Gastrointestinal | Bile Synthesis

I'm engineers in this video we are gonna talk about bile synthesis super-important super importance pathway that is occurring in the liver if you guys haven't already it is super crucial that she goes go watch our video on liver physiology on the metabolism protein synthesis and the storage ok functions of it then after that it's also super important that you guys see our other liver physiology video that talks about xenobiotic metabolism okay in this video we're gonna talk about biosynthesis super crucial super important so let's go ahead and get started all right biosynthesis in order for

us to understand all this stuff we're gonna talk about we should really really understand what the heck is bile made up of that's important before we can even go any further we really need to understand what is bile so what is bile okay so bile is made up of a bunch of different things okay we're not gonna go through every single one of them I want us to get the main components of it because we're gonna have another lecture where we're gonna talk about the biliary system along with jaundice so it's really really important that

we understand some of the main components of bile so one of the big ones please don't forget this one this is really the most important one it is called bile acids okay so the first one that we're gonna have to talk about is going to be bile acids so let's write that one down bile acids are super important we'll talk about these guys like kolak acid and chino deoxycholic acid and those guys okay after that we really should understand that there's another one that's really really important and that is going to be bilirubin bilirubin this

guy is super important specifically for the clinical aspect in this relationship with jaundice another one that we're gonna talk a lot about here is going to be phospholipids okay we'll talk about one of the main ones that's actually associated with the bile which is phosphatidylcholine okay really really important forceful but there's also other ones like phosphatidic acid and phosphatidyl serine but they're really important as well another component is going to be cholesterol cholesterol is also really important because that's some of the ways that we can get rid of some of the excess cholesterol that might

be stored within the liver and there is also going to be these are the big ones these are some of the main components that I want you guys remember your bile acids your bilirubin your phospholipids your cholesterol another really big one that's why it goes hand-in-hand here is your xenobiotics again how would you define a xenobiotic it's any chemical or substance that is present in the that is not usually present within the human body or it's not produced in the human body or it's an excessively high concentrations more than usual okay these are the main

ones other components of the bile are going to be things like obviously water waters are really important one okay it's actually undergoing passive movement into the bile we'll talk about more of that passive an active processes and transport in the biliary system video another component is going to be a lots and lots of electrolytes tons of electrolytes sodium okay is a really big one calcium is a really big one another really important one which is important for the alkaline environment of the bile is going to be bicarbonate another component is going to be you might

even have some amino acids and some urea but another really important one that we'll talk about briefly is also called glutathione okay called glutathione and he's an antioxidant all right so these are some of the main things now what we're gonna talk about mainly in this video here is we're gonna primarily talk about bile acids and bilirubin okay and when we talk about the biliary system in jaundice we'll talk more about phospholipids cholesterol is antibiotics water electrolytes glutathione and other things that are moving into the biliary system but for right now these are the two

main things that I really want to Zone in on and talk about with respect to bile okay bile acids is going to be the main discussion here though okay bile acids what are the two types okay there's Kolok acid in Chino deoxycholic acid for us to understand that we have to understand what these two suckers are derived from and they are derived from cholesterol now the question that you should ask yourself going back to the metabolism video when we talked about liver physiology with respect to metabolism is cholesterol where did it come from it can

come from chylomicrons remember they were delivering some of that actual cholesterol from the ingestion of fat so chylomicrons they were important because they were bringing some of that cholesterol via the exogenous pathway what else did we say we can get some of this cholesterol from we can get it from high levels of acetyl co a so we can synthesize it and we can get it whenever we're actually recycling it through the lipoprotein pathway right but we're not going to get into that in much detail but I would you want you to understand that the liver

is making bile acids which are gonna be coming from cholesterol now cholesterol we're not going to go into the super super crazy structure of it I'm just gonna give you the basic things that are happening here well let's actually draw out the structure of cholesterol really quickly here and all right this guy here cholesterol is actually super important it's got these four different ring structures right if you remember from our cholesterol synthesis video is the a ring B ring C ring D ring and as this little like antenna thing popping out there also there is

