Understanding Bile Synthesis and Function

Hi, Run Doctor Mike here. In this video, we're taking a look at bile synthesis, focusing on bile acid and bile salt synthesis. Let's take a look. All right, to begin, let's orientate ourselves with what I've drawn up here. So firstly, we've got the liver where this takes place, bile synthesis and bile acid synthesis, specifically in the hepatocyte. Keep that in mind. Now from the liver, We've got its connection with the gallbladder, which stores and concentrates bile and can secrete it into the small intestines. Small intestines have three components. The first, the duodenum, then the jejunum, and then finally, the most terminal part of the small intestines, the ileum, before it moves into the colon or the large intestines. We also have here the portal vein or the portal system. So this is important because it absorbs all those important... vitamins, electrolytes, nutrients that need to be transported back to the liver. So here we've got everything we need. Now to begin, let's talk about bile itself, what bile is. So firstly, let's talk about the components within bile. Now, number one component in bile, more than 95% of bile is made up of water. Number two, the second most prominent component is going to be that of bile acids. and bile salts. And that's going to be the focus of today's lecture. Then you've got a whole range of other things. So you've got bilirubin. Now bilirubin is a metabolite, a breakdown product of red blood cells. It's the reason why your poo is brown and your wee is yellow. You've got cholesterol. You've got fatty acids. You've got proteins and amino acids. You've got... ions like sodium and bicarbonate, as an example, you've got a whole range of things inside of this bile. Now, what's the purpose of it? Well, the main component in bile outside of the water being the bile acids and bile salts, they are the most important component because they do two things. One, they help us emulsify the fats that we ingest through our diet. Emulsification is taking a big fat globule and helping breaking it up into smaller, more manageable pieces that the lipase, which is the enzymes that the pancreas produces, so it can chop it up more easily. And secondly, absorption. So these bile acids and bile salts are really important for the absorption of fat soluble substances. So not just what makes up triglycerides, which are fatty acids and glycerol, but also... for other lipophilic substances like cholesterol and phospholipids and very importantly fat soluble vitamins like vitamins D, E, K and A and that's an easy way for you to remember the fat soluble vitamins as deca. So we need bile acids and bile salts to break down fats into small more manageable pieces but also the absorption of lipophilic substances in our gut into the bloodstream. Now, how do we make these bile acids and bile salts? Great question. We need to begin in the liver. So remember, we're starting in a hepatocyte. So that's one of the major cells within the liver that performs most of the functions. And what this hepatocyte does is it takes cholesterol and it transforms it. Now, where do we get this cholesterol from? So number one, we get it from our diet. So we can take cholesterol from the foods that we eat. Or we can synthesize cholesterol. from Acetyl-CoA, which we know is very important in the Krebs cycle. If you want to know more about Acetyl-CoA, watch my Krebs cycle video. Now, if cholesterol looks like this, for example, like this little guy, what we want to do in the liver, in the hepatocyte, is turn that cholesterol into two major things. We want to turn it into cholesterol into something called colic acid and something called chino-deoxy-colic acid. Now these two acids are what we call our bile acids. If we want to be specific they're called our primary bile acids. Which makes you think maybe there's going to be some secondary bile acids. And they are metabolites of cholesterol. In actual fact There's many steps to go from cholesterol to these two components, but the right limiting step involves a really important enzyme called CYP. C-Y-P-7-A-1. And it's actually the rate limiting step. That's why it's the most important step. Now, CYP tells you it's from cytochrome P450 family. What is that? This is a family of genes that are really important in metabolism and specifically xenobiotic metabolism, breaking down toxins and drugs into more manageable metabolites. So this is part of that family. Now, I said if cholesterol looks like this guy, colic acid would effectively look like this. And chino-deoxy-cholic acid would effectively look like this. So they're very similar is the point that I'm trying to get across. Now, what happens with these? Well, a couple of things can happen. First is that they are secreted out of the intestines and they are sent off to the gallbladder. Now, in the gallbladder, a couple of things. One, they can just be stored. And two, they can be... concentrated. And they can be concentrated by up to 10 times more concentrated. They're the two important functions of the gallbladder. They can also just be secreted directly into the intestines where they remain predominantly unchanged until they get all the way up to the ileum or even the cecum. Now, what happens when they get to this particular point? So what we have are bacteria, as you know, in our intestines, predominantly the large intestines. and the distal portion of the small intestines. And this bacteria will take colic acid and chino-deoxy-colic acid and turn them into something else. What they turn them into are the following. They turn them into deoxy-colic acid, and they turn them into litho-colic acid. Now, if you want to know which ones, Colic acid turns into the deoxycolic acid, and the chenodeoxycolic acid turns into the lithocolic acid. And so if you were to look at how they look, so the colic acid turns into deoxycolic acid, this guy's going to look like this. And the lithocolic acid is going to look like this, right? So again, very similar. These are what we call our secondary bile. acids. Now these secondary bile acids, about 5% of them can be pooped out. So it can be thrown out throughout faeces. But 95% of them will go back into our portal vein and head back towards the liver. It'll be thrown back into the liver. Now what do we do with them in the liver? Well, let's draw them up, right? Let's draw them up next to these two. So we've got one here with both arms pointing down, and we've got another one here with both arms pointing up. And let's just label them. So