Metabolism | Cholesterol Metabolism

iron engineers in this video we're going to talk about cholesterol metabolism so cholesterol metabolism is extremely important because cholesterol is the basic unit for a lot of different things one of the things that we'll talk about is four bile salts which are really really important for being able to help with the emulsification of large fat globules that we take in through ingestion they're also important for a lot of the steroid hormones that we utilize on our body like testosterone progesterone estrogen vastra and cortisol and they're also important because they are actually packaged there's specific molecules

specifically called lipoproteins and we'll talk about a couple of them in this video we'll have another video on more detail on that but we'll talk a little bit about how they're involved in actual transport of cholesterol and then also it's a very integral component of the membrane but we'll talk about all that but the significance of this whole video is to see how we're going to be able to synthesize cholesterol with a basic unit of acetyl co a and how that can be used for synthesis mechanisms we'll talk about a couple enzymes along the way

okay so cholesterol metabolism is primarily going to be occurring inside of the liver we can take cholesterol in through an exogenous pathway via through the ingestion of foods and we can take them transport them to different tissues via what's called chylomicrons but the endogenous pathway of cholesterol is actually going to be taking place within the liver so let's see how we do that well if you guys remember from a lot of these videos we could take a molecule called glucose and we could take glucose and what can we do with them if you guys remember

we could take glucose and we could eventually convert that glucose into pyruvate through glycolysis right and then another thing we could do is we could take that pyruvate and eventually convert it into acetyl co a but what can happen with the acetyl co if you guys remember acetyl co a can actually go through a specific sequence of cyclic steps right which is called the Krebs cycle and then from the Krebs cycle what do you generate you generate a lot of NADH is you generate a lot of fadh2s even generate a little bit of ATP through

substrate phosphorylation but these guys are generally taking their information to thee what the electron transport chain and what happens if the electron transport chain you make ATP so that is the overall goal of this process right now what happens though whenever we have too much acetyl co a what happens if you guys remember the main anabolic hormone I want you guys to really really remember this one that hormone was called insulin insulin is the main anabolic hormone of the body okay so insulin is extremely important in this process of cholesterol metabolism so what is he

going to do we'll talk about that in a second well now let's see how this if there's too much acetyl co a we already know that it can go into two different pathways that we talked about one was a tiny little pathway we can say over here that we can make ketone bodies if you guys remember through ketogenesis and then what can happen with these ketone bodies if you remember they can be taken up by two different specific tissues the brain the central nervous system tissue as well as the muscles and can be utilized to

make what they can be utilized to make ATP but there's another side pathway that we can push acetyl COAS into and that is into a cholesterol synthesis so now let's talk about that so let's say that I take this acetyl co a I put it right it'll actually no let's bring it over here then let's say that I take these acetyl co eggs and we start here and see how this is all happening so now acetyl co a let's say I take an acetyl co a here and I take another acetyl co a and I'm

going to react these two molecules together so I'm going to take these two molecules and I'm going to react them together so let's say I react these two together and I'm going to use them together when i fuse acetyl co a and acetyl co a together there's a special enzyme there's a lot of different names for it but I like the simple names it's easier for me to remember so I like thiolase it's just an easier time to remember as compared to like acetyl co a acetyl transferase Idol I just like the thiolase okay but

there is another enzyme that you could utilize for this step okay now in this step what am i doing I'm taking a seat Ocoee and a CoA and reacting them together in this first step of the reaction but what am I going to get out of this out of this I'm going to produce a molecule called a cito acetyl co a now this might seem very very familiar if you guys have already watched our ketone body videos the actual beginning steps of this process is going to be almost exactly the same as the ketone bodies

now we're not going to go through every single step to make cholesterol it's about 30 steps long so to do that would be ridiculous we want to get the significant components out of this video but here's what we we need to notice look at this we have acetyl co a an acetyl co a how many of utica ways is that that's I'm sorry how many Co ways is that that's two Koei's then what I did is I converted that into a cito acetyl co a there's only one Co a there so what did I lose

in this stuff I lost a co a so in this step I lost a co enzyme a and I made a cito acetyl co a now and the next step I'm going to do this reaction and what I'm going to do is I'm going to combine another molecule and this next molecule is exactly the same as what we had over here guess what I'm going to have coming over here I'm going to have a seat okole so I'm going to feed another acetyl co a into this reaction so now I'm going to take this acetyl

co a and feed it into this reaction here okay so let's actually show this in the same color then so that we make it look all nice and Purdy acetyl co a here with the acetyl acetyl co a is going to react and what am I going to do I'm going to lose another Co a so out of this reaction what's going to come popping out I'm going to pop out a CO a now now I'm going to form a very special molecule now there's two there's actually two names for this the abbreviation I'm just

