CLASS: 10:00-11:00Scribe: Caleb Landrum

DATE: 9/2/10Proof: Jordan Ridgeway

PROFESSOR: WhikehartLipid CatalysisPage1 of 6

LIPID CATABOLISM(BREAKDOWN, STORAGE AND SUPPLY PROCESSES) [S1]
SLIDE TITLE [S2]
We talked about lipids yesterday, and there are some problems with storage accumulation that we have to not talk about in this lecture involving fat and plaque formation. Lipids are important; we can’t do without them in our diets. But we’re not going to be talking about weight control. Instead, this is going to be a biochemical expose on how lipids are digested.
Outline: [S3]
Here is an outline of what we’re going to be looking at:
What actually happens with the ingestion and the breakdown of lipids.
The transport of the dietary lipids to the cells, and I’ll mention the cholesterol connection because that’s important today.
Storage of lipids and some variations on that theme.
The mobilization of lipids from their storage cells.
Finally, how lipids are converted to their energy forms in the form of acetyl CoA.
Lipids are ingested into the body in two forms [S4]
There are two forms of lipids that are ingested in the foods we eat: they are either triacylglycerols (TAGs) or cholesteryl esters. This occurs in a 9:1 ratio of TAGs to cholesteryl esters.
The body will use the fatty acids… [S5]
The body is going to use the fatty acids from the TAGs and cholesteryl esters for primarily two purposes. One is for energy, and the other is for membrane synthesis.
The cholesterol will used for membrane synthesis and hormone formation, as well as some other roles that I’ll mention as we go along.
Ingestion [S6]
In the GI tract there are 3 possible areas where the lipids could be broken down or processed. These would be the stomach, the duodenum, and the intestinal epithelium (primarily in the small intestine).
The stomach and duodenum [S7]
The stomach really is not a good place, and the reason for that is that the stomach acidity is too high to be able to successfully break these lipids down. Also because of the high acidity, there is an absence of enzymes there.
So we go immediately to the duodenum. This is an alkaline atmosphere, as far the lipids are concerned. There are secretions in that area from the pancreas and gallbladder, and these secretions are made up of lipases (the most important of the two enzymes), esterases, and something called bile salts.
Bile salts are derivatives of cholesterol (you see an example of one here called glycocolate) will carry out the process of breakdown by emulsification, which means spreading these lipids out into very fine divided particles. It’s something like the little bottle I showed you yesterday that had a mixture of lipids and water in it, how you shake it up and you see a very fine cloud. That’s what the emulsifier does in the intestine.
The TAGs for example, are broken down by the lipases, and you see that happening (referring to slide) at the #1 and #3 positions of the glycerol portion of the TAG. Not too much is broken from #2, although some is and it can be done with so-called n-sp lipases. The n-sp lipases will also remove the fatty acid from the cholesteryl esters, which are taken down. So there are really two variations on the same enzymes that are involved in this breakdown process.
Intestinal epithelia (mucosal cells) [S8]
When you get to the intestinal epithelium, the mucosal cells are going to be responsible for the uptake of these broken down lipids.
Short chain fatty acids are directly taken up into the intestinal mucosal cells, while the longer chain fatty acids will react or be distributed by the bile salts into something called mixed micelles and carried into the epithelial cells for uptake.
(Pointing to slide) Here we have the epithelial cells, fatty acids, and CoA. CoA is going to complex with the fatty acids in order to put the whole thing back together again. The reason for this breaking down and reassembly is simply due to the fact that we have this lipid solubility problem in the aqueous environment of the intestinal lumen and the inside of the epithelial cells themselves.
The reaction that involves the reassembly is called condensation. In this process, we have an acyl transferase that allows that reaction to take place. Here we see the monoglycerol reacting with two fatty acyl CoA enzymes, forming TAGs. Then this great mixture of lipids (which have been reassembled), are even further assembled into a lipid body called a “chlymicron.”
This is a packaging process, and in the process they are combined with a protein called an “apolipoprotein.” When you have a chylomicron, it has all these lipids together with the apolipoproteins, which are present on the outside of this lipid body.
Transport [S9]
This is what one of these lipid bodies (chylomicrons) looks like. All of these lipid bodies will have internal lipids, surface lipids, and surface proteins called apolipoproteins.
The apolipoproteins (of which there are many) will be concerned with the release and transport outward of the lipids that are contained in the lipid bodies themselves. They do it in two ways: one is a recognition process to the target cell that they’re going to, and the other is the release process which will involve an enzyme of some sort.
So the apolipoproteins act as markers and activators for the release of chylomicron contents at specified kinds of cells.
In the transport of lipids… [S10]
Here is a table that you will need to study very carefully.
(Pointing to board) Here are the intestines, the liver, and the chylomicrons that have been transported into the bloodstream from the intestine itself. The chylomicrons act as a major source of transported lipids to adipose tissue, and to peripheral tissues, which could include muscles or blood vessels.
