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Lecture 3

PSL425 Lecture 3.docx

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PSL425 Lecture 3 Classification and Function of Lipids - Carbohydrates defined by their structure - Lipid defined by the insolubility of water (physical property) - Chemically: very heterogeneous class of substances - COOH (acid) end at the end; long or short aliphatic chains - Triglyceride: esters of fatty acids and a poly-aocohol: glycerol (derived in body from glycolysis) - Phospholipid: more complex lipid, some similar to TG, but with a phosphate on instead of 3 FA rd - Increasing complexity down the column (in relation to the slide); sphingolipids complex - Most of the complex lipids make up mmbrn - Cholesterol metabolism important in atherosclerosis, important for mmbrn structure, phospholipids and cholesterol provide some signaling molecules - Lipids in terms of energy metabolism – Ketones: acids, some solubility in water, but still grouped with the lipids, they are metabolic products of FA oxidation - Sterols: includes cholesterol and steroid hormones that are derivatives (sex hormones, adrenal steroids, vitamin D that is sterol-like) of cholesterol, detergents (bile salts also made from cholesterol) Nomenclature of Fatty acids - General structure of FA = most important in terms of energy metabolism - carboxylate terminus – why an acid; and methyl terminus - carbon of the acid group is 1, number increasing on subsequent carbon; also alpha, beta, gamma (alpha first carbon beside COOH) - can start from numbering from methyl terminus: n- or omega- - 3 carbon including COOH (FA undergo beta oxidation at this site) - Most FA in circulation are long FA, 14-22 - Most prevalent FA circulating: oleate, then palmitate; oleate also in olive oil (70%) - Oleate aka oleaic acid, depends on the pH; number of carbons:# of double bonds (position of double bond) e.g 18:1 (9) - Mono-unsaturated (1 DB); more than one DB=polyunsaturated: most prevalent linoleate (position n-6 from the methyl terminus) - Very long –chain FA important in e.g. prostaglandins related to lipid signaling - Short-chain – e.g. butyrate, mostly produced by bacteria in gut; can feed into glucose metabolism in some ways; absorbed into the portal vein - Medium-chain – smaller = gradually more soluble in water, undergo beta-oxidation, goes into portal vein o Some say very healthy, b/c easily metabolized: immediately oxidized (don’t use transferase system), they do not undergo lipoprotein metabolism (go through portal vein) Fat Digestion – 3 FA released - Lipase participates in this, secreted from the pancreas, first thing that goes is the lipid metabolism in pancreatic insufficiency – get fatty diarrhea, b/c fat not absorbed - Most problem for lipase: get 2 FFA and 1 monoglycerides (small enough to be absorbed) – problem is getting to plasma mmbrn, once there, fat can be absorbed very well - How can FA get to plasma - Eat fat – insoluble in water – tend to coalesce together – need to be dispersed b/c if all in one chunk, lipase cannot physically penetrate it - Bile salts (bipolar) – emulsifier, breaks fat into little pieces; coat fat in such a way that the non- polar part (in contact with fat part) is inside and polar part is outside (in contact with fluid) - Negative charges from bile salts’ polar parts imparted onto surfaces– repel each other and prevents them from re-coalescing – mechanism of soaps (dispersal) - Increase surface area for lipase action – out of the small droplets, it makes monoglycerides and FFA’s – still fats, but smaller fats – little bit more soluble than TG in initial droplets, and they can penetrate smaller particles called micelles - Micelles are the monoglycerides and FA’s after the pancreatic lipase acted - Micelles coated by bile salts together with cholesterl, and cholesterol enters the micelles and end up with FA’s and monoglycerides - Now particles small enough to interact and bring the FA’s and monoglycerides closer to plasma mmbrn – can penetrate the microvilli of enterocytes (intestinal epithelial cells) – monoglycerides and FA’s can be absorbed and enter the cell - Once they enter the cell, they are a little bit polar (both the FA’s and monoglycerides), but cells don’t want polar substances, b/c polar substances like (with one polar and one non-polar end) tend to disrupt mmbrn and so immediately want to block polar end and store them as inert non- polar substance – so the enterocyte resynthesizes them into TG and it has to put them out onto substances that can travel in blood – i.e. lipoproteins - Lipoproteins – small ball of fat that are coated by proteins, b/c proteins make droplets soluble in water, so it can travel in water (coat in polar groups) - Chylomicrons are pretty big – can’t get into venous circulation of gut, but they enter into lymph system, b/c lymph vessels are more permeable – lymph – lymph system then converges into peripheral system (ends in vena cava)– IMPORTANT! Bypass liver - Goes to tissues that mostly uses it, and it can be stored if in excess w/o chocking liver - Medium and short-chain FA’s are small enough to have some solubility and not very soap-like (small, so no h-phobic end), can absorbed as they are and go into the portal vein and go to the liver; dietary fat = chylomicrons (don’t provide