a double bond right here and there's an O H coming here off of the third carbon this is your basic cholesterol molecule now what we do is we send this cholesterol to the smooth endoplasmic reticulum look at this guy here's gonna be one tube here and then here's going to be the other tube look at this okay here's our smooth endoplasmic reticulum the cholesterol is gonna travel down through this actual smooth endoplasmic reticulum so now look at this right in there okay when he's in there there's a bunch of different enzymes two really important ones

that are a part of your cytochrome p450 system look at this guy here let's draw him here's his little nose there's this little fauxhawk again here's this little body his legs are holding on here for dear life onto this it's got one hand holding on here and it's got one arm up there this guy right here he loves to wear a shirt that says seven I want to know why because this particular enzyme is called 7 alpha hydroxylase or we can say it's C YP 7 e1 ok this is a cytochrome p450 enzyme it's called

a 7 alpha hydroxylase what do you think it does to the cholesterol then it's gonna put a hydroxyl group on the seventh carbon of this cholesterol so now watch this guy we're gonna follow him down through this pathway here so we'll follow this guy down here it's gonna react there and it's gonna come out as what let's redraw this molecule here here we're gonna have the three rings and what we do is we also cleave off a chunk there's so many different steps this is only one of the big crucial steps that are involved in

biosynthesis this is one of the crucial steps there's other steps and what happens in those steps is you actually cleave off a part of that antena portion and actually what happens is is you get this carboxylic acid that you're adding on that's why it's called Kolok acid or chino deoxycholic acid because you're actually converting a part of that hydrocarbon into a carboxylic acid and we have this o age group there in the third carbon well what do we say that that 7 - hydroxylase does it adds a oh wait group on to the seventh carbon

there it is okay this right here this molecule he is one of our primary bile acids so we have cholesterol we're gonna synthesize a primary bile acid this primary bile acid is called Kolok I'm sorry Chino deoxycholic acid Chino deoxy Kolak acid alrighty so that's one super super important one this is one of our primary bile acids okay the other one is we're going to take this cholesterol we're gonna have it react with that seven alpha hydroxyl a so now let's draw that guy in there afterwards we'll take this cholesterol and we'll say another guy

one of the other ones he after reacting with that cytochrome 7 cytochrome 71 or 7 alpha hydroxylase he goes to another enzyme so now let's draw this guy here here's our four range structure like this okay and let's assume that he's already broken that piece off right there I made the hide that ah carboxylic acid and he's got the O H right there it's actually put in purple to be consistent here's the O H on the seventh carbon that's already happened now there's another enzyme he's waiting on down here look at this dude he is

going to be another really important enzyme and he's got one arm there he's got the other arm over here he's got his foot over here and he's got his foot like this this guy he has a 12 on his chest he's got a 12 - Jesse likes to wear a shirt that has 12 now this one actually comes from a cytochrome family particular 8b1 alright so this guy right here rcy pap 1 I know it seems odd but he is really our 12 alpha hydroxylase just like over here so this one actually does make sense

right cy said p 71 this was our seven alpha hydroxylase these are really important in the formation of the bile acids well what happens is this guy right here he sticks his nice little fat foot out here and he actually puts a hydroxyl group on to the seventh carbon of this cholesterol molecule and now look what happens when he comes out of the smooth ER he comes out and now we are going to have still that four range structure like this okay now that I 10 apart again it was broken off we should have a

carboxylic acid right here we should have a double bond right there and OAH right there he should have an OS on this carbon the third the actual seventh carbon let's make that nice and big there and now we should have another Oh H but now it's going to be on the twelfth carbon okay so now we're gonna have that Oh H right there this guy is called Kolak acid so what does this one called he is called Kolak acid these are the two primary bile acids that we are synthesizing okay now something that can happen

is the liver can actually just go and excrete these bad boys out into the biliary system like pretend here like right over here let's say that here is our biliary can now like you lie okay here's our biliary can I'll lick you like we can take now if we need to if we want to we can take some of these primary bile acids and we can go ahead and shunt these guys and put them into the biliary system through specific types of transporters that we'll talk about one of the main ones that we actually utilize