going to call it H M G Co a but there is another name for it I will mention it but it's easier to do this one but it actually goes 3 hydroxy three methyl blue Carol Calais or beta hydroxy beta methyl gluten okay now you guys probably get why I would just call it a gym GK it's easier to say that but the whole point is that we do have a hydroxy group on the third carbon and then we have a methyl group on the third carbon and then it's a glute arrow kolay okay what

enzymes catalyzing this step a very very important enzyme and this is called hmg-coa synthase okay he is catalyzing this stuff he's stimulating this step to fuse acetyl coa with acetyl co and make HMG coa now we go into the most most important one of the most regulated steps of all metabolism in the entire body okay let's make sure that we understand that so I'm going to do this in a really really thick red arrow here this is one of the most regulated enzymatic steps in the entire body okay the enzyme that's regulating this step here

I specifically called h mg co a reductase so hmg-coa reductase is the rate limiting step here it's very very important I'm going to put below it it is the rate limiting step so it's one of the slowest step it's one of the most important and most regulated steps so this is one of the most regulated steps in our body here this step right here why because it's very very crucial that we regulate how much cholesterol is being made so how do we do that well you know you know there's actually drugs you know people have

really really high cholesterol they have to take certain types of drugs to be able to lower the cholesterol you know how they actually do it one of the drugs that you guys have probably heard of called lipitor so you've probably heard of the drug called lipitor and we're like its branding the lipitor lipitor is actually what's called a statin so there's different type of statins and statins are basically just drugs that can come and inhibit this enzyme so this hmg-coa reductase could be in by certain types of drugs which can inhibit the cholesterol synthesis which

is good for people who have high cholesterol levels they've been eating too much Burger King too many whoppers right so we need to cut that down take their lipitor and watch what they're eating but anyway this HMG co-reductase is very very important because it's what's controlling the conversion of HMG calais and to another very important molecule which is going to be the precursor so this molecule is called methyl on it Armel ilanic acids doesn't matter I'm just going to call it neva law neat so this next enzyme again is called methyl on eight now methyl

on e is actually important because he's going to be the precursor for the synthesis of cholesterol now like I said we're not going to go over every single enzymatic step it's ridiculous there's so many will come some of the more significant ones like you know mevalonic can actually be converted into another molecule which is called isopentyl pyrophosphate so that molecule is called ISO pencil pyro phosphate now why am i mentioning this because whenever this methyl Ani he goes through a couple steps and eventually gets converted into isopentyl pyrophosphate isopentyl pyrophosphate is going to be kind

of the building block for this also because what happens is I'm going to take a whole bunch of different types of isomerase forms of the isopentyl I saw pyrophosphate or just the isopentyl pyrophosphate itself and I'm going to combine a ton of them I'm talking boatloads of these isopentyl pyrophosphates and eventually I'm going to form a very special molecule and this process right here I'm completely bypassing a lot of important information here or I'm sorry not a lot of information because you know just for me to convert this isopentyl pyrophosphate into this next molecule this

next molecule is called squalene so isopentyl pyrophosphate technically in between here if I were to actually kind of have an in-between step here isopentyl pyrophosphate let's actually just do it here in this step I just do here we say that we take the isopentyl pyrophosphate and I take and I actually convert that and to these molecules which are called isoprene units I so preen units and these isoprene units are important because it takes a ton of isoprene units to eventually get converted into a very important molecule called squalene okay so now we'll talk about the

scaling so squalene in order for me so this is a complete oversimplification because simply going from these isoprene units to the scaling can take up to 21 steps so let me write that down because it's significant me going just from the isoprene units to the scaling it can take up to 21 steps now one of the more important enzymes in throughout this process green is called squalene synthase and the squalene synthase is an environments helping with in these processes to convert these isoprene units into squalene now squalene is then going to be the precursor to

make another molecule and this molecule is called 7d hydro cholesterol so 7d hydro collector I guess apply heard of that whenever we talk about the parathyroid hormone with toughly to make vitamin D so you can actually make vitamin D from this point here but look we're going to make another molecule called 7d hydro cholesterol then what happens at 7d hydro cholesterol okay now here's where we get into the good stuff so now this 7d hydro cholesterol what can happen with this molecule there's 70 hydro cholesterol I'm going to put this squealing synthase under here that

we have some room to come back down again this is called squalene synthase now here's where it's important so let's make this a really big line here 7d hydro cholesterol can be converted into the molecule that we know as cholesterol so in this process here what am i doing I'm taking the 7d hydro cholesterol and I'm converting it into a molecule called cholesterol now this cholesterol that I'm making you it's crazy to see how we just take these two carbon fragments acetic aways and we synthesize a huge 27 carbon molecule like you would guys want

to know what I a cholesterol looks like I'll tell you I know you guys are excited you guys are chomping at the bit to see the structure of cholesterol so look here because I know you guys are chomping at the bit for so look I'm going to have three six carbon rings like this right then I'm gonna have another six carbon ring like this and then I'm going to have a five carbon ring like this then I like to put a methyl right here and a methyl right here so now let's number all of these

puppies here this right here is number one two three four then I'm going to come over here to five six seven eight nine and then I come to this last point here ten okay then I'm going to come up over here 11 12 13 I'm going to go over here 14 15 16 17 then we come over here 18 19 but I told you all the way exact you said it was 27 it is 27 coming off of the 17th carbon I'm going to have a branch like that 1 2 3 4 5 so 1