deoxycolic acid, deoxycolic acid, and lithocolic acid. Brilliant. Now what can happen? All right. So in the liver, in the hepatocyte, we've got a couple of other things. Importantly, what we have is this. We have amino acids. Amino acids like, and I'm going to change color. There we go. Amino acids like glycine and amino acids like taurine. Now think of these amino acids like hats. So the taurine looks like a regular little hat and the glycine looks like a big top hat from the Victorian era. What can happen in the liver, in the hepatocyte is these primary and secondary bile acids are unconjugated. So nothing's linked to them. Now we're going to conjugate these amino acids to them. And this is what the hepatocyte does. Now, effectively you can put a glycine on colic acid, canodeoxycolic acid. deoxycholic acid or lithocholic acid. It can go on any of them. Same thing with the taurine. It can go on any of them, but we're just going to draw as an example. Let's just put the top hat, the glycine on the colic acid. And let's say we're going to put it on the lithocholic acid and let's put a taurine hat on the chino deoxycholic acid and the deoxycholic acid. What have we just created? We've now created what we call conjugated. We've just created conjugated bile salts. We've just created bile salts. Very important. And what are these bile salts called? So if it's got a glycine, how is this going to be called? Glycolic acid or glycolic salt, right? This is going to be called, because it's got the taurine, taurokinodeoxycolic acid. And this one? taurine is going to be called toro deoxycolic acid and this one glycine glycolitho colic acid or colic salt but effectively they are now bile salts what is the point of putting these hats on we know amino acids are quite negatively charged right now that means they love water which means we have now just created where are they going to go They get pushed into, again, the gallbladder to be stored and concentrated as conjugated bile salts, and they can be thrown into the small intestines. So what you have floating around are both these bile acids and the bile salts. Now, you might be thinking, okay, but what happens once they get to the bacteria? Great question again. If they're wearing the hats and they're conjugated, the bacteria can unconjugate. Unconjugate. So what the bacteria can do... is it can basically get rid of the hats at this point and throw either the primary or secondary bile acids now back into the liver to be conjugated again. Unconjugated, conjugated. Unconjugated, conjugated, right? Primary, secondary. Primary, secondary. This whole thing here, right? As you can see, we've just created this thing that goes like this. I'll just draw it simplistically like this, right? This is called the enterohepatic circulation. Enterohepatic circulation. That's really important. This 95% of these bile acids and bile salts keep getting circulated back. All right. What is the point of them? I said we need them for emulsification and absorption. How? How do they do this? All right. Let's take a look. So. If you were to ingest a fatty meal, right? So you're going to have fats coming from the stomach. And in this fat, you're going to have fatty acids. You're going to have glycerol. You're going to have cholesterol. You might even have phospholipids, right? You could even have vitamins D and E and K, whatever it might be. They're going to enter the duodenum. They haven't really been digested yet. In the mouth, we do release a little bit of... lipase in what's called lingual lipase and a little bit in the stomach, but mostly undigested until the duodenum. Once this fat gets into the duodenum, it stimulates a group of cells. Now, these cells are called enteroendocrine cells. And when the fat comes across these enteroendocrine cells, it triggers them. to release an important hormone called CCK, cholecystokinin. Now, cholecystokinin, cholecystokinin, cholecysto means gallbladder, kinin means contract. So what this hormone does, unsurprisingly, is it tells the gallbladder to contract and release bile. Brilliant. It also tells the liver to release bile. Again, brilliant. Now, when we release this bile, remember that we've got two important components here. We've got the thing that's made out of the cholesterol, right? Which loves fat. It's lipophilic. And we've got the hat on it, the amino acid, which loves water. Let's just draw the... glycine hat here and this is hydrophilic this is brilliant this is exactly what we want because if we take that big bit of fat right it's too big for the molecular scissors the lipase to chop up it's too big so that's lipase but what we can do is the lipophilic part can bind to the fats And the water part, or the water-loving part, the amino acids, can be exposed to the fluid environment. the bowel of the lumen of the bowel and then it allows for it to be broken down into smaller pieces. So effectively it then allows for it to be broken down so that we can have smaller more manageable pieces. And this is what the lipase can chop up. Now, where does the lipase come from? Remember this? Remember we've got our pancreas, right? We've got our pancreas and the pancreas is going to be connected up. And unsurprisingly, Collie's sister Kynan triggers the pancreas to release lipase and amylase and the various proteases and they all get released into here to help chop them up. Now, I said they help with absorption as well. That's important because what happens is that we can surround these smaller bits of fat, which we call myceles, and then we can bring them over to the enterocytes, and they facilitate all the fat-soluble substances to be absorbed. Again, what is it? Like the not triglycerides, but fatty acids and glycerol. and vitamin D and E and K and A and cholesterol. And they can then get absorbed into predominantly the lymphatic system and be sent to the body. Now, once they're in the lymphatic system, this is just for completion sake, they get bound up into something called a chylomicron. And the chylomicron contains fatty acids, glycerol, the fat soluble vitamins, cholesterol, and so forth. Sike. Hopefully this helps you. This is a quick run through of bile acids, bile salts, and how we synthesize bile. I'm Dr. Mike. Hi everyone, Dr. Mike here. If you enjoyed this video, please hit like and subscribe. We've got hundreds of others just like this. If you want to contact us, please do so on social media. We are on Instagram, Twitter, and TikTok at Dr. Mike Todorovic, at D-R-M-I-K-E-T-O-D-O-R-O-V-I-C. Speak to you soon.

