Lipid Metabolism PDF

# Lipid Metabolism ## Lipids - a group of heterogenous biomolecules that are insoluble in water and soluble in non-polar solvents ### Biological functions: - energy source - insulation of vital organs - covering of nerve fibers - components of cell membrane - chemical messengers (hormones...

# Lipid Metabolism ## Lipids - a group of heterogenous biomolecules that are insoluble in water and soluble in non-polar solvents ### Biological functions: - energy source - insulation of vital organs - covering of nerve fibers - components of cell membrane - chemical messengers (hormones) ## Fatty Acid Formula - condensed and line-bond formula; shorthand notation - Eg. caprylic acid (C8, saturated) - `CH3CH2CH2CH2CH2CH2CH2COOH` - `CH3-(CH2)6-COOH` - Octanoic acid (8:0) | Number of C atoms | Common name | Formula | Occurrence | Melting point, °C | |---|---|---|---|---| | 4 | Butyric acid | `CH3(CH2)2COOH` | 4-5% butter | -7.9 | | 6 | Caproic Acid | `CH3(CH2)4COOH` | goat's milk | -3.4 | | 8 | Caprylic Acid | `CH3(CH2)6COOH` | | 16.3 | | 10 | Capric Acid | `CH3(CH2)8COOH` | | 31.2 | | 12 | Lauric Acid | `CH3(CH2)10COOH` | vegetable oils, coconut oil | 43.9 | | 14 | Myristic Acid | `CH3(CH2)12COOH` | animal, vegetable, palm, milk, sperm whale oil | 54.1 | | 16 | Palmitic Acid | `CH3(CH2)14COOH` | extensively found in many fats and oils | 62.7 | | 18 | Stearic acid | `CH3(CH2)16COOH` | extensively found in many fats and oils | 69.9 | | 20 | Arachidic acid | `CH3(CH2)18COOH` | peanut oil | 75.4 | | 22 | Behenic acid | `CH3(CH2)20COOH` | minor constituent of most seed oils, marine animal fats | 79.9 | | 24 | Lignoceric acid | `CH3(CH2)22COOH` | seed fat from Indian tree | 84.2 | | 26 | Cerotic acid | `CH3(CH2)24COOH` | beeswax | 87.7 | ## Fatty Acid Formula - Eg. palmitoleic acid (C16, monounsaturated) - `CH3CH2CH2CH2CH2CH2CH=CHCH2CH2CH2CH2CH2CH2CH2COOH` - `CH3(CH2)5CH=CH(CH2)7COOH` - cis-9-hexadecenoic acid 16:1(49) ## Sat'd VS Unsat'd FAs - (c) `0000` (d) `0000` - HIGH MP - LOW MP ## Essential Fatty Acids - fatty acids that mammals cannot synthesize - Eg. omega-3 and omega-6 fatty acids - polyunsaturated fatty acids - essential in normal visual and central nervous system development - omega notation: indicates the position of the first double bond starting from the last carbon | No. of C atoms | Common name | Formula | Melting point, °C | |---|---|---|---| | 16 | Palmitoleic acid | `CH3(CH2)5CH=CH(CH2)7COOH (cis)` | 0.5 | | 18 | Oleic acid | `CH3(CH2)7CH=CH(CH2)7COOH (cis)` | 13.4 | | 18* | Linoleic acid | `CH3(CH2)4CH=CHCH2CH=CH(CH2)7COOH(cis, cis)` | -5 to -5.27 | | 18* | Linolenic acid | `CH3CH2CH=CHCH2CH=CHCH2CH=CH(CH2)7COOH (cis, cis, cis)` | -10 to -11.3 | | 20 | Arachidonic acid | `CH3(CH2)4CH=CHCH2CH=CHCH2CH=CHCH2CH=CH(CH2) 3COOH (cis, cis, cis, cis)` | -4 9.5 | | *essential fatty acid | ## Omega-3 and Omega-6 FAs - Alpha-linolenic acid (ALA, C18:3, omega-3) - Eicosapentaenoic acid (EPA, C20:5, omega-3) - Docosahexaenoic acid (DHA, C22:6, omega-3) - Linoleic acid (LA, C18:2, omega-6) - Arachidonic acid (AA, C20:4, omega-6) ## Classification of Lipids ### Saponifiable - glyceryl esters: - triglycerides, glycerophospholipids - non-glyceryl esters: - sphingophospholipids, waxes, glycolipids ### Non-Saponifiable - steroids - eicosanoids - terpenes - pheromones - fat-soluble vitamins ## Saponifiable Lipids - produce fatty acid salts upon treatment with base ## Fats vs. Oils ### Fats - TAGs that contain high percentage of saturated fatty acids - solid at RT - usually coming from animal sources ### Oils - TAGs that contain high percentage of unsaturated fatty acids - liquid at RT - usually coming from plant sources ## 1. Triacylglycerols/Triglycerides - esters of glycerol and fatty acids ## Simple vs. Mixed TAGs - simple triclyceride (fat) - mixed triglyceride (fat) - mixed triglyceride (oil) ## 2a. Glycerophospholipids - common constituents of cell membranes - a triester in which - first two (2) -OH groups of glycerol are esterified with fatty acids (need not to be identical) - third -OH group esterified with a phosphate group that is in turn esterified to an alcohol ## 2b. Sphingophospholipids - derivatives of ceramide (sphingosine + fatty acid) - fatty acid is connected with the -NH3+ group via an amide linkage - a polar group is usually esterified with the -OH group on the terminal carbon ## 3. Waxes - esters formed from fatty acids and long-chain monohydric alcohols - can be found on: - leaf surfaces - prevents excessive water loss and water absorption which can lead to leaf dissolution - feathers of birds - hair ## 4. Glycolipids - contain monosaccharides bonded to the -OH group of ceramide through a glycosidic bond - cerebrosides - glycolipid present in the brain and myelin sheath of the nerves - sugar is either galactose or glucose - ganglioside - sugar moiety can be more than one monosaccharides, disaccharides or trisaccharides ## NON-SAPONIFIABLE LIPIDS ## 1. Steroids - lipids containing the steroid nucleus which is a fused structure of four rings - cholesterol - bile salts - hormones - vitamin D ## 1.1 Cholesterol - most abundant steroid in the body `- can be synthesized in the liver and obtained from diet` ## 1.2 Bile Salts - `synthesized from cholesterol and released by the gall bladder` - emulsify fats and oils to give a greater surface area for lipid digesting enzymes ##1.3 Steroid Hormones - cortisol - corticosterone - aldosterone - progesterone - B-estradiol - testosterone ## 2. Eicosanoids - signaling molecules derived from arachidonic acid - act a messengers in the central nervous system - prostaglandins - thromboxanes - leukotrienes ## 2.1 Prostaglandins - function in the regulation of contraction and relaxation of smooth muscle tissues; contains a 5-carbon ring - Arachidonic acid - Analgesics - Pain, fever, inflammation ## 2.2 Thromboxanes - promote formation of blood clots; contains a 6-membered ring containing an ether - Thromboxane A2 - Thromboxane B2 ## 2.3 Leukotrienes - Signaling lipids for inflammatory and hypersensitivity responses; contain 3 conjugated double bonds - LEUKOTRIENE B4 - LEUKOTRIENE C4 - LEUKOTRIENE E4 - LEUKOTRIENE D4 ## 3. Terpenes - hydrocarbons or hydrocarbon derivatives constructed from recurring isoprene units - responsible for the scents and tastes of plant products ### Monoterpenes (C10) - limonene - citronellal - menthol - phytol ### Diterpenes (C20) ### Triterpene (C30) ### Tetraterpene (C40) - Lycopene ## 4. Pheromones - chemicals secreted by insects and animals to transmit messages to other members of the species - long chain alkenes with oxygen-containing functional group ## 4. Fat Soluble Vitamins - vitamin A - vitamin D2 - vitamin E - vitamin K1 ## Digestion of Dietary Lipids - regular intake: -60-150 g lipids/day; 90% are TAGS - Digestion: ### 1. Mouth - mechanical breaking of food into smaller particles - exposes maximum