FFA in circulation) Circulating lipids - FFA or non-esterified FA: those floating in our circulation they are from breakdown of fat in adipocytes – lipolysis during fasting stimulated by low insulin levels, very few glucagon receptor on fat cells; insulin is very anti-lipolytic - Only when glucagon in very high levels does it contribute to lipolysis – i.e. uncontrolled diabetes; but normal person, mainly controlled by insulin levles - They are bound to albumin in our circulation – IMPORTANT! like infusing soaps (emulsifiers) – bad hemolysis (RBC destroyed) - Binding to albumin buffers the FA’s, prevents detergent-like effects on plasma mmbrn, and mmbrn integrity is maintained; only way FFA travels in blood - Another system exploited by dietary fat; Dietary fat is not absorbed as FA’s, but as chylomicrons (lipoproteins) and non-toxic fats - Chylomicron are balls of TG covered with protein; mimick this in giving fat through IV – making small emulsions that mimick the lipoproteins - Assuming dietary fat in lipoproteins (blocked esterified fats); LPLipase secreted by adipose tissue, but is also present in and secreted by muscles; once secreted lipoprotein lipase stuck on wall of capillary endothelia - Experimentally: one way of liberating LPL is by heparin – releases LPL from capillary wall into circulation, by releasing this enzyme increase lipolysis - LPL – lipase of lipoproteins, acts in peripheral circulation; diff from other lipases - When chylomicron get to capillary wall, breaks TG of lipoprotein down into FA and glycerol; FA’s generally never appear in circulation - As soon as FA released there, they are utilized there, only in situations of excessive lipolysis you can increases in level FA - After a meal, generally do not have increase in FA in circulation – FA goes down in of insulin – actually chylomicrons increase, muscles and fat get fat directly from chylomicrons - FA’s enter passively, also transporters there for fatty acids; transporters-system more regulated - Lot of FA movement is passive, although transporters there as well - Once inside the cell, FA, if not blocked – toxic and detergent-like; so cell first neutralizes them: esterification with e.g. co-enzyme A - CoA esterifies FA that enter the cell – forming acyl CoA, involves breakdown of ATP and PP to make this synthetic product (synthetic reaction) - FA: metabolism occurs from the Fatty acyl CoA (CoA derivatives) Transport of FA across mitochondrial membranes - Muscle cells mostly the ones that need FA – for energy! - Energy provided by FA much more than that from glucose – used by muscles! - FA need to be oxidized (broken down) for energy to be utilized - FA oxidization occurs in mitochondria – here there is FA oxidizing system - Cells that do not have mitochondria (e.g. RBC) cannot metabolize fat - Beta-oxidation occurs in the mitochondria matrix = 1 oxidation of FA (at beta carbon), but before this, the FA has to enter the mitochondria - Medium chain FA can enter mitochondria mmbrn freely, same way as they are absorbed (do not be blocked by acyl CoA) – more easily oxidized - All long chain FA have to be blocked by acyl CoA (prevention of soap-likeness) in thioester linkage but now they are big and cannot easily traverse mitochondrial membrane - System: CPT (carnitine palmitoyltransferase) – 2 enzymes; 2 CPT, one in outer and one in inner mmbrn of mitochondria that allow the passage into mitochondria - Acyl CoA can penetrate outer mmbrn up to a certain point: interacting with CPT-1 - CPT switches CoA with small molecule carnitine (esterified to FA moiety) b/c CoA is big molecule, and carnitine has a free passage - But, once inside mitochondria, the carnitine is switched back by another enzyme to acyl CoA – acyl CoA regeneration inside mitochondria - Whole system is a double transfer - Important: system is also REGULATED; malonyl CoA is a big regulator of this system - Malonyl CoA is an intermediate of fatty acid synthesis, also can be derived from glucose – lot of it=lots of energy – no need for further energy – oxidation of FA stopped, even before oxidation occurs, it stopped at the entrance of FA into mitochondria (passage of LC FA) - Insulin also increases malonyl CoA – why insulin decreases fat oxidation Inside mitochondria - Beta-oxidation in mitochondrial matrix - 1) Introduces double bonds to unsaturated FA (via dehydrogenases) 2) Add a molecule of water: O group goes to one carbon, proton goes to other carbon – forms hydroxyacyl acid 3) Dehydrogenase again – forming ketoacid in position beta 4) then split (thioloysis) – catalyzed by enzyme thiolase, which liberates 1 acetyl CoA and 1 FA with 2 less carbon - Left over continues until FA split into 2C units – cycle: each cycle yields NADH (at hydroxyacyl dehydrogenase), a reduced FADH2 - reduced co-enzyme can feed the ETC, and acetyl CoA can go to the Krebs cycle - FA has lots of carbons – produce lots of energy Synthesis – recapitulates some of the processes as seen in breakdown, but diff enzymes, diff co- enzymes, and diff sites - Occurs in cytosol vs breakdown in mitochondria (diff locations) - One of the products of synthesis is also acetyl CoA, but is the one in cytosol NOT in mitochondria - Synthesize FA when you have a positive energy balance: energy from gluco
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