So firstly, we've got the liver where this takes place, bile synthesis and bile acid synthesis, specifically in the hepatocyte. Keep that in mind. Now from the liver, We've got its connection with the gallbladder, which stores and concentrates bile and can secrete it into the small intestines.

Small intestines have three components. The first, the duodenum, then the jejunum, and then finally, the most terminal part of the small intestines, the ileum, before it moves into the colon or the large intestines. We also have here the portal vein or the portal system.

So this is important because it absorbs all those important... vitamins, electrolytes, nutrients that need to be transported back to the liver. So here we've got everything we need.

Now to begin, let's talk about bile itself, what bile is. So firstly, let's talk about the components within bile. Now, number one component in bile, more than 95% of bile is made up of water.

Number two, the second most prominent component is going to be that of bile acids. and bile salts. And that's going to be the focus of today's lecture.

Then you've got a whole range of other things. So you've got bilirubin. Now bilirubin is a metabolite, a breakdown product of red blood cells.

It's the reason why your poo is brown and your wee is yellow. You've got cholesterol. You've got fatty acids.

You've got proteins and amino acids. You've got... ions like sodium and bicarbonate, as an example, you've got a whole range of things inside of this bile. Now, what's the purpose of it? Well, the main component in bile outside of the water being the bile acids and bile salts, they are the most important component because they do two things.

One, they help us emulsify the fats that we ingest through our diet. Emulsification is taking a big fat globule and helping breaking it up into smaller, more manageable pieces that the lipase, which is the enzymes that the pancreas produces, so it can chop it up more easily. And secondly, absorption. So these bile acids and bile salts are really important for the absorption of fat soluble substances. So not just what makes up triglycerides, which are fatty acids and glycerol, but also...

for other lipophilic substances like cholesterol and phospholipids and very importantly fat soluble vitamins like vitamins D, E, K and A and that's an easy way for you to remember the fat soluble vitamins as deca. So we need bile acids and bile salts to break down fats into small more manageable pieces but also the absorption of lipophilic substances in our gut into the bloodstream. Now, how do we make these bile acids and bile salts?

Great question. We need to begin in the liver. So remember, we're starting in a hepatocyte.