2 3 4 5 and then like this and now let's count these carbons over here 17 18 19 this is going to be 20 21 22 23 24 25 26 27 why am I telling you all this because there's important points throughout all of this on the third carbon there's a special thing that's going to determine the difference between certain types of steroid hormones on that third carbon there's usually a alcohol okay and then in between the fifth in the six-carbon there should be a double bond so now I like to just call this a

ring the B ring C ring and the D ring and then you got this little antenna structure this is our cholesterol molecule now we synthesize this cholesterol what is this cholesterol used for because it's extremely important we said that it's important to be able to take this cholesterol and synthesize a bunch of different structures so now let's take this cholesterol and see what we can actually do with this cholesterol okay so I told you that I could take this cholesterol molokai I'm not going to drill every single carbon again I'm just going to take this

carbon unit so that you can see that we have cholesterol here and what we're going to do with this cholesterol is we're going to take this cholesterol and use it to make a whole bunch of different molecules and again we can if you want to a ring B ring C ring D ring okay what I can do with this cholesterol is I can put it into the actual cell membrane you're the cell membranes are really important why why is the cell membrane important let's say that I have here the cell membrane and in the cell

membrane here you know we have phospholipids that are making up the actual cell membrane if I were to kind of zoom in on this a little bit let's say here's my glycerol okay and then coming on one side have the fatty acids right but you know that this specifically the cell membrane is a lipid bilayer so on the other side I'll also have another group of phospholipids but now here's the important thing phospholipids are you know they're they're basically they can make things not as fluid like but cholesterol is making it better and not being

so fluid like making a little bit more rigid so if I take this cholesterol molecule and I put this cholesterol molecule into the structure let's say I erased this part here and I put my cholesterol molecule in here so now what I do is I take my cholesterol molecule and I incorporate this cholesterol molecule into this structure what is that going to do what this does is it's actually first off it does two things two things that this does being cool incorporate into the membrane one is it makes the membrane less fluid like Les like

les fluidity less fluidity okay that's one thing so it's going to make it less fluid the other thing it's going to prevent drastic changes in phase transitions so changing from different phases so it prevents it prevents phase transitions you know it's another important thing it's also combining with a molecule that is present in this area let's say here I have a molecule special molecule that it's combining with to form a very special structure what is this green molecule here called this is called glyco sphingo lipids so these glycosphingolipids are combining with the cholesterol and as

a structure they're forming this whole thing here if I were to kind of encase it here they're forming what's called the lipid raft which is important in certain types of signaling pathways as well as a lot of other processes so again what's one thing that we can do with this cholesterol right away one thing I can do with this cholesterol is I can incorporate this cholesterol into the cell membranes because it's naturally in normal physiological levels is helping the membrane become less fluid helping it to be more rigid and hold up its actual structure the

other thing is preventing excessive phase transitions okay also it's combining with these glycosphingolipids within the cell membrane to form lipid rafts structures which are important for a lot of different functions like cell signaling processes what else can we do with the cholesterol so that's one thing we can do with it another thing that we can do with this is we can take and convert it into steroid hormones steroid hormones are very very important so I can actually make steroid hormones what kind of steroid hormones can I make you know there's many many different types of

steroid hormones we talked about some of them and endocrine I can make testosterone I can make estrogen I can make corticosteroids which includes your out dosterone and your cortisol I can make tons of different things progesterone a lot of different molecules that can come from this right so we can make steroid hormones we can make progesterone testosterone estrogen a lot of different corticosteroids like cortisol AB astron can add a corticoids so many different types of things that we could do with this so that's another basic unit for the cholesterol so cholesterol can be used for

its cell membrane structures steroid hormones what how it's going to be used for it also could be used for bile salts you know there's these things called bile salts and these vile salts are important because bio salts are important you know there's let's call Kolok acid there's called Kolak acid and then there's another one called deoxycholic acid and these are bile salts and they're important for what you know they're important we actually make this in the liver and they're incorporated into the bile which is excreted into the small intestine like specifically the duodenum what does

that help for it it helps with the emulsification of lipids you know taking lipids that are very very water insoluble and trying to make them more water-soluble by spreading them out into smaller fatty droplets that we'll talk about called me cells okay and a lasting we'll have another video specifically on this in detail but you know what else we can do with that cholesterol we can package this cholesterol and we can send it to other tissues so I can actually package this cholesterol and to do special lipoprotein molecule so let's say I take that cholesterol