to pump these suckers out here is called B Sep bile salt export pump okay super important one but guess what else we don't always have to just do that we also do something else that's really really important when we take these guys in the liver we can do what's called conjugation so what we did here is we actually did some hydroxylation reactions all right then we can do some conjugation reaction so you notice here this is type of this is a type of xenobiotic metabolism if you think it right right so now what we can

do here is we can take this guy here the Chino deoxycholic acid we can send it through two pathways we can take the cola Cassatt and we can send this bad boy through two pathways let's say that now that carboxylic acid there it's really good if I actually deprotonate that bad boy and then I add on a specific type of molecule that I can react with it our conjugate with it that can make it super super polar because right now it's not very polar ice maybe slightly polar well let's make it really polar so now

let's take these molecules here I'm gonna draw my two cholesterol molecules here I'm gonna have all these guys and what we're gonna do is is we're gonna go ahead and add on a special molecule here and let's say that this guy that we're gonna add on here we're gonna add it on here in blue okay here's this blue molecule that we added let's say that that blue molecule that we added is called glycine he is one of our amino acids we can do that to both of these guys so we can add it onto the

ccino deoxycholic acid or we could add it onto the cola Cassidy so now look at this guy here boom put the O H right there put our blue o H right here and again what did we add on to this bad boy we added on a glycine and the glycine is able to have this charge which makes this molecule this new molecule super polar what do we call this guy since it's glycine we call it glyco this is Chi no deoxy Kolok and I said it's a mouthful we can do something else we can add

on a let's do this one and purple actually yeah purple we can add on something else we could add on what's called a taurine okay it's another kind of amino acid basic structure right so now what I'm gonna do is I'm gonna take and add that guy on there so now let me draw my four rings here okay and again I'm gonna have here my carbonyl group right there and what did I add on to it I added on to this bad boy here a taurine molecule and again what will I have right here I'll

have an OHA off right there I'll have a double bond right there and I'll have a OS right there this molecule where I conjugated it with the taurine this is called Toro Chino deoxycholic acid so Toro Chino deoxy Kolak acid these are the two types of conjugated bile salts okay now same thing I can take here with the cola Cassatt and do the same process here doing here is I'm just conjugating these badboys to make my bile acids more polar that's it so now hey let's rip through these bad boys so here I'm gonna have

my four ring structure here and again carbonyl group right there double bond o H have an OS on two points now one on the third carbon and the other one is actually orange and that should be on the 12 carbon okay now what do I need to do here okay I need to add on a glycine molecule okay and this is gonna make it super super charged molecule what do you call this bad boy we call this glyco Cola gas and a lot easier one for for this guy here okay so we just call this

glyco Kolok acid same thing with the other one all we're gonna do is we're gonna add a touring on to it so let's come over here let's make a little bit more space here for this bad boy so here's this guy come over here reacting with the taurine what are we gonna get let's have a four ring structure you guys better know how to draw cholesterol the basic structure but by now after this so now let's have this guy right here here's our double bond right there and again what am I gonna have connected on

to this I'm going to have my Tori molecule which is gonna make this guy super charged and a lot more polar and again what will I have here Oh H coming off of the seventh carbon I'll have my normal Oh H coming off of the third carbon I don't have an O H here coming off of the 12th carbon okay what do you call this molecule Toro Kolak acid so this is called Toro Kolak acid so again just remember these guys right here super super important these are our primary these were a primary bile acids

the chena deoxycholic acid and the cola Cassatt then what we did is we conjugated them with glycine and taurine to make them more polar if you remember what did I tell you though it could happen I told you that some of these guys the Chino deoxycholic acid in the kulluk acid we could take this put it into our biliary system all right now the biliary system you know will combine with the pancreatic system right you have your common bile duct combined with the main pancreatic duct and then what happens they form the ampulla of Vater

or the pout of pancreatic ampulla which is controlled or opening is controlled by the apado pancreatic sphincter or the sphincter of Oddi but basically what happens is it pushes those bile acids out here so let's just put out here what do we have now Kolak acid and this monster over here called Chino deoxy Kolok acid these guys can be metabolized by bacterial enzymes so there is bacterial enzymes located within our intestines so let's say here's some bacteria here look here's our bacteria look at this dude he is ready to help out know if he's got

