Exam 3 Material
Exam 3 Material HUN3224
Popular in Intermediary Metabolism
Popular in Nutrition and Food Sciences
This 36 page Bundle was uploaded by Channelle Brown on Saturday April 23, 2016. The Bundle belongs to HUN3224 at Florida State University taught by Dr. Farrell in Spring 2016. Since its upload, it has received 20 views. For similar materials see Intermediary Metabolism in Nutrition and Food Sciences at Florida State University.
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Date Created: 04/23/16
Atherosclerosis What is atherosclerosis? o Thickening of arterial walls causing decreased blood flow Primarily affects arteries Coronary arteries supply myocardium Vessels in lower extremitiesPAD (peripheral artery disease) o Can cause cramping, numbness, feeling cold in feet/toes Leads to coronary artery disease (CAD) o Atherosclerotic Plaque Formation Endothelial damage Endothelium – single layer of cells lining lumen Can be physical, caused by free radicals, etc. LDLs penetrate endothelium More damaged or older LDLs or just a high number of LDLs flow aroundmore likely to be dropped off in vascular system Aggregation of platelets, monocytes, and t-lymphocytes Macrophages take up LDLs Growth factors released from platelets and macrophages Growth factors stimulate smooth muscle cell growth and attract more macrophages Smooth muscle cells Fatty streaks form Arterial narrowing Decreased blood flow Increased blood pressure Vessels compensate by vasodilation Eventually it can’t vasodilate anymore Increased pressure causes cracks in plaque, more endothelial damage If it occurs in the brainmost damage More platelet aggregation (cyclic process) Platelet aggregation Continued narrowing of vessels If loose=blood clot, can get stuck in narrowed vessels Total blockage by plaque Myocardial infarction (heart attack) Stroke (in brain) Poor circulation in lower extremities Can cause tissue/cell death (no blood flow) Fatty streaksearly plaque formationarterial narrowinglocalized slowing of blood flowcracks in plaqueplatelet recruitment o Treatment (surgery) Stent Medicated or non-medicated Dilated balloon catheter Lasts about 10 years; get it checked out and it can either stay in or may have to change it Presses plaque against artery walls Medications: antiplatelet aggregation meds help prevent more plaque more building around stent Balloon angioplasty – inflate then take out CABG “coronary artery bypass graft” AKA open heart surgery (obviously very invasive) Going in and removing the plaque Use a bypass graft from a vein and it is then used to go around a blockage This helps reduce the pressure on the blockage and helps supply the myocardium Can be done multiple times if needed (e.g. – triple bypass surgery=3 grafts) o Possible causes of endothelial damage Foam cells erupt Oxidized LDLs Damaged LDLs-more likely to deposit cholesterol on arteries High blood pressure Increases especially when foam cells are already present Smoking Increased endothelial damage Accelerates atherosclerotic lesion formation Source of free radicals Secondhand smoke can cause problems as well Smoking decreases nitric oxide (helps vasodilate)increased blood pressure o Serum Cholesterol Total cholesterol Tells value of all cholesterol in blood Recommendation: <200 mg/dL LDL: recommendation <100 mg/dL HDL: recommendation >60 mg/dL A negative risk factor (cancels out/counteracts LDLs) Total/HDL ratio: should be 3.8 or lower Better indicator than just total cholesterol values TopHat: Who has healthier cholesterol? Bill or Jill? Bill – o Total Cholesterol=230 o LDL=150 o HDL=65 o TC/HDL ratio230/65=3.5 Jill - o Total cholesterol=190 o LDL=100 o HDL=35 o TC/HDL ratio190/35=5.4 Answer: Bill does because his TC/HDL ratio is below 3.8 (higher HDL count than Jill). How to modify cholesterol HDL – increase by o Exercise o Moderate alcohol intake of red wine (1 glass/day – women; 2 glasses/day – men) LDL – want to decrease: o Fat intake Saturated Polyunsaturated Monounsaturated o Weight loss It’s been shown that any method of weight loss will result in decreased LDLs Dietary approaches: o Lower saturated fats o Lower trans fats o High fiber o Role of antioxidants Replace SFA (sat.) in diet with: o SFA (sat. f.a.’s) in diet with: o CHO (simple)=no decreased risk of CHD o PUFA (polyunsat.)