Fundamentals I
9-10-08
10:00-11:00
Dr. Baggott
Lipid Metabolism
I’m going to talk about a type of patient that everybody will see in their practice.
Dr. Baggott shows a slide of Newborn and Adult Adipose Tissue:
This is adipose tissue here on the left there of a newborn rat. Here on the right are adipose cells of an adult rat. You can see the size of the cells have increased from anywhere from 20-50 times. You can expand your fat cells quite a bit.
All of you are going to see the obese patient. It’s important for you to recognize in many instances that the obese patient, it won’t be their fault. It will be the fault of genetics. This is not covered very well in other classes, so we will cover it here in this introduction so you have a feel for what kind of experiments have been done in the field of obesity to prove that it’s a genetic problem. If you go back to the days of Moses you would realize that in times of feast and famine, in the time of feast you have to lay down fat stores, and when famine came you would have to use these up. If I use too many of these up I’m dead. Can I pass on my genes if I’m dead? NO
What happened in evolution is that the people who were very efficient in storing fat survived. That’s most of us. The ones who couldn’t store fat died. What genes they passed on were fat-storing efficiency genes. We don’t know what we are, but we do know that they’re there.
It’s experiments like the one carried out by Stunkered in the 1980’s, and people don’t appreciate them. What Stunkered did was follow the biological children from fat people and thin people who were adopted at a really early age. These people didn’t keep their kids- they were adopted. Who were they adopted by? They were adopted by fat people and thin people, and they were raised, of course, by their adoptive parents. All these people did was produce a kid. The adoptive parents raised them. So, we look at the child, and we say who does the child, teenager, or young adult look like in terms of fatness? Do they look like the people who produced them or the people who adopted them? Refers to graph on the board. This is the BMI of the biological parents. This is the BMI of the adoptee. If the adoptee was obese- they came from obese parents. It had nothing to do with the BMI of the adopted parents. There is no correlation here. It doesn’t matter if this adopted child came from fat people was adopted by thin people, they were still obese when they grew up. It didn’t matter if this child of thin people was adopted by fat people- they were still thin when they grew up. This shows that this is genetic- not environmental.
This other study looked adopted identical twins that were raised apart. These were adopted twins- twins that were adopted. 50-70% of their fatness or leaness was due to their biological parents- not adopted parents. It is genetics that’s driving this. Before you feel that you are very special because you can stay lean you chose your parents right.
Dr. Baggott is referring to Absorption/Oxidation Fatty Acids picture, which is labeledd General Aspects of Catabolism- Major pathways for ATP synthesis from lipid and carbohydrates.
What we’re gonna do with that is oxidize it to Acetyl Co-A units with a few exceptions. We’ll go over those exceptions. They are going to be put into the TCA cycle to generate ATP and essentially oxidative phosphorylation- just like glycolysis.
· First you have to absorb the fat- digest the fat.
· Almost all of our energy comes from triglycerides, which just has a glycerol backbone, and three R groups esterified to that backbone. (He draws a picture of this on the board.) That’s basically the energy source from fat. There’s a few phosphlipds and sterols where you get a little bit of energy, but it’s mostly from triglycerides, so we’re gonna focus on them.
Absorption of Long Chain Triglycerides C12 or greater. He Refers to a picture of fatty acids with Triglycerides and Lipase.
· In order to absorb long chain triglycerides equal to or greater than 12 long, you are going to need bile salts and pancreatic lipase, which combines with a colipase to act on triglycerides. Triglycerides are these little things here-the triangular things on this figure. They are labeled.
· The triglyceride does not need to be hydrolyzed to glycerol and free fatty acids. All you need to do is take off 2 of the fats on the fatty acid chains. Usually the two end fats are taken off by the lipases. So that monoglycerides are absorbed just fine
· Bile salts and lipase is needed for triglycerides greater than 12 units long.
· Bile salts are needed to emulsify the triglyceride droplet and bring it close to lipase.
Medium Chain- C8-C10
· You just need the lipase. You don’t need the bile salts to digest.
