Fatty Acid Synthesis - Part I

- [Instructor] Now the ultimate goal in fat metabolism is to be able to deliver some triacylglycerides, which I'm gonna abbreviate here at TAG, which remember is the chemical name for a fat molecule, or free fatty acids, which I'll abbreviate here at FFA, which if you recall are the kind of monomer subunits of these fat molecules directly into the bloodstream where they can eventually reach capillary beds like the one that I've drawn here. So I'll go ahead and label this as a capillary bed, and it's important that they reach these capillary beds because it's at this point where they can diffuse to surrounding tissues such as muscle or heart tissue, for example, where they can be taken up by these tissues and oxidized to obtain cellular energy in the form of ATP. Now I want to remind you that there are three main sources of these triacylglycerides or free fatty acids that can enter the bloodstream, and so I'm gonna go ahead and scroll up here and show you kind of what I've already drawn out here and go ahead and explain it. Starting off here on the far left I've drawn a cheeseburger, perhaps not the best drawing in the world, but just to remind us that one of our sources of fat that ultimately reaches our bloodstream is directly from our diet. So recall that our small intestine digests our food and packages the fat molecules, the triacylglycerides, into protein carrier molecules called chylomicrons, which travel through the lymphatic circulation but eventually empty into our bloodstream where they can enter capillary beds. Now the second way that we can get some fat into our bloodstream is directly from adipose cells. So recall that adipose cells are specialized cells inside of our body that can store large amounts of fat, and so that's kind of what I've drawn here in these yellow circles within these cells, these large fatty droplets. And several hours after a meal, when your hormone insulin begins to drop inside of your body and other hormones such as glucagon begin to rise, they signal these adipose cells to release free fatty acids directly into the bloodstream, and recall that free fatty acids are very hydrophobic, so they kind of surf, essentially they kind of attach themselves onto albumin molecules, which is a special type of protein that's always found inside of our bloodstream. Now the third way that we can get some fat into our bloodstream is by synthesizing it directly inside of the liver, which I've kind of drawn an outline of here. Now the liver cells are especially equipped with the right type and number of enzymes to be able to convert excess glucose, that is the glucose that's not being used for ATP synthesis or glycogen synthesis, into fatty acids. Then, like the small intestine, the liver essentially packages these fatty acids into triacylglyceride molecules and packages them together with cholesterol, another hydrophobic molecule, into another specialized protein carrier molecule like chylomicrons, but this one has a slightly different name. It's called very low density lipoprotein, or VLDL for short. And this of course is sent off to the bloodstream, where it will eventually reach capillary beds and be taken up by surrounding tissues, even perhaps adipose cells, which might store it up for later use. So now that we've gone over this overview, I want to zoom in on one of these steps. I want to zoom in on this step here, going from glucose to fatty acids inside of the liver, which is commonly referred to simply as fatty acid synthesis. And to do this, I want to go ahead and kind of just zoom in on one single cell inside of the liver to visualize what's going on at the cellular level to be able to allow us to convert glucose into a fatty acid. And so I'm gonna go ahead and scroll the screen here so we can have some more room. All right, so I'm gonna quickly draw an outline of a representative cell, and then we'll go ahead and quickly label some important compartments that we want to talk about. So the first one is simply the cytoplasm, and there's a lot going on in the cytoplasm. But we also need to talk about what's going on in another organelle inside the cell, and that organelle is the mitochondria, and I'm gonna go ahead and draw the kind of two membranes that it has here. We're not gonna talk about this too much, but just because it is important to remember that this has an inner membrane and an outer membrane. Remember that the electron transport chain is of course located on the inner membrane, and the mitochondria is also within it. It's the site of the Krebs cycle, which continues, notably, to break down glucose following glycolysis, which takes place inside of the cytoplasm. Now since we ultimately want to get down to how extra glucose can be eventually converted into fatty acids, we need to actually make sure and remind ourselves how the breakdown of glucose proceeds. So as a very, very quick review, recall that glucose enters our cells from the bloodstream and it enters the metabolic pathway called glycolysis, which takes place inside the cytoplasm. And the end product of glycolysis is pyruvate, and I'll also remind you that for every one molecule of glucose, which is a six-carbon molecule, so one, two, three, four, five, six, we form two molecules of pyruvate, which is a three-carbon compound. Subsequently, pyruvate is actively transported across the mitochondrial membrane by specialized carrier proteins located on the membrane, and once pyruvate reaches the inside of the mitochondria, also known as the inner mitochondrial matrix, there is a enzyme that's only found in the mitochondria called pyruvate dehydrogenase, often abbreviated as PDH, which oxidizes and removes one carbon from pyruvate. So remember, we had three carbons, and now it turns it into a two-carbon molecule called acetyl-CoA. Now you might recall that this two-carbon structure is not done being broken down or oxidized. There's still some energy that we can extract from this two-carbon molecule, and it's extracted inside of the Krebs cycle. So remember that there are many, many intermediates along the Krebs cycle, but I only want to mention a couple that will be relevant when we talk about how this breakdown of glucose converges with the synthesis of fatty acids. So remember first off that a