Metabolisms of Triacylglycerides

Hey, everybody! It’s weird to be back here at school, but I also feel like I just woke up from a deep sleep or something. I don’t know. It’s weird. At home this week, I was waking up at nine and going, “Noooooo…” This morning, I was up at 6:45 doing Japanese homework that I forgot about. I guess there’s a “school” switch somewhere…? Can one of you neurobio people please find it?

Anyway, now that I’ve gone to my language classes, been thoroughly schooled in how much of my speaking ability I lost in a week, and taken a nap, it’s time for me to write a post on the lecture that I was putting off because I accidentally left it in my dorm! It’s really a rather interesting one (sarcasm up for interpretation)—triglyceride metabolisms!


Triacylglycerides are something that we’re all pretty familiar with, and their role in our lives isn’t really anything of a mystery. They’re just fat. Fat that makes us, you know, fat. We’re not really their biggest fans.

However, they serve that important function that I told you about, the one where they provide us with energy. Really, it’s the reason we have such a hard time getting rid of them—they’re really great for storing energy in a super compact way.

Now, we talked about how fatty acids are oxidized once they’re liberated from TAG, but we haven’t really talked much about how we get to that point. Lucky you, we’re about to! Aren’t you excited?

(No? Oh, come on! Where’s your sense of adventure?)

Like most catabolisms, it all starts with glucagon. As we already know, glucagon is a pancreatic hormone that tells us when our blood glucose level is too low (glucose… gone…). When it’s floating around in our blood, it tells a whole lot of metabolic pathways to start making energy. One of those is the pathway by which we catabolize TAGs!

Glucagon binds to a receptor protein on the cytoplasmic membranes of adipose cells (adipocytes), which are cells that store TAGs. (If you didn’t previously know that, I bet that Doctor Who episode makes more sense now!) The binding of glucagon triggers a cascade that eventually results in the production of the secondary messenger cAMP (cyclic AMP) within the cell. cAMP stimulates kinases that activate the metabolic enzymes needed in this metabolism by phosphorylating them.

Activated lipases within the cell happily hydrolyze TAGs to glycerol and three fatty acids. They do this by chopping off fatty acids one at a time, first making a TAG into a DAG, and then an MAG.

These free fatty acids are bound to fatty acid binding proteins (to improve their solubility, because, you know, oil and water). They’re then released into the blood, where they bind to serum albumin, a transporter protein produced in the liver. The very water soluble glycerol is also released into serum, where it can provide energy to tissues, as well.

Now, glycerol may not be an energy-generating superstar, but our liver isn’t picky. Once it makes it into the blood, our liver sucks it up and puts it to work making energy. Firstly, a cytosolic enzyme called glycerol kinase phosphorylates glycerol using ATP, making ADP and glycerol-3-Pi. (This is really spontaneous, since, in comparison to the energy in the broken phosphoanhydride bond in ATP, the energy of the formed phosphoester bond is chump change.) Because this is going on, usually, the glycerol-3-Pi to glycerol ratio in liver cells is 5/1.

Once glycerol is phosphorylated into glycerol-3-Pi, glycerol-3-Pi is oxidized into dihydroxyacetone-Pi (DHAP). This produces NADH (yay!) and a glycolytic intermediate. The DHAP can then either be turned into pyruvate (glycolysis) or glucose (gluconeogenesis). The fact that it can be turned into glucose is important, since under catabolic (low-glucose) conditions, the liver is responsible for replenshing blood glucose while the rest of our body munches away on its energy-storing molecules (like fat…).

Now, we do have a slight predicament with getting energy out of glycerol this way. As you may remember, because our cells are freakin’ geniuses, we don’t have a way to directly transport NADH into our mitochondria for use in, you know, energy production. Now, when we were doing glycolysis and the TCA cycle, we studied the malate-aspartate shuttle. We should do that here too, right? You betcha! However, we’ve got another shuttle that helps, too!

The glycerol-3-Pi shuttle is responsible for helping in transporting electrons from glycerol metabolism into the mitochondria while regenerating NAD+ in the cytosol. It does this by using an enzyme called Glycerol-3-Pi Dehydrogenase I (GPD1) to reduce DHAP to glycerol-3-Pi using NADH (whaaa?). Then Glycerol-3-Pi Dehydrogenase II (GPD2), which is embedded in the inner matrix membrane, oxidizes it back to DHAP using FAD (—> FADH2 —> CoQH2). This replenishes the Q-Pool. Don’t quote me on this, but I would suspect that this is why cytosolic NADH are worth less than matrix NADH (CoQH2 is worth one ATP less than NADH, remember?).

All right, so that’s how we break these guys down, but what if we want to build them up? (“Waaaah,” we say, “we hate fat.” Well, yeah, but we’d also hate having soap in our cells, so it’s kind of a toss up, really.) Well, that’s not terribly complicated either. All you need are some fatty acids, a glycerol, and some ATP:

Glycerol + 3 Fatty Acids + 4 ATP —> TAG + 1 ADP + 3 AMP + 7 Pi

Fatty acids can come from diet or from biosynthesis (don’t believe me? Allow me to direct you here, 😉 ). Glycerol-3-Pi comes from a number of sources—metabolism of glycerol, metabolism of pyruvate through gluconeogenesis, and metabolism of glucose using glycerol-3-Pi dehydrogenase (glycerol-3-Pi shuttle, anyone?). Of all of these, the last is most important—it, when coupled with gluconeogenesis, forms a metabolism called glyceroneogenesis.

The biosynthesis of TAGs is a neato pathway that uses five relatively simple reactions to make these reactants into our desired (“desired”) product. Observe:

Step 1: Activation of Glycerol

The first reaction is the same as the first reaction of TAG breakdown: glycerol is converted into glycerol-3-Pi using glycerol kinase and ATP. As we saw above, this is a spontaneous reaction.

Step 2: Activation of Fatty Acids

Next, quite naturally, we activate our three fatty acids to three acyl-CoAs using ATP and CoASH. For each fatty acid, we cash in both of ATP’s phosphoanhydride bonds (read: make AMP) by spitting out the inevitably-metabolized pyrophosphate (PPi). This is accomplished by using the carboxylate oxygen on the fatty acid to displace pyrophosphate from ATP, making an acyl-adenylate intermediate that is then turned into acyl-CoA using CoASH. The energy we get out of the ATP is sufficient to make the thioester bond formation spontaneous.

Step 3: Transfer of 2 Acyl-CoA to Glycerol-3-Pi

Now, two acyl-CoAs are transferred to glycerol-3-Pi using acyl transferase enzymes. These reactions don’t need ATP, since they’re using the high-energy thioester bonds already put there by the activation step. Two fatty acids are transferred to the glycerol backbone in this “step” via spontaneous reactions, producing phosphatidate as a product.

Step 4: Hydrolysis of Phosphate

In this step, we hydrolyze the phosphate group off of the phosphatidate, leaving us with a diacylglyceride that has a very vulnerable-looking -OH group.

Step 5: Transfer of Final Acyl-CoA

Finally, we transfer our final acyl-CoA to the DAG, generating a TAG.

Pretty nifty, huh? We used a good bit of energy, but in return, we got a molecule that’s high-energy, easy to store, and not out to murder-kill stuff. I’d say that’s a good investment.

All right! That wasn’t too painful, was it? And I even broke a thousand words! I swear, it’s the magic of chemistry (or, you know, being back in my dorm room)! Now that we’ve done fat, we can move on to talk about some other biomolecules—for example, how’s about we start making some nucleotide bases?


Questions? Comments? Clever playlist names? Put ‘er down there.

 

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