Short chains
· Nothing.
· You don’t need anything to absorb them.
· If somebody has bile salt insufficiency, do you feed them long chain triglycerides? NO -You feed them short chains.
Dr. Baggott is now referring to the Picture of the liver, and intestines, which is showing lipid transport via Chylomicrons.
· The next thing we’re going to do is package up our fatty acids and glycerol. After absorption we package them as a triglyceride in the form of chylomicrons, which is acted upon by lipoprotein lipase, which is another form of lipase that hydrolyzes triglycerides, and eventually the remnant comes back to the liver.
· When we make fat, in our liver primarily, it is packaged up in a triglyceride in the lipoprotein particle VLDL. That’s also acted upon by the lipoprotein lipase to release the free fatty acid.
· So that’s how the free fatty acid is delivered from dietary fat from the chylomicron and from fat that we make in our liver in the form of VLDL.
· Wait a minute… that’s not all the fat. What about that fat? (Referring to pinching the fat on his tummy.)
He is now referring to a pathway in Fig. 23.2 in his handouts.
· That fat is mobilized when a hormone (usually this is catecholamine hormone, but we don’t need to go into that. Let’s just leave it as a hormone.) Activates an intracellular triacylglycerol lipase- just know this is a cascade that activates it. It has a kinase and everything- great. This is the inside of an adipose cell. Then this activated lipase cleaves the triglycerides to free fatty acids shown here, and the free fatty acids are picked up by serum albumin, which is kinda like the sponge of the blood, which picks them up and delivers them to other tissue than adipose tissue. This is how we mobilize fat from adipose tissues.
Dr. Baggott is now referring to Fig 24-2. Overview of Beta-oxidation of fatty acids, which is on page 5 of his handouts.
· What are we gonna do with the fat? How are we going to oxidize it?
· The overall scheme for even chain fatty acids is to cleave off successive Acetyl Co-A units. Acetyl means two carbon units.
· So, you’d be surprised how many people don’t get this right.
· If I had a C16 fatty acid or Palmitate, how many Acetyl Co-A units do I get?
· No response. (Laughs) Answer from a member of the class: 8.
· Dr. Baggott: Yea, 8- you get an A+ for today.
· Dr. Baggott draws this on the board:
C16à 8 Acetyl Co-A
Dr. Baggott is now referring to Fig.23.9 The formation of acylcarnitines and their transport across the inner mitochondrial membrane.
· Ok, good.
· Where inside the cell am I going to oxidize something? Am I going to oxidize something in the cytoplasm where I have all of these biosynthetic pathways going? Um….NO
· What subcellular organelle do I want to take my fat in to oxidize it?
· That’s right…. The mitochondria.
· It turns out that…and also…. We’re going to perform all oxidation in biosynthetic reactions, using fat, we’re going to perform them when the fat is on a thioester. He draws a thioester on the board. If this were oxygen instead of sulfur it would be an oxygen ester. It’s not though; it’s a thioester.
· The reason Mother Nature did that is because a thioester is much more reactive than an oxygen ester.
· So, we have to use thioesters to do this biochemistry on fat.
· This works for both oxidizing and biosynthesizing the fat, as we’ll see.
· In order to get the fat across the mitochondrial membranes, we need to trade our Co-A for a carnitine, which forms an oxygen ester. Carnitine is a metabolite of Lys. Lys is converted to carnitine in our body. We probally don’t have a dietary requirement for carnitine in our body. However, people waste money by going to health food stores and buying carnitine. And why would you buy carnitine? Because it’s a fat mobilizer and oxidizer. Good luck with that.
· This acyl carnitine, which is an oxygen ester, can cross the mitochondrial membrane. Once it’s crossed the mitochondrial membrane we convert it back to Acyl-CoA.
· OK. That’s all I want you to know. Carnitine forms an oxygen ester with the fat. Once that oxygen ester transverses the mitochondrial membrane, we have our thioester back. We exchange the carnitine for Co-A and get our thioester back.