surface area for enzyme to act on later ### 2. Stomach - big chunks of fats floating in the aqueous environment are turned into small droplets/globules - chyme - a semi-liquid mass of food formed after churning action in the stomach ### 3. Small intestine - where fat digestion begins - arrival of TAGs triggers the secretion of cholecystokinin - cholecystokinin triggers release of pancreatic lipases and bile stored in the gall bladder ### Emulsification of fats - bile is a mixture of bile salts, bile acids and cholesterol that acts as emulsifiers. - emulsified fats are formed in the duodenum then acted upon by pancreatic lipase ## Action of Pancreatic Lipase - pancreatic lipases hydrolyzes ester linkages at positions 1 and 3; net products are two fatty acids and 2-monoacylglycerol ## Lipoproteins - conjugated proteins used for transport of TAGs and cholesterol - Chylomicrons - brings TAGs to the liver; contains the highest amount of TAGS - HDL- scavenges cholesterol in the blood and brings it to the liver - LDL - brings cholesterol from the liver to other tissues - VLDL - carries TAGs from liver to other tissues ## Transport of Dietary TAGs - TAGS passes through the blood vessels through the lymphatic system which join the blood vessels via the thoracic duct ## 3 Stages of FA catabolism ### 1. Lipid mobilization from adipose tissues or Lipolysis ### 2a. Fatty acid activation - FA + CoA-SH → fatty acyl CoA - fatty acyl CoA enters the mitochondria from the cytosol - catalyzed by fatty acyl CoA synthetase ### 2b. Transport of fatty acyl CoA - OUTER mitochondrial membrane - INNER mitochondrial membrane ### 3. β-oxidation of fatty acyl-CoA - converts each 2C unit of fatty acids into acetyl CoA - four steps (for saturated fatty acids): - oxidation/dehydrogenation - hydration - oxidation/dehydrogenation - chain cleavage ## β-Oxidation of Fatty Acyl-CoA ### 1. Oxidation/Dehydrogenation ### 2. Hydration ### 3. Oxidation/Dehydrogenation ### 4 . Cleavage ## β-Oxidation of Fatty Acyl-CoA - For the oxidation of an even-numbered saturated fatty acyl CoA: ## β-Oxidation of Unsatd Fatty Acyl-CoA - required two new set of enzymes ## β-OXIDATION OF EVEN NUMBERED UNSATURATED FATTY ACIDS ## β-Oxidation of Odd Satd Fatty Acyl-CoA - odd-numbered fatty acids are oxidized in same pathway for even-numbered FAs - substrate for the last pass of beta oxidation contains 5 carbons - products are acetyl CoA and propionyl-CoA ## KETOGENESIS: Synthesis of Ketone Bodies ## Ketogenesis - formation of ketone bodies - occurs in liver mitochondria during: - starvation, when [glucose] is very low - high fat, low carb diet (↑[acetyl CoA]) - diabetic conditions where the body cannot adequately process glucose ## Ketone Bodies - alternative fuel for the cells - soluble in aqueous medium thus need not be incorporated in lipoproteins for transport to the peripheral tissues through the blood - used by skeletal and cardiac muscles and also by the brain ## Steps in Ketogenesis ## Utilization of Ketone Bodies (in tissues) ## Fatty Acid Biosynthesis - occurs in the cytosol - Requirements: - acetyl CoA - malonyl CoA (a 3-carbon intermediate) - NADPH (provided by the pentose phosphate pathway) - fatty acid synthase complex ## Fatty Acid Synthase Complex - a multifunctional enzyme complex - has seven (7) enzymatic activities that catalyze each steps in fatty acid biosynthesis - end product is palmitoyl-ACP (C16) ## 1a. Production of Acetyl CoA