Cholesterol, Phospholipids,
Triglycerides and Lipoproteins


Cholesterol molecules as part of the plasma membrane.

Let's review a bit about the digestion and absorption of fats and cholesterol. After swallowing the triglycerides and phospholipids and cholesterols, the triglycerides and phospholipids are chemically digested by both lingual lipase from the mouth and pancreatic lipase. Remember also that along with the chemical cleaving of the covalent bonds holding these molecules together by the lipases, these molecules are also separated apart from each other by bile from the gall bladder and liver. This separation of molecules that would normally clump together in the watery environment of the intestine is called emulsification.
After the lipase is done cleaving apart a triglyceride, some of the triglyceride is only cleaved twice, leaving two free fatty acid chains (tails) and the monoglyceride still intact. Some triglyceride is completed cleaved apart (hydrolysed) into three free fatty acids and glycerol. In either case, all these fragments are absorped into the absorptive cells of the small intestine by simple diffusion.

At this point we need to define two new terms. The different types of fats, the different types of triglycerides, have different names because chemically they are different. How are they different? Well, they all have a glycerol backbone and three fatty acid chains. What varies is the length of the fatty acid chains. Each of the three chains can be unique in not only it's length but also the number of single and double bonds between the carbons. A short-chain fatty acid has fewer than 10-12 carbons in their chains. A long-chain fatty acid have more, and can be quite long in fact.

The short-chain and long-chain fatty acids are transported differently. Since the short-chain fatty acids are 'short', they do not tend to form large aggregates in the watery environment of the small intestine. So the short-chain fatty acids do not require bile (the bile salts) to help keep them emulsified. Also because of their relatively small sizes, the short-chain fatty acids are absorbed by simple diffusion and then deposited out of the bottom of the absorptive cells into the blood capillaries of the hepatic portal system and directly onto the liver. The long-chain fatty acids however are handled a bit differently, mostly because of their larger size.

Bile is actually a mixture of many different molecules. These molecules are referred to as bile salts and they have the same internal cyclic structure of cholesterol. As you can then guess, they are made from cholesterol by the hepatocytes of the liver.

     

Just so you can say you've seen their names, the most abundant bile salts are: cholic acid; chenocholic acid; deoxycholic acid; and lithocholic acid. Many of them have chemical properites similar to these fats (triglycerides and phospholipids) we're trying to digest and absorb. These bile salts are like phospholipids in that they have hydrophilic ends and hydrophobic ends. So when these bile salts are deposited into the watery small intestine, they form small spherical membranes, like a very, very small, hollow cell. The monoglycerides and long chain fatty acids of the small intestine enter these small, hollow membranes. This is called a micelle. A membrane of bile salts containing the large monoglycerides and long-chain free fatty acids.

Since the wall of the micelle is made up of hydrophilic and hydrophobic bile salts, it freely interacts with the phospholipid bilayer plasma membrane of the absorptive cells of the small intestine. In this way, the contents of the micelle are delivered into the absorptive cell. The micelles thereby 'ferry' the monoglycerides and long-chain fatty acids into the absorptive cells. Eventually the bile salts are also reabsorbed into the absorptive cells of the ileum and thus redelivered back to the liver (via the hepatic portal system) to be put back into bile.

Once inside the absorptive cell, some of the monoglycerides are now cleaved into glycerol and one free fatty acid. Regardless, the absorbed free fatty acids and glycerols are now reassembled into triglycerides (likewise with the phospholipids). The phospholipids are used to construct a one layered membrane and the triglycerides and cholesterols are packaged inside this membrane. This is done in the smooth endoplasmic reticulum. There are specific proteins inserted into the outer membrane also. This spherical ball of outer phospholipid and protein with cholesterols and triglycerids inside (away from the watery environment of the cell) is called a chylomicron.

These chylomicrons are exocytoses from the bottom of the absorptive cells and enter the lymphatic capillaries (the lacteals). Can you remember your lymphatic circulation? Well, let me remind you. Once inside the lymphatic system now, they travel up the throacic duct and enter the left subclavian vein. And so these chylomicrons are now in the blood stream and will enter the heart via the vena cava. This means that they will also be pumped out of the heart via the aorta to the entire body.

Eventually these chylomicrons will pass through the liver, where they are removed from the blood stream. How do the triglycerides get into the hepatocytes of the liver? Well, they first have to be broken down. The enzyme to do this is called lipoprotein lipase and is actually located on the liver capillary endothelial cells. So the chylomicron (its phospholipids, cholesterol and triglycerides) enter the hepatocytes.