Dr. Baggott puts up the overhead with Figure 24-4, which is page 6 of his handout.
· Now we’re ready to do oxidation.
· Oxidation is not really hard to understand. It’s a few basic steps, and I’ll tell you right know that if you understand the steps of oxidation, the steps for biosynthesis, you’ll understand those two because it’s the reverse a lot of the time. There’s a few exceptions- we’ll talk about those later.
· The first step in fatty acid oxidation is to take our Acyl Co-A here and oxidize it, creating a double bond here. The double bond is at the Beta carbon. That’s why this is often called beta-oxidation. The coenzyme is riboflavin coenzyme (FAD). FAD becomes reduced, and we oxidize this single bond to a double bond.
· Second step: Hydration. Is there any oxidation or reduction going on here? No. The hydrated molecule is in the same oxidation state as the double bond molecule.
· Now we have a hydroxy compound here. We need to oxidize it again using NAD+ to oxidize the hydroxy to the keto form.
· Now we have a b-keto acid that is cleaved with another Co-A, which comes here and we have an Acyl Co-A shortened by to carbon units because we have the Acetyl over here.
Dr. Baggott now puts up Fig.23.10 The b-oxidation of saturated fatty acids.
· Now here’s the really wingding colorized version.
· Again it’s called b-oxidation because we’re oxidizing the bcarbon.
· The first part is to oxidize the single bond to a double bond, hydrate the double bond with a hydratase, oxidize the beta hydroxy group to a beta keto group, cleave off the two carbon acetyl group, add another Co-A, and away we go around and around until we complete the oxidation.
Dr. Baggott now puts up Figure 24.23 from Garrett & Grisham, which is on page 7 of his handouts.
· You’ve just oxidized an even-chain saturated fatty acid.
· What other types of fatty acids do we have besides saturated fatty acids? Unsaturated fatty acids.
· If you take a typical unsaturated fatty acid like Oleic acid and you go through the successive steps of oxidation, you will get something that looks like this. Dr. Baggott draws this: -C=C-C-COOH
· You will not have a conjugated system. You will have a double bond here. (At C3, counting from the carbonyl.) The hydratase that hydrates this double bond doesn’t recognize this. It hydrates double bonds only at the 2 position. We need another enzyme to get our double bond in the correct position. Where is the correct position? At C2.
· We need an isomerase. The isomerase takes the double bond from C3 to C2.
· We need an isomerase for monounsaturated fatty acids.
· That’s what all this gobbledy gook shows you (on the overhead).
Dr. Baggot puts up the overhead with Figure 24.24 from Garrett & Grisham. This is page 7 on his handouts.
· Wait a minute… aren’t there polyunsaturated fatty acids? Aw crap, polyunsaturated fatty acids.
· If you go through the oxidation of a typical polyunsaturated fatty acid such as linoleic acid, you’re going to get something that looks like this:
-C=C-C=C-COOH.
· It’s gonna have double bond, single bond, double bond, single bond, double bond. Hydratase likes the C2 double bond, but it doesn’t like the C4 double bond.
· We have too many double bonds, so we need another enzyme.
· We need a reductase, which reduces the two double bonds to one double bond. It reduces the C2 and C4 double bond to one C3 double bond. So now we have single bond, single bond, double bond, single bond, single bond, double bond. Aw… geez… is this (C3) in the right place? NO
· But wait…I have my isomerase. My isomerase then can take the C3 to the C2 position.
· For polyunsaturated, you need a reductase followed by an isomerase.
· For monounsaturated you only need an isomerase.
· That type of question is frequently asked.
Dr. Baggott now puts up Figure 16-12, which is 7B from his handouts.
Odd Chain Fatty Acids
· So far we have done even chained fatty acids.
· What else can we eat? Do we always have to eat an even-chained fatty acid? No. We can eat an odd-chained fatty acid. Say we eat a C9 fatty acid. What do we get? Do we get 4 Acetyl Co-A (Total 8 C) and one formate? No