=reduction in CHD Omega-3: decreased risk of CVD EPA, DHA – fish ALA – flax, canola, walnuts Omega-6: decreased risk of CHD? Depends; we need more omega-6’s than omega-3’s but if there is a big difference between the two and we have too many omega-6’s, it can come with an inflammatory response Comes from plant oils (corn oil, soybean oil, nuts, seed, flax) o MUFA (monounsat.)=reduction in blood cholesterol but doesn’t decrease risk of CHD Sources: olive oil, canola oil, avocados TopHat: Sources of Omega-6 fatty acids include… o Answer: sunflower oil (plant oils) Decrease trans fats: o Trans fats with increase LDLs and decrease HDLs o Sources: Naturally occurring: meats, dairy products Chem. Processed: cis to trans configuration during hydrogenation o Labeling laws 2006-trans fats must be included on label Rounded to nearest 0.5 g if less than 5 g Rounded to nearest g if over 5 g If total fat is less than 0.5 g, can state 0 g of trans fats o US Dietary Guidelines: <2g/day Fiber: o Fermented in colon – short chain fatty acids Acetic acid Butyric acid Propionic acid o Functions of short chain FAs Stimulates water and sodium absorption into mucosal cells Provide colonocytes with energy Enhanced immune function Stimulates immune cells (most of immune system is in gut) Stimulates good bacteria production Decreased atrophy of the gut Atrophy leads to gaps between cellsinflammation (e.g. – IBS) Decreased cholesterol by: Decreasing pH of the gut=decreasing reabsorption (recycling) of bile (made from cholesterol) Inhibits cholesterol synthesis in liver? o More research being done o HMG CoA? o Excreted as fecal matter Carries bile with it Soluble carries more than insoluble o Sources: veggies, fruits, whole grains Antioxidants o Reactive oxygen species = more ROS o Oxidation Metabolic: complexes of ETC and MEOS, lipoxygenase and cyclooxygenase pathways External poulltants o Oxidation of: Endothelium - increased deposition of cholesterol to vascular system LDLs-atherosclerosis o Antioxidants: Vitamins E & C Carotenoids (give fruits/veggies their color) Glutathione Coenzyme Q o Sources: Plants/plant oils HUN 3224 Exam 3 Notes: Lipids Fatty acids o Straight hydrocarbon chain 4-24 carbons long 14 or more C – nutritionally significant Most have even numbers of carbons o Short chain – made from fiber o Medium chain – found in coconut oil; metabolized differently o Long chain – omegas Saturation o Saturated fatty acids All C’s are saturated with H’s No double bonds Solid at room temperature Typically animal fats (e.g. – fat on chicken, steak and butter, etc.) o Monounsaturated fatty acids Unsaturated – healthier than saturated One double bond (C=C) All liquid at room temperature E.g. – olive oil, canola oil o Polyunsaturated fatty acids Multiple C=C bonds Cis is the predominant form E.g. – vegetable oils, nut/seed oils, omega 3, omega 6 Hydrogenation o Liquidsolid o Adding hydrogens to unsaturated fatty acids to make solid at room temperature (e.g. – Crisco) o Often used in commercially processed foods (e.g. – crackers, cookies) o Trans fats are usually unhealthier than cis fats o Hydrogenationsdouble bonds left over Usually in trans configuration Nomenclature o Count # of carbons o Count # of double bonds (always 3 carbons apart) o Omega or alpha end Alpha: carboxyl group (Δ) Omega: methyl end (n) Essential Fatty Acids o We eat them; we cannot synthesize them o Linoleic Acid (18:2w6 or 18:2Δ9, 12) Omega-6 2 double bonds o Alpha-Linolenic Acid (18:3w3 or 18:3Δ9, 12, 15) Omega-3 3 double bonds o We lack the enzymes to add C=C bonds beyond Δ9 o Both of these acids are 18 carbons long o When we make fatty acids and add double bonds, we cannot add any that are past Δ9 (e.g. – cannot add Δ12 or Δ15) o When we look at fatty acids with double bonds