So that's one of the major cells within the liver that performs most of the functions. And what this hepatocyte does is it takes cholesterol and it transforms it. Now, where do we get this cholesterol from? So number one, we get it from our diet.

So we can take cholesterol from the foods that we eat. Or we can synthesize cholesterol. from Acetyl-CoA, which we know is very important in the Krebs cycle.

If you want to know more about Acetyl-CoA, watch my Krebs cycle video. Now, if cholesterol looks like this, for example, like this little guy, what we want to do in the liver, in the hepatocyte, is turn that cholesterol into two major things. We want to turn it into cholesterol into something called colic acid and something called chino-deoxy-colic acid.

Now these two acids are what we call our bile acids. If we want to be specific they're called our primary bile acids. Which makes you think maybe there's going to be some secondary bile acids. And they are metabolites of cholesterol.

In actual fact There's many steps to go from cholesterol to these two components, but the right limiting step involves a really important enzyme called CYP. C-Y-P-7-A-1. And it's actually the rate limiting step.

That's why it's the most important step. Now, CYP tells you it's from cytochrome P450 family. What is that? This is a family of genes that are really important in metabolism and specifically xenobiotic metabolism, breaking down toxins and drugs into more manageable metabolites.

So this is part of that family. Now, I said if cholesterol looks like this guy, colic acid would effectively look like this. And chino-deoxy-cholic acid would effectively look like this. So they're very similar is the point that I'm trying to get across. Now, what happens with these?

Well, a couple of things can happen. First is that they are secreted out of the intestines and they are sent off to the gallbladder. Now, in the gallbladder, a couple of things.

One, they can just be stored. And two, they can be... concentrated.

And they can be concentrated by up to 10 times more concentrated. They're the two important functions of the gallbladder. They can also just be secreted directly into the intestines where they remain predominantly unchanged until they get all the way up to the ileum or even the cecum.

Now, what happens when they get to this particular point? So what we have are bacteria, as you know, in our intestines, predominantly the large intestines. and the distal portion of the small intestines.

And this bacteria will take colic acid and chino-deoxy-colic acid and turn them into something else. What they turn them into are the following. They turn them into deoxy-colic acid, and they turn them into litho-colic acid. Now, if you want to know which ones, Colic acid turns into the deoxycolic acid, and the chenodeoxycolic acid turns into the lithocolic acid. And so if you were to look at how they look, so the colic acid turns into deoxycolic acid, this guy's going to look like this.

And the lithocolic acid is going to look like this, right? So again, very similar. These are what we call our secondary bile.

acids. Now these secondary bile acids, about 5% of them can be pooped out. So it can be thrown out throughout faeces. But 95% of them will go back into our portal vein and head back towards the liver.

It'll be thrown back into the liver. Now what do we do with them in the liver? Well, let's draw them up, right? Let's draw them up next to these two.

So we've got one here with both arms pointing down, and we've got another one here with both arms pointing up. And let's just label them. So deoxycolic acid, deoxycolic acid, and lithocolic acid. Brilliant.

Now what can happen? All right. So in the liver, in the hepatocyte, we've got a couple of other things.

Importantly, what we have is this. We have amino acids. Amino acids like, and I'm going to change color. There we go.

Amino acids like glycine and amino acids like taurine. Now think of these amino acids like hats. So the taurine looks like a regular little hat and the glycine looks like a big top hat from the Victorian era.

What can happen in the liver, in the hepatocyte is these primary and secondary bile acids are unconjugated. So nothing's linked to them. Now we're going to conjugate these amino acids to them.

And this is what the hepatocyte does. Now, effectively you can put a glycine on colic acid, canodeoxycolic acid. deoxycholic acid or lithocholic acid. It can go on any of them. Same thing with the taurine.

It can go on any of them, but we're just going to draw as an example. Let's just put the top hat, the glycine on the colic acid. And let's say we're going to put it on the lithocholic acid and let's put a taurine hat on the chino deoxycholic acid and the deoxycholic acid. What have we just created?

We've now created what we call conjugated. We've just created conjugated bile salts. We've just created bile salts. Very important. And what are these bile salts called?

