Fundamentals 10-11Scribe: Jake Nolen

Thursday Sept 3, 2009Proof: Hillary Carney

Dr. WeikhartLipid CatabolismPage1 of 1

Abbrevs: TAG= triacyldlycerols

DAG= diacylglycerols

FA = Fatty Acid

IE = Intestinal Epithelium

ALP = Apolipoprotein

CM = Chlomicron

  1. Introduction [S1]:
  1. Lipids are a part of our diet [S2]
  2. Lipids are a part of our diet. Problems for storage and accumulation: fat and plaque. We can’t do without lipids in our diet
  3. This lecture will discuss how lipids are digested
  4. Outline [S3]
  5. He just read the slide
  6. he said we’re also going to talk about we’re also going to talk about the cholesterol connection and the terms of so-called “good” and “bad” cholesterol
  1. Forms of Lipids that are taken into the body[S4]
  2. Taken into body in form of Triacylglycerols (TAG’s) and cholesteryl esters in a ratio of 9:1. That is, 9 TAG’s are taken in for every 1 cholsteryl ester taken in in the same form. We’ve seen these structures before.
  1. Uses for Fatty Acids [S5]
  2. Body uses these for energy and for synthesis of membranes.
  3. Lipids can also be used to make hormones as in the case of cholesterol.
  1. Ingestion [S6]
  2. A person consumes a big mac
  3. The big mac goes to the stomach then duodenum, then to the intestinal epithelium. What happens to the lipids?
  1. Stomach vs. Duodenum [S7]
  2. Stomach is the first organ where TAG’s and cholesterol reside for a time
  3. As far as these lipids are concerned, not much happens in the stomach due to two factors: the acidity present in the stomach (strong) and the absence of enzymes. If there were enzymes there, they wouldn’t operate because of the acidity, so there is no use having them.
  4. For duodenum, ph changes to alkaline nature due to pancreatic and gall bladder secretions which are made up of enzymes called lipases, esterases, and bile salts (bile salts are derivatives of cholesterol)
  5. An example of a bile salt is shown on the bottom of the slide.
  6. What’s going to occur with TAG’s is FA’s are removed 1 by 1 by combined efforts of the two enzymes
  7. This is an exact quote, but I have no idea what he means by this : “Lipases remove the fatty acid from the 2 position two positions as well as the fatty acids from the cholesterol esters. So this is just not true for the TAG but also for the esters of cholesterol.” He was talking about the note on the bottom of the slide. It’s probably not too important.
  1. Intestinal Epithilium (IE) [S8]
  2. The real interesting things start happening in the IE
  3. –diagram shows intestinal lumen on the inside of the gut of the intestine or the gi tract.
  4. The Lymph duct which carries away products from the ingested lipids and then the epithelial cells that will process these FA’s.
  5. So follow this through: short chain FA’s which are <10 Carbons (there aren’t many), will be taken into intestinal mucosal cells.
  6. The longer FA’s and bile salts which occur as mixed micelles will be taken to epithelial cells for uptake.
  7. What the bile salts do is spread these lipids out in a homogenous fashion. They don’t make true solutions but this allows for the uptake to occur. Inside the epithelial cells new tag’s formed from condensation reactions. It sounds useless, but it’s necessary for the formation of the lipid bodies that we’re going to be looking at.
  8. This occurs by an acyl transferase enzyme. So far, we’ve taken these lipids, we’ve broken them down, we’ve taken them up into the epithelial cells and formed a condensation reaction where they are reassembled into new TAG’s and new cholesteryl esters.
  9. At that point , there is a packaging process where all these lipids are assembled together into a lipid body in which the lipid body has apolipoproteins. The body itself is called a chylomicron.
  10. We take the lipids, we break them down, we reassemble them in the epithelial cell, and then we package them in this lipid body called a chylomicron.
  11. The chylomicron is nothing more than a carrying device.
  1. Transport [S9]