but you know in order for me to take this cholesterol and put it into this actual vesicle I'm sorry this lipoprotein structure I need a special enzyme and this enzyme is called a cat and a cat is an enzyme that basically converts cholesterol into a cholesterol ester so again what what am i convert so if you guys remember here on the a on that third carbon I had an alcohol what I'm going to do is I'm going to take in this vesicle here I'm going to convert inside here I'm going to take and I'm going

to basically take and add an acyl group onto it so you know a cat is basically an ACO Co a and specifically what I'm doing here is I'm transferring on a a so group so in other words let me show you what I'm doing here so I'm going to take that actual group here I'm going to put on a double bond like I see CH 3 there so let's say I add on a 2 carbon group there now this is a cholesterol ester and if I were to draw the rest of the structure here you

guys would get the point here that basically I'm packaging this molecule into a nice big vesicle so let me draw a big vesicle here lipoprotein molecule so now this lipoprotein is going to have my cholesterol ester in it so again what is this molecule here called this is a cholesterol ester and this a cat enzyme is transferring that a co group that 2 carbon group onto the cholesterol molecule so it's acting as a a co cholesterol transferase enzyme and then after we package this into a protein covering so now this is actually going to be

the actual cholesterol component and around that I'm going to have my protein component and on the protein component I can have specific types of April proteins that we'll talk about depending upon the type of life of protein it is so for example this can be one type you know what this one is actually then we can actually call this one LDL bad cholesterol okay and this one is actually very dangerous if it's if there's really really high LDL levels that's why whenever people have high cholesterol mainly LDL you want to give them statins or lipitor

because if you remember that's going to inhibit the hmg-coa reductase enzyme so you don't make as much cholesterol so you can't utilize it in the lipoprotein pathway so again what is the small you're called it's called a lipo proteins so it's very important for making lipo proteins which can go and get transported to other different tissues you know there's another one that you can make here there's another one it's actually called VLDL we talked about that in the triglyceride synthesis video the only difference is is that instead of having a significant amount of cholesterol you

also add in triglycerides triglycerides are also added into the vldls and significant amount there's a lot of triglycerides and not as much cholesterol esters but nonetheless your liver can make vldls and LDL s it can also make other lipoproteins which you guys are probably heard of called HDLs which are going to help for being able to pull some of the cholesterol off of the vessel walls but we'll have an individual video on that but again understanding all of this is important but understanding the significance of why the cholesterol metabolism is occurring is more important understand

that I can use this for synthesis pathways incorporating into the cell membrane making steroid hormones making bile salt and actually helping to make lipoproteins for other different tissues because if you imagine LDL is actually taking and transporting some of that cholesterol to like the adrenal cortex you know in the adrenal cortex they need that cholesterol they need that cholesterol to be able to make their steroid hormones so it's very important that we have that cholesterol so taking it to the testes to be able to make testosterone and estrogen so without that there could actually be

potential like life-threatening problems but too much of it is also pretty bad and again knowing that out of this this is one of the most important metabolic steps in the entire body you know not only lipitor isn't actually inhibiting this oh and another thing I'm so sorry I didn't mention this this step right here we need NADPH too in a dp+ if you guys remember this was a very very strong reducing agent and we need him in this step because of his reducing power NADPH is utilized in a lot of different pathways you know not

just in steroid synthesis not just in triglyceride synthesis but also for nucleotide as well and even to train the synthesis of neurotransmitters - so NADPH is actually utilized in this step but remember this is a highly regulated enzyme another thing that can actually inhibit this guy at this point here is also going to be cholesterol cholesterol itself can inhibit this HMG co-reductase so high amounts of cholesterol can act on this hmg-coa reductase and actually inhibit the synthesis of himself he does it by activating specific proteolytic enzymes so he activates proteolytic enzymes that will actually help

to specifically inhibit this hmg-coa reductase but like I told you before insulin is also extremely important because insulin is also going to try to stimulate this enzyme activating this enzymes for certain types of second messenger intra cellular pathways to stimulate this enzyme whereas the actual guy who tries to oppose insulin is glucagon and you guys know that glucagon wants to be able to do what - this enzyme he wants to inhibit this enzyme inhibit the actual synthesis of cholesterol use it for making glucose use that ASC decoy to make glucose or to help to be

able to generate ATP instead primarily let it make glucose okay so very very highly regulated enzyme here alright so in this video we covered a lot of information I hope it all made sense I hope you guys really did enjoy it I hope it clicked if it didn't if you guys enjoy - hit that like button subscribe put a comment down in the comment section guys we really look forward to hearing from you guys alright engineers until next time