past Δ9, we know that they must be essential Eicosanoids o Hormone-like substance Modulation of: Blood pressure Platelet aggregation Immune system Nervous system Smooth muscle contraction Essential fatty acids are important because we metabolize them into eicosanoids (20 C fatty acids) and are hormone-like in substance They function where they are made (different from other hormones) o Families Prostacyclins Thromboxanes Leukotrienes o Synthesized from: Arachidonate acid (20:4w6) Eicosatrienoic acid (20:3w6) Eicosapentanoic acid (20:5w3) o Omega end of a fatty acid never changes (n3 will always be n3) E.g. – EPA is 20:5w3 has an omega-3 end made from alpha- linolenic acid o Aspirin: non-steroidal anti-inflammatory drug, blocks formation of eicosanoids to bring down fever, swelling, etc. o *TopHat Question: EPA is a conditionally essential fatty acid, t/f. Answer: true – we can make EPA (eicosapentanoic acid) under conditions that we eat linolenic acid Characteristics of Eicosanoids: Eicosanoid family Site of Synthesis Mode of Action Prostacyclins Vascular endothelium Vasodilator, platelet anti- aggregation Thromboxanes Platelets Vasoconstrictor, platelet aggregation Leukotrienes Leukocytes Vascular contraction, inflammation Prostaglandins Endothelium of a variety Vascular smooth muscle of cells contraction or relaxation Triglycerides: o Glycerol backbone 3-C chain and 3 fatty acids Storage – adipose tissue (similar to glycogen for storing carbs) Phospholipids o Glycerol backbone o One or more fatty acid o One phosphate group A polar head group is attached to the phosphate Glycolipids o Lipid and carbohydrate o 2 fatty acids and 1 or more carbs Sterols o Steroid nucleus 4 fused rings o Cholesterol Bile acids Steroidal sex hormones Adrenocortical hormones Vitamin D o Too much cholesterol is bad but it is still important o Every cell can make cholesterol o *TopHat Question: Where are most TG’s located in the body? Answer: adipose tissue o *TopHat Question: Where are the majority of our phospholipids? Answer: cell membranes Lipid Digestion o Lingual lipase Secreted at base of tongue Stable at a low pH Efficient digestion of milk fat (e.g. – in infants) o Biliary Emulsification In small intestine Emulsification: Dispersion of fat in an aqueous solution Spreads out so everything can get digested Allows for lipase action (break down of fats) Bile salt – emulsifying agent Made from cholesterol Cholesterol likes lipids Has a Na+ on one end Na+ likes water o Lipolysis (via bile salts) 3 main enzymes Pancreatic lipase o Breaks TG 1,2 diacylglycerol + fatty acid o Breaks 1,2 diacylglycerolmonoglycerol + fatty acids o Breaks monoglycerolglycerol +fatty acid o Altogether: 3 fatty acids and a glycerol o We can absorb monoglycerols Cholesterol esterase o Cholesterol ester free cholesterol + free fatty acid Lecithinase o Lecithinlysolecithin + free fatty acid Lipid Absorption o Micelle formation Fatty elements and fat soluble vitamins surrounded by bile salts Passive diffusion of fatty elements and vitamins at distal duodenum and jejunum (their enterocyte membranes) In first part(s) of SI Bile salts absorbed in ileum (at end of SI) and returned to liver via EHC o Inside enterocyte Long chain fatty acids (>12 C) and other fatty components Reformation of triglycerides, cholesterol esters, and phospholipids Triglycerides + fatty components + proteins = chylomicron (lipoprotein) Chylomicron – too big to fit in circulatory system; goes to lymph Short-chain fatty acids attach to albumin Lipoproteins o 5 kinds (big to small): chylomicrons, VLDL, LDL, IDL, HDL o They are complexes which carry lipid products in the blood and lymph to various tissues o Has cholesterol, enzymes, etc. o Each kind has different kinds of apoproteins o 1 layer – phospholipid membrane o Only a carrier proteins TopHat question: Chylomicrons are made from what? o Answer: the fat that we eat Chylomicrons o Formation Synthesis in enterocytes from exogenous lipids (food we eat) Released into lymph (thoracic ducttissues) o Composition