a couple hairs here he's smiling he's ready to roll he produces particular enzymes that can rip off a hydroxyl group off of these two guys guess what part it rips it off that it's a seven alpha D hydroxylase when it does that this is important when the bacteria break down these primary bile acids like Kolak acid and Chino deoxycholic acid it converts it into secondary bile acids so now you should actually know let's actually do a small little diagram over here small little diagram say here's your liver okay how's the form ligament right there let's

just say that here we're just gonna represent this tube just to say as in simple diagram here this tube is representing your gastrointestinal tract we're gonna represent this right here as your biliary system okay that's connecting to the actual gastrointestinal tract here like it's just a functional diagram and then there's going to be a circulation that returns some of the actual bio components back to the liver this right here is a super important thing okay this actual a portal circulation here we call this whenever we have our remember what were we actually making here let's

put bile acids they were put into our biliary system brought here into the intestines helped to emulsify some of the fat then metabolized by bacteria and they can be taken back and moved through this portal circulation back to the liver what do you call this whole circulation they call this the inteiro hepatic circulation it's super-important okay we'll talk more about it later but I want you guys to understand that what happens is that these got actual bile salts the bile acids primary once they go to the biliary system go to the intestines get broken down

by bacterial enzymes and get converted into secondary bile acids so now when they come back let's just represent here here's our portal circulation and they're gonna come back to the liver here okay let's represent here our liver okay what are these molecules called after their Mac metabolized by the actual bacteria we should know what those are called so now we take the cola Casson and it's acted on by that bacterial enzyme called 7 alpha I'm gonna put do HD hydroxylase or we take the other one which was the Chi no deoxycholic acid and we break

that one down by the 7 alpha D hydroxylase all right what do they turn into now they are now going to be secondary bile axes let's do these ones in this blue here they are now going to become kolak acid will become deoxy Kolak acid okay the Chi no deoxycholic acid when it's broken down by the 7 alpha D hydraulics remember this is coming from the bacteria it converts it into what's called light Oh Kolak acid these two right here are your secondary bile acids okay so these were your primary your Chino deoxycholic acid in

the cola cassadee they can be either conjugated or excreted into the bile brought back through the entero patek circulation after bacterial breakdown of the seven alpha the seven hydroxyl group converted into secondary bile acids so these are my secondary bile acids and guess what I can do with these guys I can do the same thing I could either conjugate them with taurine or I could conjugate them with glycine and if I conjugate the deoxycholic acid with glycine I get glyco deoxycholic acid if I do it with taurine I'll get Toro deoxycholic acid if I conjugate

the lytic Olek acid glycine a bit glycol I toke Olek acid and if I conjugate the lytic Olek acid with the touring I get Toro lytic Olek acid that is the significance here with the bile acids these are attempt telling you guys you guys can't forget this this is the most important they account for about 70 percent of the super important components of the bile the bile acids without these emulsification of fat wouldn't be possible so one more thing before we continue to go on to the next thing I wanted to talk about which is

to Billy Rubin and biochemistry you guys know that there's an important thing called regulation all right we have two allosteric lis regulate particular enzymes this enzyme right here the seven alpha hydroxy so the cytochrome p or at the cytochrome 71 this is our rate limiting step okay so we should remember that let's do this here in this orange here this is our rate limiting step so in other words it controls it's the slowest step and it's the one of the most important steps so what happens is whenever there is a lot of kolak acid or

chino deoxycholic acid these bile acids here let's do this in this black here these guys can actually look come back here and allosteric ly regulate that enzyme so if there's a lot of Kulik acid a lot of Chi no deoxycholic acid they can come back and inhibit this enzyme will cholesterol be able to convert be converted into Kolak acid and chino deoxycholic acid anymore no so that's important for the regulation step there okay last thing and that is going to be the bilirubin first off we have to understand where in the world does the bilirubin