So if it's got a glycine, how is this going to be called? Glycolic acid or glycolic salt, right? This is going to be called, because it's got the taurine, taurokinodeoxycolic acid. And this one?

taurine is going to be called toro deoxycolic acid and this one glycine glycolitho colic acid or colic salt but effectively they are now bile salts what is the point of putting these hats on we know amino acids are quite negatively charged right now that means they love water which means we have now just created where are they going to go They get pushed into, again, the gallbladder to be stored and concentrated as conjugated bile salts, and they can be thrown into the small intestines. So what you have floating around are both these bile acids and the bile salts. Now, you might be thinking, okay, but what happens once they get to the bacteria? Great question again. If they're wearing the hats and they're conjugated, the bacteria can unconjugate.

Unconjugate. So what the bacteria can do... is it can basically get rid of the hats at this point and throw either the primary or secondary bile acids now back into the liver to be conjugated again.

Unconjugated, conjugated. Unconjugated, conjugated, right? Primary, secondary.

Primary, secondary. This whole thing here, right? As you can see, we've just created this thing that goes like this.

I'll just draw it simplistically like this, right? This is called the enterohepatic circulation. Enterohepatic circulation. That's really important. This 95% of these bile acids and bile salts keep getting circulated back.

All right. What is the point of them? I said we need them for emulsification and absorption.

How? How do they do this? All right.

Let's take a look. So. If you were to ingest a fatty meal, right?

So you're going to have fats coming from the stomach. And in this fat, you're going to have fatty acids. You're going to have glycerol.

You're going to have cholesterol. You might even have phospholipids, right? You could even have vitamins D and E and K, whatever it might be. They're going to enter the duodenum. They haven't really been digested yet.

In the mouth, we do release a little bit of... lipase in what's called lingual lipase and a little bit in the stomach, but mostly undigested until the duodenum. Once this fat gets into the duodenum, it stimulates a group of cells. Now, these cells are called enteroendocrine cells. And when the fat comes across these enteroendocrine cells, it triggers them.

to release an important hormone called CCK, cholecystokinin. Now, cholecystokinin, cholecystokinin, cholecysto means gallbladder, kinin means contract. So what this hormone does, unsurprisingly, is it tells the gallbladder to contract and release bile.

Brilliant. It also tells the liver to release bile. Again, brilliant.

Now, when we release this bile, remember that we've got two important components here. We've got the thing that's made out of the cholesterol, right? Which loves fat. It's lipophilic.

And we've got the hat on it, the amino acid, which loves water. Let's just draw the... glycine hat here and this is hydrophilic this is brilliant this is exactly what we want because if we take that big bit of fat right it's too big for the molecular scissors the lipase to chop up it's too big so that's lipase but what we can do is the lipophilic part can bind to the fats And the water part, or the water-loving part, the amino acids, can be exposed to the fluid environment.

the bowel of the lumen of the bowel and then it allows for it to be broken down into smaller pieces. So effectively it then allows for it to be broken down so that we can have smaller more manageable pieces. And this is what the lipase can chop up. Now, where does the lipase come from?

Remember this? Remember we've got our pancreas, right? We've got our pancreas and the pancreas is going to be connected up.

And unsurprisingly, Collie's sister Kynan triggers the pancreas to release lipase and amylase and the various proteases and they all get released into here to help chop them up. Now, I said they help with absorption as well. That's important because what happens is that we can surround these smaller bits of fat, which we call myceles, and then we can bring them over to the enterocytes, and they facilitate all the fat-soluble substances to be absorbed. Again, what is it? Like the not triglycerides, but fatty acids and glycerol.

and vitamin D and E and K and A and cholesterol. And they can then get absorbed into predominantly the lymphatic system and be sent to the body. Now, once they're in the lymphatic system, this is just for completion sake, they get bound up into something called a chylomicron.

And the chylomicron contains fatty acids, glycerol, the fat soluble vitamins, cholesterol, and so forth. Sike. Hopefully this helps you.

This is a quick run through of bile acids, bile salts, and how we synthesize bile. I'm Dr. Mike. Hi everyone, Dr. Mike here. If you enjoyed this video, please hit like and subscribe.

We've got hundreds of others just like this. If you want to contact us, please do so on social media. We are on Instagram, Twitter, and TikTok at Dr. Mike Todorovic, at D-R-M-I-K-E-T-O-D-O-R-O-V-I-C. Speak to you soon.

Transcript for:Understanding Bile Synthesis and Function

Transcript for:
Understanding Bile Synthesis and Function