In order to transport these essential molecules to all of the other cells of the body, they must first be packaged into a spherical membrane bound mini-cell similar to the chylomicron. And for the very same reason we made the chylomicron in the first place. You cannot transport these water insoluble molecules free in the watery blood. They'd just clump together in your tiny blood vessels just like they do in your kitchen sink. The hepatocytes make a membrane of phospholipids, with some proteins sprinkled in, and on the inside package triglycerides and cholesterols. This is dumped out into the blood. This is called a very low density lipoprotein (VLDL). As it travels throughout the body in the blood, the cells of the body can tap into it and remove any needed triglycerides, phospholipids, and/or cholesterols. As it becomes smaller, it is then referred to as a intermediate density lipoprotein (IDL). As this IDL is depleted, it's smaller version is called a low density lipoprotein (LDL). This LDL is taken back into the liver and resupplied with triglycerides, phospholipids, and cholesterols and sent out again as a VLDL.

Lastly, the cells of your body are constantly remodeling themselves and so there is a constant production of waste triglycerides, phospholipids, and cholesterols (mostly their fragments or the wrong kind for the cell's use). These waste molecules cannot just be dumped into the blood. They are all water insoluble. So the cell itself packages them in a phospholipid membrane and exocytosed this into the blood. This is called a high density lipoprotein (HDL). This HDL eventually will travel through the liver where the hepatocytes will remove it from the blood. The liver cells now can recycle these molecules by putting them into the VLDL's they are releasing into the blood.

Just a couple of parting interesting facts about cholesterol. The ring structures of cholesterol cannot be broken down by the body. If you look back over the pathways involving cholesterol, it is taken in by diet with it's rings intact, absorbed intact, and transported around intact. All that is ever done to it is that it is modified by adding and subtracting side groups onto these rings. And this then brings me to my last point about cholesterol. How do we get rid of excess cholesterol since we cannot break it down? We can make it from 'scratch' if need be. The body can link carbons together to make it. But what about eliminating it? If you remember, the bile salts are derived from cholesterol. If the body has excess cholesterol, the excess is converted into bile salts and secreted via the gall bladder into the small intestine. Whatever bile salts are not reabsorbed by the absorptive cells of the ileum remain in the intestines and pass out of the body in the feces. You know fat floats in your kitchen sink. Those fats and phospholipids and cholesterols float on water. If you have enough cholesterol (in the form of bile salts) in your 'poop', it will float. Take a look sometime and remember back to what you've been eating. Enjoy!


Here you can compare the relative sizes of the family of lipoproteins.

Cholesterol: The Practical Health Aspects
(You will be required to click on all the topics listed at the left of this page.

Cholesterol: The Complicated Biochemistry

Take a look at the synthesis pathway for cholesterol.
No, you will not be responsible for learning each step, but you will be responsible
for knowing about what I'm about to explain.
So there is some useful information to be learned by looking at this complicated pathway.
First, the multiple rings of cholesterol are made 'from scratch' by linking carbons together.
And all this starts by linking a 2-carbon Acetyl-CoA to a 4-carbon Acetoacetyl-CoA,
making a 6-carbon HMG-CoA molecule (HMG = 3-hydroxy-3-methylglutaryl-CoA).

The enzyme HMG-CoA Reductase then catalyzes the conversion of HMG-CoA into Mevalonate.
And from there, the rings are assembled by adding more and more carbons.
Remember, the cells of the body only need to make cholesterol 'from scratch' if there
is not enough available from the diet. So the liver cells, the hepatocytes, usually
only make 10-15% of the body's cholesterol 'from scratch' (which is referred to as 'de novo').

If there is sufficient cholesterol, the enzyme HMG-CoA Reductase is turned 'off'.
A negative feedback loop. If cholesterol levels are low, HMG-CoA Reductase is turned 'on'
and cholesterol is then synthesized 'de novo'.

And one of the other reasons we are so interested in the structure of this complicated, cyclic molecule is that it is used as the building block for the synthesis of several very important hormones;
namely: estrogen; testosterone; aldosterone; cortisol and progesterone.
Below you can see how they are all very closely related structurally.


Bilirubin Metabolism

Nice YouTube Video on Bilirubin Metabolism

Not required, but interesting information