Fatty Acid Metabolism and Disorders - CRASH! Medical Review Series

all right so we're going to talk here about fatty acid synthesis and oxidation now this is a complex pathway or two pathways really um and i'm going to go over this in a way that makes it as simple as possible and even though when i write all of this out it's not going to look simple i'm going to point you towards the most important things that you need to know for the exam now although step one is not a clinical exam they like to ask you questions on the basic sciences that are relevant clinically most

of the time so what you really want to hone in on therefore are the pathologies the disorders that can go wrong with each of these pathways okay so let's go ahead and start we're gonna start with fatty acid synthesis so we're making fat so we start out with acetyl coa and oxaloacetate now right off the bat you might be wondering why are we starting with that that's tca cycle right now the fact is that acetyl coa exists within the mitochondria but it can't leave the mitochondria and fatty acid synthesis takes place in the cytoplasm so

because acetyl-coa cannot leave the mitochondria we need to convert it to something that can and that something happens to be citrate well as you know we can make citrate very easily using the enzyme citrate synthase okay so this is very easy it's one of the steps of the tca cycle and so it just uses citrate synthase and now citrate can easily cross the mitochondrial membrane and enter the cytoplasm and so that's exactly what happens so here we have citrate now in the cytoplasm now citrate will then use an enzyme called atp citrate liase atp citrate

liase and what that does is it converts the citrate back into acetyl coa and of course it's going to get rid of oxaloacetate okay so you just did the reverse from citrate synthase now remember that citrate is six carbons oxaloacetate is four carbons and acetyl coa is two carbons we'll see how this is important in a little bit now the next step is to add a carbon on to acetyl coa and that's going to be important uh as we'll later see so what we do is we add carbon dioxide onto acetyl coa and we get

malonyl coa and that's just three carbons now the enzyme that does this is super important so please pay attention the enzyme that does this is called acetyl coa carboxylase and it uses biotin as a cofactor all right now the reason that this enzyme is really important is because this is the rate limiting step in fatty acid synthesis now what is going to regulate this step and this is something that will get asked about on the test because they like to go after with these enzymes they like to go after the regulators so one of the

things that induces this enzyme is citrate itself okay so you have citrate in in the cytoplasm it's going to activate this enzyme and all it's saying is okay i we've got citrate we need to do something with it so as long as i'm here you know we might as well make fat and so citrate tells acetyl coa carboxylase to start working more now another thing that does that is of course insulin now why would insulin do that well insulin is a a hormone that essentially tells the body you've got sugar do something with it either

make energy or store it as fat or glycogen but just do something with all the sugar that's laying around and so insulin is an up regulator of acetyl-coa carboxylase now what will inhibit this well naturally if insulin upregulates then it's pretty safe to say that glucagon is going to inhibit and that's indeed what happens okay all right so we have this malonyl coa and what happens is that malaynilcoa will get added to an acetyl-coa okay so that happens like this so acetyl coa then we consider acetyl-coa to be our primer it's the beginning of the

fatty acid synthesis so malonylcho a gets added to acetyl coa and then it gives off a co2 and so as you can see we've got a three carbon we've got a two carbon with acetyl coa and then we lose carbon dioxide so we wind up with four carbons okay we've got a four carbon molecule and this is going to continue and it's going to go on and on so what happens is that we add a malonyl coa and it's going to be malonyl coa that is our sort of building blocks that remember has three carbons

we lose a carbon dioxide and now we've got a six carbon molecule and this will go on and on and on until we get a 16 carbon or palmatoyl co a molecule and that is your your end product so you'll end up with palmitate which is a 16 carbon fatty acid okay so that is fatty acid synthesis important thing to know with this is that you're using the citrate shuttle you've got to have citrate in order to cross into the cytoplasm the major rate limiting enzyme is acetyl-coa carboxylase which is upregulated by citrate and insulin

inhibited by glucagon and then we add these these carbons two at a time and we end up with a 16 carbon uh fatty acid at the very end okay so now let's transition to fatty acid oxidation or degradation same thing so let's say that we start out with a fatty acid it doesn't matter what fatty acid it is um and so what we're going to first do is we're going to add a coa onto that and so we get what's called a fatty acyl coa now what needs to happen is that we need to add

something to this and this something is called carnitine carnitine is a very special uh you might call it uh i wouldn't call it a cofactor it's it's a special molecule and what carnitine is is it's the fatty acids ticket into the mitochondria and it's only in the mitochondria where you can actually do this oxidation process where you can really break down the fatty acid so think of carnitine as sort of a ticket so we're going to add carnitine onto our fatty acyl coa and we're going to get rid of that koa for now and so