Apoproteins A, B, C, E : 1-2% Triglycerides: 80% PL and cholesterol: 15% o Size The biggest lipoprotein 90-100 nm o Function Transport exogenous triglycerides to tissues Lipoprotein lipase (LPL) Hydrolyzes TG to free fatty acids and glycerol (both absorbed in tissues) o Chylomicron Remnant Remains after TG hydrolysis Taken up by hepatocytes via receptor mediated endocytosis Very-Low Density Lipoprotein (VLDL) o Formation Made in liver Released into blood o Composition Apoproteins B, C: 8% TG: 50% Cholesterol: 20% PL: 20% o Size: 30-90 nm o Function: Transport endogenous lipid from liver to extra-hepatic tissues Uses LPL (lipoprotein lipase) Hydrolyzes TG to free fatty acids and glycerol Free fatty acids and glycerol absorbed to tissues Intermediate Density Lipoprotein (IDL) o Formation From VLDL (after TG hydrolysis) Transient, very short-lived o Function Formed into LDL after TG hydrolysis via LPL Low-Density Lipoprotein o Formation From IDL after TG hydrolysis o Function Delivers cholesterol to non-hepatic tissues Uptake via RME (RME takes the whole thing wherever it needs to go) Susceptible to oxidation and dropping off cholesterol where it shouldn’t go (e.g. – cholesterol in cardiovascular systematherosclerosis) More free LDL, that means cells are full of cholesterol We will always have “in transit” LDL o Composition Apoproteins B-100: 21% TG: 9% Cholesterol: 50% Phospholipids: 23% o Size: 20-25 nm o Receptor Mediated Endocytosis (RME) Some in liver and cell Receptors located in clatharin coated pits Receptors – specific for proteins (e.g. – LDL: apoproteins B-100) LDL and receptor Receptor and LDL complex internalized vessicle forms Vesicle and lysosome, fuse Lysosome changes pH Apo B degraded to amino acids Cholesterol released into cell Receptor returns to surface Regulation HMG CoA reductase activity o Rate-limiting enzyme for cholesterol synthesis o More cholesterol in celldecreased enzyme activity LDL receptor synthesis o If cholesterol level in cell are high, this will decrease LDL receptor synthesis Therefore, high levels of dietary cholesterol in bloodmore free LDLs o LDLs, susceptible to oxidation o Free LDLs will drop off cholesterol in tissues like the cardiovascular system, etc. (e.g. – in arteries) High-Density Lipoprotein (HDL) o Formation Liver and intestine o Composition Apoprotein (A, C, D, E): 50% TGs: 3% Cholesterol:20% Phospholipids: 30% o Size: 5-25 nm (smallest lipoprotein) o Function: Removal of cholesterol from non-hepatic tissues LCAT (lecithin-cholesterol acyltransferase) Allows HDL to pick up cholesterol from cell membranes/other lipoproteins Apo-A1 binds to LCAT receptor Cholesterolcholesterol ester (CE) Phospholipidlysolecithin (a phoshpholipid w/o a fatty acid) Lysolecithin binds to albumin HDL transport CE to liver High HDLs lower LDLs Exercise helps increase HDLs HDLs never actually enter cell(s), they just “pick up” cholesterol Cholesterol o Synthesis A little more than ½ of all cholesterol in body is synthesized o Location Liver – 10% Intestine – 10% Every nucleated cell can make cholesterol Cytosol Endoplasmic reticulum o Regulation of cholesterol synthesis HMG CoA Reductase Activity Rate-limiting enzyme (regulates pathway) Reduced by: o Cholesterol o Fasting (long-term) Body needs energy over cholesterol so acetyl CoA will go through Krebs cycle instead of cholesterol synthesis o Glucagon A fasting hormone Acetyl CoA to Krebs cycle o Glucocorticoid hormones “fight or flight”needs energy Dietary cholesterol More dietary cholesterol = less synthesis Less dietary cholesterol = more synthesis in body We eat about 600 mg/d, RDA – 300 mg/d We get cholesterol from animal tissues, so vegetarians/vegans usually synthesize most of their cholesterol more than omnivores o Transportation HDL – high density lipoprotein Transports cholesterol from tissues to liver LDL – low density lipoprotein Transports cholesterol from liver to tissues o Functions Cell membranes Maintains fluidity Steroid hormones Testosterone Androgens Estrogen Progesterone Vitamin D Bile Bile