four-carbon molecule called oxaloacetoacetate, which I'm abbreviating here as OAA, combines with one molecule of acetyl-CoA to produce a sixth carbon molecule now called citrate. And citrate continues to be modified, oxidized, and even broken down a little bit more, and it returns to form oxaloacetate, which means that we lose two carbons somewhere along this cycle, which we do indeed. We lose these as two molecules of carbon dioxide, so those two carbons of acetyl-CoA exit as carbon dioxide, and we also form a number of reduced electron carrier molecules called NADH and FADH2, which shuttle their electrons from the oxidation process that occurs in the Krebs cycle to the electron transport chain, which is located on this inner mitochondrial membrane. How convenient, right? And then from there, we can produce ATP using oxidated phosphorylation. All right, so after that quick whirlwind tour of the breakdown of glucose, you might be wondering where do we convert glucose into fatty acids? And it turns out that one of the intermediates of the breakdown of glucose, which is acetyl-CoA, this two carbon molecule located in the mitochondrial inner matrix, is a precursor for fatty acid synthesis, and we're gonna go through all of the steps, but just to take a step back for a moment, the big picture way that I kind of like to think about this is that remember that fatty acids, I'm gonna go ahead and draw off to the side here, remember that most of it is just a repeating carbon hydrogen backbone shown here in this kind of line stick model here. And so in that sense, really we want to basically be able to link together carbon-carbon bonds, and this acetyl-CoA is just a pair of carbon-carbon bonds that we can ultimately link together. Now it turns out that we have an interesting situation when it comes to fatty acid synthesis and linking all of these acetyl-CoA molecules together, which is that all of the enzymes necessary for fatty acid synthesis, I'm gonna say enzymes for fatty acid synthesis, are located in the cytoplasm. And that's a bit problematic, because remember our acetyl-CoA molecule is in the mitochondria. Now your first thought might be, well, pyruvate was able to shuttle across using some protein career molecules in these membranes into the mitochondria. Why can't acetyl-CoA do the same going the opposite direction? Unfortunately, for some reason or the other, our body has evolved not to have any means to be able to transport this through its mitochondrial membrane. There are no protein transporters or carrier molecules like we had for pyruvate to be able to essentially shuttle acetyl-CoA in either direction across this mitochondrial membrane. But notably, our body does have a protein shuttle across this mitochondrial membrane for the molecule citrate, and remember that citrate contains acetyl-CoA. Of course, it also contains this molecule acetylacetate that combines with it. And so let's see what happens when this shuttles across the mitochondrial membrane. Now once citrate reaches the cytoplasm, it turns out that there is an enzyme within the cytoplasm that is able to break citrate up back into oxaloacetate, as well as the molecule that we're interested in, which is of course acetyl-CoA. Now when I first learned about this, it kind of struck me as a really roundabout way to kind of accomplish what seems like a pretty simple task, right, which is to get acetyl-CoA into the cytoplasm where the enzymes or fatty acid synthesis can link it together to form a fatty acid. But it turns out that there might be a benefit for this citrate shuttle to make fatty acid synthesis perhaps more efficient, and so I want to briefly talk about that, but I want to erase this just to give us some more room. Now it turns out that this four-carbon molecule, oxaloacetate, is not going to be used for fatty acid synthesis. And so naturally our body says why don't we recycle it? And in fact, we do have some enzymes that can convert it back to this molecule pyruvate, and notice that pyruvate can essentially, once it goes back to the mitochondria, it'll be turned into acetyl-CoA and this entire cycle can continue. Now although we're not gonna go over the detailed mechanism by which oxaloacetate is converted to pyruvate, what is important, kind of a big picture idea to note here, is that we're going from a four-carbon to three-carbon molecule, and so we're gonna lose a carbon, actually, as carbon dioxide during this process. And simultaneous with this step, we're actually oxidizing that particular intermediate. And so when we oxidize something, we're able to reduce something else, and it turns out that what we reduce in this case is a molecule of NAD+. And so it's reduced to NADPH, and you may recall that you've seen NADPH also as a product of the pentose phosphate pathway, and of course we normally think about the pentose phosphate pathway as being the major pathway for the production of NADPH, but this step also allows us to produce a molecule of NADPH as well. Now one of the uses of NADPH that you might recall is that because it's associated with these electrons, it can serve as a source of reducing power to help with anabolic reactions. And remember that anabolic reactions are anything that involve building up a molecule, including fatty acid synthesis, which is exactly what we're trying to accomplish here. So to summarize and just kind of tie up everything that we've just talked about here, we've been able to get acetyl-CoA into the cytoplasm where all of the enzymes necessary for fatty acid synthesis are located. And this is important because we're gonna use acetyl-CoA, multiple acetyl-CoA, kind of a precursor molecule, so to say, to build up a fatty acid. And of course because this is an anabolic reaction, we're going to need some ATP somewhere along the way, and we're also going to need some reducing power to kind of help form all of those carbon-carbon bonds, and we can get that using NADPH. Of course, NADPH can be supplied by the pentose phosphate pathway, but conveniently, perhaps, by using this citrate shuttle, we're also able to produce a molecule of NADPH from the conversion of oxaloacetate into pyruvate. In the next video, we'll pick up right here in the cytoplasm to talk about how this conversion from acetyl-CoA into a fatty acid occurs.