  2. – this is what a chylomicron looks like
  3. in the interior are the most apolar lipids and on the exterior are molecules like cholesterol and some of the cholesteryl esters.
  4. phospholipids taken from membranes of epithelial cells (shown in blue)
  5. Most importantly, we find apolipoproteins
  6. Apolipoproteins are a misnomer because an apo protein is one that is not combined with whatever substance it happens to bind with but the name has stuck.
  7. B48, CIII and CII are examples of apolipoproteins.
  8. Act as markers for this body and activators for release of the contents of the chylomicron to specific kinds of cells.
  9. Chylomicrons circulate from lymph and into bloodstream. Something must tell them it is time to release their contents.
  10. Transport Diagram [S10]
  11. –Be familiar with this diagram. It shows the big picture of what goes on with all these carriers
  12. Chlomicrons deliver FFA’s (and cholesterol) to adipose tissue and peripheral tissues (mostly muscle tissues
  13. Leftovers go to the liver
  14. That’s the first delivery of the lipids to adipose tissue and peripheral muscle tissue. The liver repackages them and redistributes them as ldl’s. ldl’s are analogous to chylomicrons but they have a different lipid composition and they are adding to the adipose and peripheral tissue more FA’s
  15. So first there is the delivery by the chylomicrons, then there is the second delivery of FFA’s to the tissue as well.
  16. Then, it recirculates them to the adipose and peripheral tissue
  17. We also have hdl’s which operate independently of LDL’s. They begin as a precursor substance. This means that the apolipoproteins are here and then they pick up material from dying cells in peripheral tissue
  18. What they pick up to a large degree are dying cholesterol molecules.
  19. What becomes important is where will cholesterol be released, and how efficiently, and where will it be picked up, and how is it going to be released?
  20. If the efficiency is lost, it can wind up in the interior of the blood vessels and become plaque.
  21. The most significant lipoproteins in medical research today are the Ldl’s containing the bad cholesterol and hdl’s containing the so called good cholesterol
  1. Delivery of lipids to/from cells & blood cholesterol levels [S11]
  2. –picture of a normal artery and a partly blockd artery
  3. what are roles of LDL and HDL proteins?
  4. LDL proteins carry molecules to peripheral tissues and regulate new cholesterol synthesis at these sites.
  5. HDL’s pick up cholesterol released into the blood plasma from dying cells. They are kind of a scavenger and deters the buildup of cholesterol plaque in blood vessels
  6. impt that LDL’s can deliver cholesterol to its target cells as well as the HDL’s ability to pick up the extra cholesterol
  7. How well this is working can be seen in a lab test of an HDL to LDL ratio
  8. hdl to ldl ratio should be 3.5:1
  9. The functionability related to the apolipoproteins that are found on the LDL which happens to be B100. That’s an important consideration. And the A apolipoprotein found on the HDL.
  10. B100 causes cholesterol uptake into cells but an absence of receptors for B100 causes a condition called Familial hypercholesterolemia
  1. DELIVERY MECHANISM OF CHOLESTEROL TO ADIPOCYTES AND MUSCLE CELLS[S12]
  2. – delivery mechanism of cholesterol to adipocytes and muscle cells looks very complicated.
  3. just be familiar with the first part of this process
  4. an LDL containing apolipoprotein B gets into cells by an LDL receptor (shown in green).
  5. The cell membrane invaginates and the LDL comes in where the receptor is. It gets trapped in a pinched off vesicle.
  6. Eventually the LDL receptors are lost from the vesicle and they go back to the surface where that process is repeated.
  7. The trapped LDL will be used to pick up cholesterol for example and the cholesterol will be processed.
  8. He is most interested in the first couple steps for exam purposes.
  1. HOW ARE TRIACYLGLYEROLS RELATED TO CHOLESTEROL LEVELS?