o Composition 82% water 12% bile salts 4% phospholipids 0.7% free cholesterol Electrolytes Bile pigments Bilirubin, biliverdin Give bile its yellow/green color From breakdown of heme from hemoglobin o Volume Make 500-800 mL/day o TopHat: which lipoprotein takes cholesterol to liver? Answer: HDL o Synthesis of Bile Hepatocytes (liver) CCK Secretin Gastrin Sent to gall bladder Concentrated and stored CCK stimulates release from gall bladder Contraction of gall bladder Through sphincter of Oddi Into duodenum via bile duct o Function Lipid emulsification Essential for fat digestion Gall stones Mixed with minerals and water leaves, concentration changes Can get stuck in ductsblock secretions of liver and pancreaspancreatitis Treatment: gallbladder removed o Post-treatment: not recommended to eat a lot of fat o Bile comes from liver now, just not as concentrated TopHat: what are the consequences of having the gallbladder removed? Answer: less concentrated bile; bile is made in liver now Fatty Acid Synthesis o Synthesis Glucose – primary substrate Membrane permeability Acetyl CoA and oxaloacetate cannot cross mitochondrial membrane Pyruvate and citrate can cross mitochondrial membrane Majority of synthesis is in cytosol o Fatty Acid Synthase Enzyme complex (8 subunits) Thioesterase Acyl carrier protein Ketoacyl reductase Enoyl reductase Hydratase Transcyclase (2) Ketoacyl synthase Active Complex Dimer or 2 identical polypeptide monomers o Altogether: 8 subunits x 2 monomers = 16 subunits to be active Monomers connected by 2 disulfide bonds o Desaturation Occurs after we get to 16 carbons Addition of double bonds Enzyme: desaturase Essential fatty acids Lack enzymes Δ12 and Δ15 desaturase, which add bonds past Δ9 position o Double bonds – every 3 carbons 18:2 Δ9, 12 18:2 Δ9, 12, 15 De novo fatty acids – 16 carbons long Must elongate then desaturate First double bond will be at Δ9C (n9 fatty acid) Beta Oxidation o Opposite of fatty acid synthesis o Needs oxygen When we are sitting/aerobic exercisewe burn more fat (beta- oxidation) When we are performing anaerobic exercisewe burn more carbs o Breaking down long-chain fatty acids for energy o Energy Even chains Odd chains o Regulation: malonyl CoA High levels inhibit carnitine acyl/palmitoyl transferase 1 Low levels allow for production of CAT-1/CPT-1 o Energy Count: Beta-Oxidation Outside mitochondrial membrane -2 ATP (initiation step happens once) Inside mitochondrial membrane (cleavages) (each time 2 C’s are cleaved) o +1 NADH=3 ATP o +1 FADH=2 ATP o =5 ATP total Krebs cycle (the most energy produced) (for each acetyl CoA produced – depends on length of fatty acid chain) o +3 NADH=9 ATP o +1 FADH=2 ATP o +1 GTP=1 ATP o =12 ATP total Ketones o After beta-oxidation there are 2 pathways for energy production from fatty acids Krebs cycle (from palmitate – 129 ATP) Ketone production (lack of glucose) Fasting stateketosis Ketone bodies o Acetoacetate (from Palmitate - 33 ATP) o Beta-hydroxybutarate (from palmitate - 21 ATP) o Acetone (from palmitate - 0 ATP) Fasting State: o Blood – low glucose levels o Adipose tissue (triglycerides) – lipolysis = fatty acids, glycerol o Liver Glycerolgluconeogenesis = glucose Glublood stream Brings blood glucose levels up to normal Taken up by other tissues (e.g. – brain) Fatty acidsbeta-oxidation = acetyl CoA Provides liver with more acetyl CoA than it can use Acetyl CoAketones Ketones enter blood stream and taken up by tissues (e.g. – brain) Energy (look at diagrams – Palmitate diagram) o When do we make ketones? Starvation Low CHO Increased fatty acid oxidation (burning fat stores) Low CHO diet Tricks body into ketosis E.g. – Atkin’s Diet: mimics starvation, not eating lots of CHO Ketosis usually sets in about 2-3 weeks o Normal if an average, healthy person changes food intake to low carbs Real starvation, ketosis sets in faster If on Atkin’s diet: weight gain can happen immediately when reintroduced to carbs, not a sustainable method to lose weight, lowers BMR Diabetes Insufficient insulin Uncontrolled – glucose (CHO) not taken up in cells, so cells think they are starving (glucose hanging out in bloodstream) Increased beta-oxidation o Why don’t the fatty acids go through Krebs? Low CHO = low pyruvate low OAA (oxaloacetate) Without OAA, we cannot run the Krebs cycle More acetyl CoA than the Krebs cycle can handle (backed up system) Large amounts of fatty acids being burned Limited/no fatty acid synthesis No malonyl CoA (made from F.A. synthesis) to downregulate CPT1 Energy with low CHO Proteingluconeogenesis Brain prefers glucose o Are ketones bad for us? Provide less energy than other fuel sources Will need to burn more fat to get same amount of energy inefficient system weight loss Kidney Dehydration/constipation can occur Body wi ll work harder to rid body of acid Increased urine excretion If an individual has kidney issuesshould NOT do the Atkin’s diet Ketosis is bad If it is caused by real starvation or disease (e.g. – diabetes) o TopHat: What end does desaturase work from? Answer: the carboxyl end o TopHat: “Purpose of lingual lipase is to break fatty acids into 2 C units.” Answer: FALSE; it goes through lipolysis (below) o TopHat: Under what conditions will we undergo ketosis? Answer: all the conditions above. Metabolism of Glycerol o Lipolysis Break down of a triglyceride TG 3 fatty acids (which go to beta-oxidation) + glycerol backbone o Esterification Formation of a triglyceride Organ Specific Lipid Metabolism o Mouth Lingual lipase Milk fat digestion, breaks triglycerides Breaks 3 fatty acids off glycerol backbone o Intestine Absorption of lipid from diet Formation of micelles Micelles passively diffuse to enterocytes o Enterocyte Chylomicron synthesis (transport/drop off) o Liver (*does a lot with lipids) Bile synthesis Cholesterol synthesis Fatty acid synthesis TGs, phospholipids, oxidized Beta oxidation Krebs Ketone synthesis Lipoproteins Formation of HDL & VLDL Endocytosis of chylomicron remnant (takes it up into liver) o Adipose Tissue Fatty acid synthesis and storage (triglycerides) Insulin stimulates Glucose uptake into cells Glucose as a substrate for F.A. synthesis Lipid uptake into cells o LPL Leptin Made to beat obesity Reduces appetite and increases basal metabolic rate Weight maintenance o More adipose tissue, more leptin Tells brain you’re full when sleeping o Not as much sleepweight gain Leptin gene mutation can lead to uncontrolled appetite and obesity o Very rare mutation o Mutation comes with other physical characteristics (e.g. – decreased pigmentation in skin) Overweight/obese individuals: excess leptin in blood instead of cellsleptin resistant (like insulin in diabetics) Adipocyte proliferation and differentiation o We store fat indefinitely (adipocytes) o When the fat cells get the largest they can get, then more fat cells are made o Adipocyte number cannot decrease, the cells just shrink (losing weight) o Adipocytes will eventually die, takes a long time (usually die due to age) BAT vs. WAT o Brown adipose tissue More mitochondria than white adipose tissue (mitochondria help give the brown color) Uncoupling protein 1 (UCP1) Uncouples oxidation and phosphorylation reactions at ETC inefficient ETC H+ allowed to flow back into matrix Heat and less ATP Infants have higher amounts of BAT than adults Basal metabolic rate More BAT higher BMR Obese have less BAT than leaner individuals Do muscle cells and BAT originate from the same stem line? Can we recruit BAT? Research says that it is very possible with exercise. We can get WAT to “act” like BAT. o TopHat: If BAT has more uncoupling proteins in the tissue, this tissue would be… Answer: Less efficient at making ATP than WAT. o Muscle At rest, fat is primary source of fuel (beta-oxidation) Some individuals have fat in muscles (e.g. – overweight individuals or endurance athletes, like distance runners) Exercise uses glucose as fuel (In class, we skipped Regulation of Lipid Metabolism and will possibly bring it in to the Heart Disease/Atherosclerosis PowerPoints)
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