cytosolic - MITOCH. MATRIX - CYTOSOL ## 1b. Acetyl CoA to Malonyl CoA - involves carboxylation of acetyl CoA - the committed step in FA biosynthesis ## 1c. Attachment of Malonyl CoA - acyl-carrier protein (ACP) - carrier of acyl intermediates during fatty acid synthesis - contains a phosphopantetheine group which forms a thioester with a fatty acyl CoA ## Fatty Acid Synthase Complex - B-Ketoacyl-ACP synthase - Malonyl-CoA-ACP transferase - Acetyl-CoA-ACP transacetylase - B-Ketoacyl-ACP reductase - Enoyl-ACP reductase - B-Hydroxyacyl-ACP dehydratase ## 1c. Attachment of Malonyl CoA - Malonyl CoA - Acetyl CoA - Malonyl transacylase - Acetyl CoA-ACP transacylase ## 1d. Condensation of Acetyl-ACP and Malonyl-ACP - Acyl-Malonyl-ACP condensing enzyme - Acetoacetyl-ACP ## 2. Reduction - b-ketoacyl-ACP-reductase ## 3. Dehydration - 3hdoybtyryl-AP dehydatase ## 4. Reduction - Enoyl-ACP reductase ## Translocation, Formation of New Malonyl-ACP ## Repetition of Steps 1-4 ## Release of Free Palmitic Acid - free fatty acid is detached from the fatty acid synthase complex through the action of thioesterase ## Synthesis of Longer Chain and Unsat'd FAs - FAs longer than 16 carbons are made by FA elongation systems found in the ER and mitochondria - Unsaturated FAs are made by desaturases found in the ER - Δ9-desaturase introduces a cis-double bound at carbon number 9 - mammalian desaturases cannot make a double bond beyond carbon number 9 - linoleic and alpha-linolenic acid are the major essential FAs, required for the synthesis of arachidonic acid and other PUFAs of eicosanoids ## Synthesis of Longer Chain and Unsat'd FAs - Palmitate (16:0) - elongation - desaturation - Stearate (18:0) - desaturation - Oleate (18:1 Δ') - elongation - linoleate (18:2 9,12) - desaturation - a-Linoleate 18:3 (9,12,15) - y-Linoleate (18:3 6,9,12) - Eicosatrienoate (20:3 8,11,14) - desaturation - Arachidonate (20:4 5,8,11,14) ## Regulation of FA Biosynthesis - regulatory point: Acetyl-CoA carboxylase (ACC) - (-) long-chain fatty acyl CoA - Eg. palmitoyl CoA - inhibition via feedback mechanism ## Regulation of FA Biosynthesis - regulatory point: Acetyl-CoA carboxylase (ACC) - ↑ [citrate] means that enough intermediates are available for both TCA cycle and FA biosynthesis - ↑ [citrate] means ↑ [malonyl CoA] ## Hormonal Regulation ### GLUCAGON and EPINEPHRINE - Inhibitory to ACC - F.A. biosynthesis inhibited - F.A. breakdown favored ### INSULIN - Activator of ACC - F.A. biosynthesis favored - F.A. breakdown inhibited ## Biosynthesis of TAGs - fatty acids are stored in adipose tissues as TAGS - Glycerol 3-P-acyl transferase - phosphatidate ## Biosynthesis of TAGs - phosphatidate - Diglyceride acyl transferase - TAG ## BIOSYNTHESIS OF CHOLESTEROL ## General Steps in Cholesterol Biosynthesis - Formation of mevalonate - Synthesis of isopentyl pyrophosphate - Condensation of six molecules of isopentyl pyrophosphate to form squalene - Cyclization of squalene to form lanosterol then cholesterol ## 1. Formation of Mevalonate ## 1. Formation of Mevalonate ## 2. Synthesis of Isopentyl Pyro-P ## 3. Formation of Squalene - Isopentenyl pyro-P - Dimethyl allyl pyro-P - Geranyl pyro-P - Farnesyl pyro-P - SQUALENE ## 4. Cyclization to Cholesterol - Squalene - Squalene epoxide - Lanosterol - CHOLESTEROL ## Regulation of Cholesterol Biosynthesis - Major regulatory point: HMG-CoA reductase - (+) high levels of ATP - (-) cholesterol via feedback inhibition