what we wind up with is a fatty acyl carnitine now the enzyme that does this adding of the carnitine has a name and it's called cpt-1 you may also hear it referred to as cat one doesn't really matter but cpt-1 now the major inhibitor of cpt-1 which by the way is indeed the rate limiting step of fatty acid oxidation is malonyl coa now maloneyl co-a makes sense as an inhibitor of this process because if we have malonyl coa what it's telling us is we're doing fatty acid synthesis right now so we don't want to be

breaking things down as we're putting them together right that doesn't make any sense so this malony coa is is the inhibitor of this rate limiting step so it's really the regulator of of fatty acid oxidation and to get malonyl coa in the first place depends on the activity of acetyl-coa carboxylase which itself is regulated by insulin and glucagon okay so we've got that fatty acyl carnitine and fatty acyl carnitine is then able to cross into the mitochondria remember what i said it's the ticket into the mitochondria and so what will happen then is it will

encounter cpt-2 which is a similar enzyme but it kind of just does the opposite it takes the carnitine off and it adds a coa and so what we're then left with is a fatty acyl coa and so then at this point what's going to happen is that you've got a complex of enzymes that are going to one by one by one tear off acetylchose and it's going to shorten and shorten and shorten that that fatty acid all the way down to acetyl-coa assuming that we're dealing with an even chain fatty acid and so the very

very end product of this is going to be acetyl coa now if we had an odd chain fatty acid that would not happen okay the end product would be propional a and that remember goes into that vomit pathway okay so that is different we're talking here though about even chain fatty acids okay now in the process of breaking down a fatty acyl coa we're going to produce a few different things we're going to produce nadh we're going to produce fadh2 which remember those are going to go into the electron transport chain and make atp and

then we also make acetyl coa with each step we're making acetyl coa and then we end up with acetyl coa at the very end so the major enzyme that's involved and there are multiple but you only need to know this one enzyme it's called acyl coa dehydrogenase and there's actually multiple of these enzymes depending on the length of the fatty acid that you're dealing with so you have a long chain acyl coa dehydrogenase you have a medium chain and then you have a short chain so they're different enzymes depending on how long they are all

right now the end of this is that you've got acetyl coa and acetyl coa can go into two different processes can go into the tca cycle and it can go into making ketone bodies okay so that is it that's your fatty acid synthesis and fatty acid degradation now there are two diseases that you need to be familiar with for the exam and now i'm going to point to where those are first of all there's something called systemic primary carnitine deficiency so i'm going to write systemic primary carnitine deficiency and that's exactly what it sounds like

you have a deficiency of carnitine and it actually relates to a carnitine transporter but essentially you're peeing out all the carnitine that you're taking in and so as a consequence you don't have carnitine to transport these fatty acids into the mitochondria and so you can't even start the process of fatty acid oxidation another place where you can have a problem and this is a little bit more common is with one of those acyl coa dehydrogenases that breaks down the fatty acyl coase into ultimately acetyl coa at the very end and so it happens to be

that the medium chain acyl coe dehydrogenase or mcad is the most commonly affected and so this is called mcad deficiency and so the result is that we're not able to completely break down long-chain fatty acids and medium chain fatty acids and so they begin to accumulate and the consequence of this is that we're not going to be able to successfully uh undergo fatty acid oxidation and so we wind up with issues with uh with with breaking down fats okay so let's go into this in more detail so we have our two our two uh diseases

here that i wrote out and so what do you expect to happen with this so i put down here the uh the places where you can have these diseases we're kind of going backwards here but they are right here with carnitine deficiency and then up here with mcad deficiency so the ultimate problem with this is that you're not going to be able to make a lot of acetylchoids if any acetyl coas out of your fatty acids and so if you've got deficient acetyl-coa when you need to use fat and so we're talking here about fasting

right so if you're taking in sugar and you're you know drinking your capri sun or your you know mountain dew or whatever you're fine you're getting sugar in that way you're able to make acetyl coa but once you start fasting and your body moves to using fat then you start to run into problems because you can't use that fat and so ultimately that acetyl coa will become depleted because you cannot use fats and so the result of that is that you're going to have defective gluconeogenesis and so that is going to cause hypoglycemia so i'll

just write that down here hypoglycemia now what else is going to happen well remember that fats breaking down fats is our way of making ketones remember going back that acetyl coa can be used to make ketones and ketones are our brains way of getting energy when we have low levels of glucose and so we're going to have defective hepatic ketogenesis and this these this process of of fatty acid oxidation primarily takes place in in the liver okay so we're not going to have ketogenesis now that's weird because normally when you have hypoglycemia you have ketones

you're going to have ketones in your urine but in this case because we're not able to use fats we're not able to generate those ketones and so we have a hypoketotic hypoglycemia and that's unusual that's very unusual it's common to have hypoglycemia but you're going to have ketones it's not you common to have low ketones with hypoglycemia that is very characteristic of these fatty acid oxidation disorders so when is this going to happen it's going to happen with fasting okay if you're drinking your mountain dew or eating your bread you're totally fine but once you