WHAT ABOUT THE DELIVERY OF TRIACYLGLYCERIDES TO CELLS? [S13]

  1. tag’s are transported to fat and peripheral muscle by chylomicrons first then by LDL’s and HDL’s
  2. LDL’s are a secondary way to get FA’s to muscle tissues and fat cells
  1. How does the composition of fa’s and tag’s affect lipoprotein composition? [S14]
  2. –clinically, when serum tag’s are elevated, it usually means that LDL’s are increase in relation to HDL’s
  3. when this occurs, cholesterol in LDL’s will increase, and that increases the amount of cholesterol that might be deposited in circulatory blood vessels.
  4. As an indication, you can look at the table on the bottom. Shows you where TAG’s are in LDL’s and where the HDL’s are which are lower
  5. TAG’s increased indicate a problem with the LDL:HDL ratio
  6. It says nothing about what’s actually happening to the cholesterol itself
  7. Because LDL cholesterol can be a problem, this is an indication that something is undesirable
  8. Now, we’ll look at saturated vs unsaturated fa’s and trans vs cis fa’s
  9. can’t be directly answered. What we know is that saturated fa’s increase the LDL’s. trans fatty acidsincrease LDL’s and decrease HDL’s. that’s why trans is more dangerous than saturated FA intake
  10. Some evidence indicates that this process is due to hormonal effects. We can’t do much about this.
  11. The hormonal effects are on the apolipoprotein levels that produce each apolipoprotein carrier. That is, the Amounts of apoA 1 and apoB 100.
  12. Increased trans fa’s increase ldl to hdl ratios and therefore, the amt of cholesterol that can be dumped into blood vessel interiors. He said he was giving us a heads up about this. It will probably be a test question.
  13. Comic Relief [S15]
  1. Cartoon [S16]
  1. Delivery of FA’s to adipocytes and muscle cells [S17]
  2. – back up and talk about delivery of fa’s to apocytes and muscle cells.
  3. Sophistication: chylomicron can’t directly deliver to muscle cells. Look at diagram. Chylomicron contains a lipoprotein sensitive to lipoprotein receptor not on adipocyte or muscle cell but on a cell on the inside of the blood vessel wall. That causes the release of a free fatty acid (FFA). The FFA binds to protein CD36. The CD36 is a carrier for the FFA. In that stage, the CD36 goes through the cell wall and carries the FFA to the adipocyte or the striated muscle cell. That’s more sophistication than we need to know.
  1. The Uses of FA’s – Beta Oxidation Review [S18]
  2. – beta oxidation of fa’s. impt for board exams.
  3. Fa’s must be chemically manipulated for transportation because of solubility problems of fa’s. Also true inside cells as well as outside. Another thing to consider: there are many cell types that use fa’s as an energy source when they’re starved for glycogen and glucose. Muscles and heart tissue prefer fa’s as a fuel source whereas brain tissue uses glucose and FA’s once they’ve been broken down into ketone bodies.
  4. The structures on the bottom right of the slide are ketone bodies aka soluble transfer forms for FA’s.
  5. Acetoacetate and beta hydroxybutyrate are converted to acetyl CoA for use in target tissue for tca cycle
  6. Also contribute to acidity in body. That’s a problem in diabetes where the ketone bodies are higher in concentration
  7. everyone has ketone bodies circulating through body tissues which is a way to get lipids into certain tissues.
  1. A Nutritional Review of FA vs Carbohydrate energy in Metabolism [S19]
  2. How much energy we can get from fat as compared to glucose. Book uses KJ’s. TAG’s represent 84 percent of all the stored energy that the body could have. We get that from a ratio of 555,000 to the 660,000 in the chart.
  3. In normal metabolism (normal = not fasting, starving, or diabetic), FFA’s are preferred in muscle tissue, then glucose. In the heart ketone bodies are preferred then glucose. In brain and in red blood cells, glucose then ketone bodies are preferred. In kidneys, ketone bodies are preferred then glucose. Notice the variation.
  4. The flow as far as FFA’s are concerned is FFA goes to acetyl CoA to the ketone bodies which are then transported back to the Acetyl CoA and into the TCA cycle
  1. Therefore [S20]
  2. – tag’s are an impt source of sustained energy in muscles, heart, and kidney. The latter as ketone bodies
  3. under fasting conditions, FA’s are a major source of energy even for brain tissue