come from bilirubin is the breakdown product of the heme within hemoglobin okay I want you guys to go back and think for a second about a particular organ that was super super crucial in the breakdown of old and defective red blood cells obviously it could be anywhere with sinusoidal capillaries but the big big one was the spleen okay but it could be the liver it could be the red bone marrow but the major major one here is going to be the spleen now if you remember the spleen has a bunch of different macrophages in it

and we talked about you know the chords of bill rod or the sinusoidal capillary so here's our spleen and again what do we say is really important they're really important white blood cell here it's going to be the macrophages let's draw here a macrophage here's going to be a macrophage and what we're gonna do is we're gonna assume that this red blood cell right here let's say here's our red blood cell and he's reached the end of his prime okay it's greater than a hundred and twenty days this dude's limpin by now you know he's

got a cane it's time for him to go but by this macrophage is going to engulf that red blood cell okay so now let's draw this big macrophage here let's say here's our macrophage okay it engulfs our phagocytose is that actual red blood cell now what is the main component of the red blood cell the main component is the hemoglobin obviously there's other proteins and cell membrane and stuff like that but the main one we're talking about here is the hemoglobin the hemoglobin is going to be broken into two things one is it's gonna be

broken into the heme component all right so the heme component the other component is it's broken down into what's called globine now globin is just a protein and it will get broken down into amino acids I'm gonna put your AAA amino acids which can be recycled it can be utilized in various different ways it might be sent to the bone marrow the bone marrow might use it to make more hemoglobin right the heme though is consisting of two components one is the iron and the other one is the one that we're gonna talk about here

in a second but what happens with the iron just as a curiosity here two things it could stay in this actual macrophage and bind to a polariton remember we talked about that we said a combined April fair to turn into ferritin fair to combine with a whole bunch of fair tends to make hemosiderin or we could push this iron out here and have it bind on to a particular transport protein that our liver so kindly makes to transport the iron around or to transfer it called transferrin okay so that's one really important thing here is

we can actually have it put on that guy and then take in two different tissues around the body if needed but we care about this guy the heme when he gets broken down he actually gets broken down into what's called Billy Verdun okay then Billy Verdun is reduced into a molecule called Billy Ruben okay if you really want to know the enzyme that controls this step I'm gonna put H oh it's called heme oxygenase and then the enzyme that controls the conversion of bilirubin into bilirubin is called I'm up a B R which is Billy

Ruben reductase so again he moxa jenny's converts the human to Billy verdun Billy verdun or dark stays converts to Billy verdun to Billy Ruben now Billy Ruben is not very hydrophilic it's lipid soluble it's not very water loving so when we put it into the blood we have to make sure that we bind it to a transport protein and that transport protein that we bind it to is called albumin okay it's called albumin then that Billy Rubin when it's bound to albumin is then going to shuttle that bilirubin to the liver now once it gets

to the liver the liver is gonna do a couple things to it so to take the actual bilirubin up okay it'll take it up into the cells so let's just say that now we're inside of the liver cell okay that bilirubin is what's called unconjugated bilirubin in other words it doesn't have some type of polar molecule attached to it so this is gonna be what's called on conjugated what's gonna happen is you guys remember we had a fat dude here look at this guy here draw him right here and we had him like this and

he was called udp-glucose I'll transfer a so we put him as ugt he was important because what he did is is he transferred a glue karani group onto the bilirubin okay he transfers so now he's gonna react here and he's gonna take the bilirubin which is not very water-soluble so now I'm gonna represent bilirubin is this dot here let's say that here's bilirubin not very very water soluble at all but now what we're gonna do is because we're gonna combine this bad boy with a glue karani molecule which is super super polar super super charged

this right here and that bilirubin which is bound to the glue coronate is conjugated this is conjugated and then what do we know about that then we know that the bilirubin that is now completely conjugated what are we gonna do with it we're going to take this bad boy and excrete it into our biliary system so now we're gonna do is we're gonna take this guy here and let's just say here's our biliary cannot look you lie here there's our biliary canaliculi and we're gonna excrete it out into the bile okay we have to utilize