The chylomicrons deliver these free fatty acids to these tissues and some that are left over will actually go back to the liver. In this process, the free fatty acids can be reassembled in the liver (somewhat analogous to what happens in the intestine) but then we have a new lipid vessel called a very low density lipoprotein that is going to deliver these free fatty acids as a secondary source of fatty acids to the same tissues.
In the process, when the free fatty acids are given up, the very low density lipoprotein becomes an intermediate density lipoprotein which can go back to the liver, or it can develop into a low density lipoprotein (LDL) that can be used as a source of additional fatty acids to be delivered to peripheral tissues. Now, let’s be careful about the LDLs, because these lipid bodies also contain cholesteryl esters, and cholesteryl esters can be a source of negative coating inside blood vessel walls.
Now when the peripheral tissue cells break down, or when the lipids in them are no longer of use, they go on to form an additional body called a high density lipoprotein (HDL). The HDL also contains cholesteryl esters as well as other fatty acids, but they (HDLs) are delivered to the liver.
It is the ratio of the HDL to the LDL that is going to be of concern to the health of an individual. The higher the ratio of LDLs to HDLs, the more chance there is for the possibility of coating of cholesteryl esters and other lipids into the inside of blood vessels. The most significant lipoproteins of medical research are presently the LDL containing the so-called “bad cholesterol” and the HDLs containing the so-called “good cholesterol.”
The good cholesterol is cholesterol that makes it back to the liver, while the bad cholesterol is the cholesterol that can be deposited into blood vessels.
Delivery of lipids to/from cells and blood cholesterol levels[S11]
(Referring to slide) Here a normal artery, here is an artery that is partially blocked with deposits from cholesterol esters.
A couple of things you should note: the HDLs pick up cholesterol released into blood plasma from dying cells and from cell membrane turnover, which is a normal process.
The HDL is a cholesterol scavenger and deters the build-up of cholesterol plaque inside the blood vessels. It is important that the LDL is able to deliver cholesterol to its target cells and that HDL is able to pick up discarded cholesterol.
There is an ideal HDL:LDL ratio, and this is about 3.5:1. When the LDL portion starts to increase, it is an indication that there may be a problem.
The functional ability is related to the apolipoproteins. A little bit about this term…when you talk about an apoprotein, it is usually a protein that is divorced from the component that it is bound to. When you call it a holoprotein, then it is bound to whatever functional group it has. Another example apart from that would be a molecule such as hemoglobin. If hemoglobin didn’t have heme in it, then it would be a hemoglobin apoprotein. If it has the heme portion, then it would be a holohemoglobin molecule. In some forms of research this terminology doesn’t follow through, so the term apolipoprotein is used whether the protein is bound to its lipid body or not. So don’t get confused by that.
The functional ability of this ratio is related to the apolipoproteins that are found on LDL (that particular protein is called B100), and HDL (which is called A protein). B100 causes cholesterol uptake into cells, but an absence of receptors for B100 leads to a disease called familial hypercholesterolemia.
Delivery mechanism of cholesterol to adipocytes and muscle cells[S12]
This looks like a lot, and I’m only going to ask you to be responsible for part of it.
This is a delivery mechanism for cholesterol to adipocytes and muscle cells. What occurs is that there is a process of endocytosis for the LDL lipoproteins, so you see that this is taken up into the endocytotic portion of the cell and it’s coated with an LDL receptor, and after invagination and removal of the A coat protein at (2), the trapped LDL is fused with a lysosome, which has degradative enzymes that degrade it’s apo-B and cholesteryl esters into amino acids and free cholesterol.
That’s basically how it’s taken up into the cell and that’s all I want you to be responsible for.
How are TAGs related to cholesterol levels?[S13]
Now the question comes up, “how are TAGs related to cholesterol levels?” And what about the delivery of TAGs to cells?
TAGs are the storage form of fatty acids. They are transported to adipocytes and peripheral tissues like muscles by means of chylomicrons, very low density lipoproteins, and LDLs.
The majority of the TAGs are carried in chylomicrons, which is a normal dietary supply for fat and muscle cells, and the VLDLs which is the extra supply that happens to come from the liver.
Clinically, when the serum TAGs are elevated, it usually means that the LDLs with 2.5x more TAGs than HDLs are increased in relation to the HDLs. In other words, TAG content and cholesterol content are somewhat related to one another. When this occurs, cholesterol and the LDLs increase (we don’t really know why), and that increases the cholesterol that might be deposited into blood vessels.
This table pretty well tells the story. If we look at LDLs, we see that the phospholipid and cholesteryl ester content is relatively high, but the HDLs (even though the phospholipids are about the same)have cholesteryl esters that are decreased in amount. And TAGs are decreased in amount too. There is an analogy between the two: TAGs go up, cholesteryl esters go up. TAGs go down in the HDLs, and accordingly cholesteryl esters will also go down. There is a symbiotic relationship in content between the two of them.