  4. TAG’s are consumed in higher than necessary amounts in developed nations like the USA.
  5. cholesterol can be dumped into arteries as plaque due to delivery of LDL’s containing TAG’s
  1. Mobilization of Stored Lipids [S21]
  2. – when the body senses that tag’s are required from adipocytes or other cells, it converts those TAG’s to a transport form that moves them to a location where they can be used usually but not always for energy
  3. a lot of questions can come from this statement
  4. How does the body sense such a need exists?
  5. How does the biochemical conversion take place?
  6. What is involved in the transport process?
  1. Sensation or Signalling of Lipid need and TAG breakdown [S22]
  2. There will always be a condition in which a hormone will bind to a hormone receptor which signals a 2ndary protein. In this case, it activates an enzyme called adenylate cyclase and causes it to convert atp to cyclic amp which is an internal cell hormone.
  3. The cyclic amp activates Protein kinase A which then activates TAG lipase by phosphorylating it. Tag lipase converts tag to dag until we’ve formed ffa’s
  4. That’s the mechanism for the sensation of signaling
  1. Hrmones involved in Signalling Lipid Mobilization [S23]
  2. hormones involved in signaling lipids: acth (adrenocorticotriphic hormone), epinephrine, and glucagon. Glucagon acts opposite of insulin. Insulin processes glucose to store it. Glucagon breaks stored glucose down
  1. What Happens to the Released FA’s Outside the Cells?[S24]
  2. – when FA’s are released from cells, they’re insoluble.
  3. Primary mechanism is: they are bound to albumin. Structure of albumin here. We’re looking at a bound FA in gray (actually 6 FA’s).
  4. Albumin is very common in blood. Won’t go into detail but what does the albumin do for mobilization?
  5. When the FA gets to target site, they have to be activated. That means that a chemical handle must be placed on a molecule to facilitate solubility and exposure to an enzyme for processing.
  1. Getting to Beta Oxidation - - But [S25]
  2. – here is a step in which we’re getting closer to beta oxidation. He won’t ask us details about it, but he wants us to understand what has to be done when the FA bound to coenzyme A reaches the mitochondria (where beta oxidation occurs)
  3. must be transferred into the matrix of mitochondria from the cytosol. We go through mechanism to do this because of solubility problem.
  4. The FA is bound to carnitine.
  5. carnitine transfers it through the ims to the area of the matrix where beta oxidation will occur.
  6. Know that carnitine gets FA from cell cytoplasm to inner portion of the mitochondria
  1. Beta Oxidation (Making ATP from FA’s) [S26]
  2. – things to understand:
  3. beta oxidation is taking FA and breaking it down into 2 C fragments
  4. the alpha carbon is next to the carboxy carbon and the beta C is the one next to it
  5. First, a double bond forms (oxidation rxn using FAD) don’t worry about enzyme required.
  6. We have an intermediate called Trans delta 2 enoyl coenzyme A. This is the same compound we had before but with a double bond added. We’re setting up this molecule, so it can be split.
  7. Then we add a water molecule across a double bond (hydration reaction)
  8. Next step is an oxidation rxn that forms a keto group on the beta C atom using NAD as an electron transporter to get electrons and H’s off of this active site.
  9. We wind up with a keto group without the H’s and the electrons.
  10. In the final step, we split off a 2 C fragment. What’s left must also pick up another coenzyme A. Now we have the 2 C unit and the remainder of the FA which will then cycle through the whole process again
  11. Will ask these specific things: what goes on with oxidation, hydration, oxidation, and cleavage steps on this slide? No enzymes though
  12. Beta and Other Oxidation Notes [S27]
  13. He read this slide word for word.
  1. Research Note: Brown vs. White (Yellow) Fat [S28]
  2. –interesting side note. Won’t ask about it
  1. Summary of Lipid Catabolism and Noteworthy Points [S29]
  2. He just read all of the points from the slide
  3. His summaries tell us what he will ask on the test. Use them as a study guide!
  4. Summary cont’d [S31]
  5. – he read the slide
  6. Summary Cont’d [S32]
  7. – he read the slide