particular transporters which are super super important and again we'll talk about this one because it's very very relevant to certain diseases it's specifically called M R P to multi resistance associated peptide type 2 and what it does is is it just go ahead goes ahead and pops that conjugated bilirubin into the biliary system here so now here's our gonna be our glue karani molecule here and then it's combined with the bilirubin okay here I'm gonna put here my Billy ribbon now if you guys know we're go into a more detail again in the biliary system

but what happens is is the conjugated bilirubin will then get taken from the biliary system get put into the intestines and then what can happen with it if you know here we'll do a very brief little thing of that here let's say here is going to be the here's our intestines okay there's the intestines we're gonna have this connected to it now so here's our biliary system let's say that it's connected with our intestines it's gonna go ahead and shoot that actual conjugated bilirubin out and into our gastrointestinal tract now we know that there's bacterial

enzymes okay different types of bacterial enzymes let's just say here's a bacteria here he's ready to gobble up some bilirubin okay what this guy will do is he'll actually break down some of that bilirubin and convert it into another molecule so let's say here it gets reacted with these bacterial proteases and then it gets converted to something else and I'm gonna put here for this guy it's called uro the lineage in' okay so then we're going to convert the actual conjugated bilirubin when we react with the bacterial enzymes we can convert it into urobilinogen now

some of that uribl Inogen we can get it down to the actual ileum like the distal part on the ileum and we can have it get absorbed reabsorbed and then taken back to the liver by if you guys remember this special circulation here called the in taro hepatic circulation which will take this bilirubin back up to a particular organ very very important one called the liver all right now some of that your Abba lineage in that we get the liver might just reuse it and again use it to make more bilirubin more conjugated bilirubin some

of it though might go to your kidneys and when it gets to your kidneys your kidneys will actually have the ability to convert that your Abba lineage in it'll convert it into something else okay so now here's some of this will go to your kidneys it will undergo specific metabolism and then it'll come out as uro billon and this is what causes you urine to have that yellowish pigment that yellow hue within the urine but some of the uribl Inogen will continue to get broken down by bacterial enzymes so let's say they here's some some

bacterial enzymes that your Abba lineage and just keeps going on and down its way through the intestines and it reacts again with some more bacterial enzymes it can get converted to something else which makes our poo poo brown and that is called stir Co billing so then look here there's gotta be a there's a lump of turds right there all right and that's gonna what causes our poo poo to be brown okay this circled on it gives it that brownish hue all right so that is important so now what have we talked about primarily here

we talked about the bile acids we talked about the bilirubin we talked about how we make the bile acids we talked about the bilirubin and how it's actually put into the biliary system how to put incorporate into the bile synthesis pathway again phospholipids just remember that these are coming from fatty acids okay and simple the most simplistic way here all you're doing is you're taking a molecule the main one that we talked about here is phosphatidylcholine that's one of the main phospholipids and bile all we're doing is we're taking choline essential vitamin like nutrient reacting

it with dye a seal glycerols okay when we react it with the diacylglycerol what do we get we get fossa tittle choline okay and this is important because again it's gonna play a very very crucial role in making sure to Saul you make the cholesterol really soluble helping to emulsify some of the fat and you know bile acids are pretty Patou toxic and high concentrations they can actually cause a Patou toxicity these phosphatidylcholine molecules help to reduce the apparent Aqsa city of the bile acids one last thing that I forgot about we got to make

sure that we mentioned this it's super super important within the bile is oh man this guy prevents a lot of bacterial growth these are I GA antibodies these are also another component can't believe I forgot this one I'm sorry super super important because they inhibit a lot of bacterial growth within our gastrointestinal tract so these are some of the main components about again we will talk more about how the actual bile is actually put what like what the components about how it's transported into the biliary system and its relationship with jaundice in another lecture okay

iron engineer so in this video we talked a decent amount about biosynthesis and I really do hope it made sense I really do hope you guys enjoyed it we're gonna dig into this topic even a little bit more when we talk about that in another lecture which is going to be on the biliary system and we're gonna talk a lot about jaundice in that video too I hope you guys enjoyed this video if you guys did I'm begging you please hit that like button comment on the comment section and please subscribe also if you guys

get a chance go check out our Facebook or Instagram maybe even our patreon account I ninja nerds as always until next time [Music] you