How does the composition of fatty acids in TAGs affect lipoprotein composition?[S14]
How does the composition of fatty acids in TAGs affect lipoprotein composition? By that I’m talking about saturated vs. unsaturated fatty acids and trans vs. cis fatty acids.
Well, no one really knows. All that is known for sure is that saturated fatty acids increase LDL levels only, and that trans fatty acids increase LDL level and lower HDL levels, which is undesirable. There is some evidence that suggests that this is due to hormonal effects, but research on hormonal effects of lipid metabolism is presently poorly understood. The effects that do occur affect the lipoprotein carrier proteins – that is, the amounts of apo-A, and apo-B100.
But there is no doubt that increased saturated and trans fatty acids in the diets increase the LDL to HDL ratios.
Comic relief [S15]
Comic relief [S16]
Delivery of fatty acids to adipocytes and muscle cells [S17]
Now we’ve got these fatty acids and we’ve got to get them to adipocytes and muscle cells. We know that the lipid bodies bring them to those target areas, but we haven’t discussed how they actually do that.
The carrier protein goes to this area, or the lipid body goes to this area, and they are released by the combined action of the apolipoprotein receptor that holds the carrier next to the blood vessel endothelial cell.
Here is a chylomicron and it is floating along with the bloodstream, and it is going to bump up against the inside of a blood vessel endothelial cell, where a receptor for one of these lipoproteins is going to exist. When that occurs, there is an enzyme that will release that lipid and it has to keep digging down, and the vessel gets smaller and smaller, and exposes more lipids as it goes along.
The lipids are released as free fatty acids, but they are also bound to a protein called CD36. CD36 binds to the free fatty acid and carries it through the aqueous portion of the inside portion of the blood vessel to the extracellular space where it will go on to bind to striated muscle cells or adipocytes. From there it will be taken up into whatever target cell it happens to bind to.
The uses of fatty acids [S18]
Now how are fatty acids used? You know already that fatty acids are used to make energy and are used as a source to make TAGs for membrane uses.
Fatty acids have to be chemically manipulated in order to be transported through the body because of the solubility problem. They are lipid soluble and soluble in nonpolar media, but the body has a polar media. To conquer this problem, a carrier for the fatty acids is used.
There are many cells that make use of fatty acids as an energy source when the body is starved of glycogenic glucose. Something that may surprise you is that heart tissues and muscles normally prefer fatty acids as a fuel rather than glucose. Brain tissue can also use fatty acids after they are broken down to something called ketone bodies.
We carry acetone, acetoacetate, and beta-hydroxybutyrate in our bloodstreams in very small amounts, but they are terribly important. They are carriers for the equivalents of fatty acids to get to, for example, heart tissue. The only problem with these is that in diabetes these ketone bodies get to be excessive in concentration and begin to cause medical problems.
A nutritional review of fatty acid vs. carbohydrate energy in metabolism [S19]
Here is a nutritional review of fatty acid vs. carbohydrate energy in metabolism. Look at the energy being produced by fat. The potential or available energy in fat is 555,000 kJ.
In muscle, it is about 1/5 of that.
In muscle glycogen, it is much smaller, 1/5 of 1%.
Glycogen in the liver is about the same amount.
Glucose in the extracellular fluid is very, very small.
You can see that the lion’s share goes to the fat that is stored in adipose tissues, and it represents 84% of all stored energy in the body. Once again, in starvation conditions the lipids are really important because it is all the energy you’ve got to go on, because if the lipids start to go then the next thing to be attacked is muscle tissue.
In muscles, free fatty acid is the preferred fuel, then glucose.
In the heart, ketone bodies are preferred, then glucose.
In the brain and red blood cells, glucose is preferred, then ketone bodies.
In the kidneys, ketone bodies are preferred, then glucose.
I want you to be able to tell me about these things on the test.
Therefore: [S20]
TAGs as fatty acids are an important source of sustained energy in peripheral muscle, heart, and kidneys – the latter as ketone bodies.
Under starvation conditions, fatty acids become very important as a major source of energy, even for brain tissue.
TAGs are consumed than higher than required amounts in the diets of many so-called developed nations, with the result that cholesterol may be dumped into blood vessels to form plaque due to their delivery with LDLs containing TAGs.
The mobilization of stored lipids [S21]
When the body senses that TAGs are required from storage or adipocytes or other sources, it converts the TAGs to transport form and moves them to a location where they can be used.
How does the body sense that this need is there?
How does the biochemical conversion take place?
What is involved in the transport process?
“Sensation” or signaling of lipid need and TAG breakdown [S22]
Mobilization is signaled by hormone(s) (blue sphere) binding to receptor protein (green).
This triggers a cascade mechanism of enzyme activations.