later. But they've got charged groups so they act like detergents because one part of them is very water-insoluble and one part of them is very water-soluble, just like a detergent is. They emulsify that fat to make it water-soluble. They emulsify anything in there to make it water-soluble. I'm going to specifically focus on fat for the moment but what I'm saying also is true for other compounds as well. Fat first of all has to make it across the intestinal wall in order to ultimately make it into our bloodstream. And it does that. There's a scheme that I'll actually talk about later but for our purposes at the moment we'll just say it moves across the intestinal wall. And after moving across the intestinal wall these water-insoluble compounds get dumped into the lymph system. They get dumped into the lymph system. Now something very important happens as they're getting dumped into the lymph system. They get assembled into the first of the lipoprotein complexes. And these lipoprotein complexes are known as chylomicrons. So chylomicrons are lipoprotein complexes. When I say lipoprotein complex, what does that mean? It means that it contains lipids. It's water-insoluble things. And it contains proteins to help hold those. They're actually big balls of stuff. The outside are portions that are the groups of the proteins that are interacting with water. And on the inside of these big complexes are the portions of the protein that are hydrophobic and they interact with the lipids. Well as the chylomicrons are made they are great big honking complexes that look like they're just totally destined to go plug up your arteries. And in fact they don't. They don't. They pass through your lymph system into your bloodstream and they're the biggest and fluffiest of all of these complexes. they're quite large. Their density you'll see is the lowest of all of the complexes and these complexes vary in their density. So we have chylomicrons, we have very low density, we have intermediate density, we have low density, and we have high density. The lower the density the fluffier, as it were, that they are, and the size. They're also the biggest. They're quite large complexes. Well these guys are full of fat, they're full of cholesterol and they're full of fat-soluble vitamins. They're needed nutrients for cells. Those chylomicrons dump into the bloodstream and it's like I said it looks like they're going to go plug something up but they don't plug up anything that causes problems. They do plug something up though. They go and they hit the capillaries. And when they hit the capillaries they plug up the capillaries. Doesn't that cause problems? No. The capillaries are integrated with the tissue and that tissue is needing the nutrients that's contained in these chylomicrons. So it contains nutrients that are needed in there and so these tissues around the capillaries will secrete enzymes that will start to break down the fat. They will start to break down the fat. They will not touch the cholesterol. The fat when we break it down produces fatty acids and it produces glycerol. The fatty acids can be taken up by cells and used as an energy source. The fatty acids can also be released into the bloodstream where they get taken up by serum albumin. So fatty acids really can go either way. Either into the target, into the cells that are digesting them, or into the bloodstream where they're gobbled up by serum albumin. Serum albumin is the protein that carries fatty acids in the bloodstream and that's partly because fatty acids themselves can act like detergents, and if you think about detergents what do they do to the structure of proteins? Denature, right? So if we have something to contain them and keep them from causing problems, that's what cells do. Well after the enzymes in the target tissues and the capillaries have had a pretty good lunch munching on the fat in those chylomicrons, the chylomicrons start to shrink. And as they shrink and they shrink and they shrink, remember that the cholesterol hasn't been touched so the cholesterol is still in them, as they start to shrink they get smaller and smaller in size. Ultimately they're small enough to pass through the capillaries. At that point they're called chylomicron remnants. The chylomicron remnants have one destination and that destination is the liver. So the remnants go to the liver and they get absorbed by the liver. So we saw that the liver played an important role in sugar metabolism. Now we're starting to see that the liver plays a very important role in lipid metabolism. The liver absorbs the cholesterol, the fat, fat-soluble vitamins that didn't get taken up on that pass through the capillaries. Well how do we get these other complexes? This is where the story gets a little complicated. The liver is now a bank, as it were, of cholesterol, of fat, and of fatty acids. It's not an infinite reservoir. It can't take things forever. It's ability to balance things, that is to let out cholesterol and so forth when it's needed and absorb it when it's eaten, is partly a function of the fatty state of the liver. If we exceed that capacity then virtually every cholesterol we eat is going to go into our bloodstream. One of the things that your doctor will try to do with you if they determine that your cholesterol levels are too high, is the very first thing they do, they will not give you drugs. They will try to get you to manage your diet. Lose some weight and eat less foods that tend to have cholesterol in them. Eat less fatty foods as well because fat is a player in this process. So those are the things your doctor will try to do with you. If your diet can manage your cholesterol, that is you can sort of increase the capacity of your liver to manage things, then you don't need drugs, and any time you can avoid drugs you're probably in better shape. That's not always possible and we'll see some reasons for why that can happen later. So if that doesn't work then the doctor might say, "Okay, well let's be thinking about putting you on statins," because when we think about cholesterol we think about how much you're getting in your diet, but we also think about how much you're making. What we can control pretty readily is how much you're making. So if you can't control diet we'll go statins. So the liver has all this cholesterol in it. How does it get it all back out? The liver has to understand what the body's needs are for cholesterol. So first of all I'm going to tell you what the liver does to put cholesterol out into the body. The body, the liver's getting a signal which I'll describe in a bit, and that signal is telling the liver, "Hey we need some help out here. "We need some fat, we need some cholesterol, "we need some vitamins." The liver says, "Okay, I've got plenty sitting here. "I'm going to package it up into very low density lipoproteins." So the liver makes a new complex. They're called VLDLs. And these guys are fairly large also. And they are very fluffy. And these guys don't cause heart attacks either. VLDLs are not really a problem in the overall scheme. What do VLDLs do? Well they go out to target tissues and guess what? They get stuck and they get attacked by enzymes just like the chylomicrons were. And some of the fat gets dissolved. Some of the fatty acids get taken. Some of the fat-soluble vitamins get taken. But none of the cholesterol. Cholesterol does not make it into cells through VLDLs. As the VLDL starts getting its insides eaten away it starts shrinking in size. It becomes an intermediate density lipoprotein. And these are less fluffy, they're less big, but they're not really a problem either. Only when we've gotten all the way down to the LDL state, the low density lipoproteins do we start thinking about problems with cholesterol. Why? Well first of all, cholesterol concentration is highest in the LDLs. The cell has been taking fat and fat-soluble vitamins away from these complexes but it hasn't been touching the cholesterol. So relatively speaking, the LDL has the highest cholesterol within it. So LDLs are bad, no? Well your doctor will probably describe it as bad cholesterol but LDLs have a very important role in our body, and the role that they have is that they are the delivery mechanism to get cholesterol directly into cells. How does that happen? Student: It gets in by endocytosis. Kevin Ahern: It gets in by-oh she's answering the question. It gets in by endocytosis. There's a receptor on the cell that binds to LDLs. It grabs them and it internalizes them. The entire LDL gets gobbled up by cells. The cell gets everything that's in it at that point. Whatever fat's leftover, whatever fat-soluble vitamins, and the cholesterol that's there. Now I'm almost out of time but I'm going to finish with one more thought and then I'll pick it up next time. How can we tell how much the cells need? The liver can tell it by looking to see how many LDLs make it back to the liver. The more LDLs that make it back to the liver, the less got taken up. The cells must be happy. The more LDLs get taken up, the liver says, "Oh wow, they ate up everything I put out there. "I'd better put out some more." Just like a mother feeding her kids. If the kids eat everything maybe I need to give them some more because they need some more food, right? So if the LDLs coming back to the liver are low the liver says, "Gotta put more out." That's a good stopping point. Let's stop there and we'll talk about this more on Friday. [class murmuring] Oh by the way, when you come and seat yourselves next time, seat yourselves like we did last term, okay? Row one, row one, row one. [END]