start relying on fats you're going to have a severe fasting hypoglycemia and again this is characteristic of these fatty acid oxidation disorders now what symptoms would we expect in a person with one of these disorders well it's going to be related to hypoglycemia so they're going to have nausea they're going to have vomiting because they are hypoglycemic they can have seizures and ultimately they can go into coma and die so this is the presentation what's going to happen this is going to be a child because this is a disorder of of metabolism what's going to

happen is that you're going to have a child probably around two or three months once they you know maybe even a little older once they're not bottle feeding all the time mom kind of lets the baby go a little bit longer maybe at night going seven eight hours without you know without waking up to feed and they're going to wind up very very hypoglycemic and they're going to have nausea seizures vomiting coma this is not going to present in a neonate because they are being fed frequently so this is going to happen when the infant

starts fasting a little bit more once you start needing to rely on on fat stores so expect this to show up in a newborn but not in a neonate so this is going to present within the first year of life okay so how do we tell systemic primary carnitine deficiency from mcad deficiency i don't expect you're going to be asked this on the exam you'll probably be given one or the other as an answer choice but just in case let's talk about how this could present on an exam so with systemic primary carnitine deficiency although

it does cause this hypoketotic hypoglycemia and can present that way it's typical that you have a different thing that presents first and that thing is a progressive dilated cardiomyopathy so it tends to be that that's the presenting symptom of of primary carnitine deficiency not the hypoketotic hypoglycemia just because it's not quite as severe now they can get it but usually it shows up as a dilated cardiomyopathy so if you have a very very young child with heart failure and you find on echo that it's dilated cardiomyopathy then this is something that you need to consider

now fortunately with neonatal or with newborn screening we're able to diagnose these things before it becomes a problem but on the exam they're probably not going to tell you that what they'll tell you is that you've got a child with heart failure you find that you've got dilatation of the heart dilated cardiomyopathy and then you get maybe the patient has a history of hypoglycemia and episodes related to that or they may tell you that you have a decreased level of free and total carnitine well then you know what you're dealing with i don't expect they're

gonna tell you uh about the carnitine labs because uh that kind of gives it away the disorder after all is called primary carnitine deficiency uh but that's how you would know and so to treat this you give carnitine supplements if you give the patient enough carnitine they'll be able to get by even though they're peeing a lot of it out they're going to be able to get by if you give them levels of carnitine not just the amount that you would rely on in your diet now with mcad deficiency this is a little bit worse

so what goes on here is that you get fat building up in your liver because you're not able to use it and so you get hepatic steatosis now if you see a child with hepatic steatosis if that's told to you do not assume it's rye syndrome because that's the other way that you can get hepatic steatosis and liver failure in a child remember that's going to be probably an older child six seven eight years old that has a viral illness mom gave him aspirin and now he's got signs of elevated intracranial pressure and liver failure

this is going to occur in a newborn so hepatic steatosis and of course you're also going to have hyperaminemia and the reason there is because the liver is not working and so the urea cycle is not functioning correctly there's also some thought that some of these fats that accumulate can directly inhibit the urea cycle but just think of it as the liver is not working so the urea cycle's not working you're gonna have hyperaminemia now one way that they could ask you about this is they could say we took a muscle biopsy and we found

increased acyl carnitines now what that means is that you've got these fatty acids and they've got carnitine attached to them but you can't really go much further and these are accumulating well you know from that then because carnitine is present you're not dealing with primary carnitine deficiency you're dealing with something else and it's only going to be mcad deficiency now in real life there's like 20 of these fatty acid oxidation disorders but these are the only two that you need to know for your exam so the treatment for mcad deficiency is really just preventative we

just avoid fasting as long as you're avoiding fasting you don't need to rely on fat stores to get your energy and so you're not going to become hypoglycemic so in many ways it's kind of a similar uh treatment to von gierke's disorder with the glycogen storage disease that you just avoid the hypoglycemia by persistent eating by by giving sugars the difference versus von gierke's disorder is that here we're going to have low ketones whereas with von gierke's it's going to be normal or high elevated ketones with the hypoglycemia now in general though the treatment if

you ever have a patient with hypoketotic hypoglycemia or really any hypoglycemia is that you need to address that so that's always the emergent treatment and you would just give 10 dextrose for that okay and that's it so i know this was long but uh if you focus on these two disorders and then of course if you focus on that acetyl-coa carboxylase and the uh the regulators of that that's really important understand that citrate is how we shuttle acetyl coa from the mitochondria into the cytoplasm and then understand that carnitine is the ticket for fatty acids

to get into the mitochondria and then know these two disorders and where they happen you're going to be good to go [Music]