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Lipolysis and fattyacid oxidation Dr.Siddiqui Abdulmoeed Associate Professor College of medicine Al-Jouf university Objectives • • • • • • • • • • • Define lipolysis List the steps of lipolysis Mention the site of occurrence and importance of lipolysis List the products lipolysis and their fates Define beta oxidation of fatty acid Mention the sub cellular site of occurrence of beta oxidation of fatty acids List the steps of beta oxidation of fattyacids Mention the function of carnitine List the products of beta oxidation of fatty acids and fate of these products Mention the importance of beta oxidation of fatty acids Mention the bioenergetics of beta oxidation of fatty acid (palmitic acid and stearic acid} LIPIDS Lipids are heterogeneous group of compounds actually or potentially related to fatty acids .Soluble in non-polar solvents and insoluble in polar solvents. Lipids are not polymers. Lipids are classified as: 1. Fatty acids 2. Neutral fats and oils 3. Waxes 4. Phospholipids 5. Sterols Lipid FACTS Lipids are energy rich and provides 9 kcal/gm dietary lipids 90% triacylglycerols (TAGs) also include cholesterol esters, phospholipids, essential unsaturated fatty acids; fat-soluble vitamins most dietary fat transported to adipose for storage dietary TAGs hydrolyzed in the intestine by pancreatic lipases; then reassembled in the intestinal cells dietary fats transported to tissues as TAG or cholesterol via chylomicrons at peripheral tissues (e.g., adipose or muscle), FA removed from the TAG by a lipoprotein lipase in the capillary walls; released fatty acids diffuse into the cell Lipolysis Hormone (Adrenalin, Glucagon, ACTH) Receptor (7TM) Activates ATP Insulin blocks this step Adenylyl Cyclase c-AMP Activates lipase Triacylglycerols Glycerol + Fatty acids Adipose Cell Blood 5 Pyruvate Fate of Glycerol In Liver: OH OH OH Glycolysis Dihydroxyacetone Phosphate Gluconeogenesis Glycerol Glucose 6 Processing of Lipid Reserves: Overview 1. Lipid Mobilization: In adipose tissue TAGs hydrolyzed to fatty acids plus glycerol 2. Transport of Fatty Acids in Blood To Tissues 3. Activation of Fatty Acids as CoA Ester 4. Transport into Mitochondria 5. Metabolism to Acetyl CoA 7 saturated fatty acid: unsaturated fatty acid: polyunsaturated fatty acid: CH3-(CH2)n-COOH CH3-CH=CH-(CH2)n-COOH CH3-CH=CH-CH2-CH=CH-(CH2)n-COOH CH2----OOC-R1 | HOOC-R1 | Lipolysis R2-COO----CH | CH2OH CH2----OOC-R3 Triacylglycerol CHOH HOOC-R2 | CH2OH Glycerol HOOC-R3 Fatty acids Figure 1. General structures of fatty acids and triacylglycerol. Lipolysis of stored triacylglycerol by lipases produces fatty acids plus glycerol. LIPOLYSIS fatty acids hydrolytically cleaved from triacylglycerol largely in adipose to release fatty acids as a fuel may also occur in muscle or liver - smaller amounts of fatty acids are stored hormone-sensitive (cyclic AMP-regulated) lipase initiates lipolysis – cleaves first fatty acid this lipase and others remove remaining fatty acids fatty acids/glycerol released from adipose to the blood hydrophobic fatty acids bind to albumin, in the blood, for transport CAPILLARY Lipoproteins (Chylomicrons or VLDL) FA FA albumin FA [1] from fat cell L P L [2] FA FABP FA MITOCHONDRION acetyl-CoA TCA [7] cycle A [3] [4] C -oxidation [6] S FA acyl-CoA acyl-CoA FABP FABP [5] carnitine CYTOPLASM transporter cell membrane FA = fatty acid LPL = lipoprotein lipase FABP = fatty acid binding protein ACS = acyl CoA synthetase Figure 2. Overview of fatty acid degradation ATP + CoA AMP + PPi palmitate palmitoyl-CoA Cytoplasm ACS CPT-I [2] [1] CoA palmitoyl-CoA Intermembrane Space OUTER MITOCHONDRIAL MEMBRANE carnitine palmitoyl-carnitine Figure 3 (top). Activation of palmitate to palmitoyl CoA (step 4, Fig. 2) and conversion to palmitoyl carnitine CPT-I palmitoyl-CoA Intermembrane Space CoA palmitoyl-carnitine carnitine CAT [3] INNER MITOCHONDRIAL MEMBRANE CPT-II Matrix carnitine palmitoyl-carnitine [4] palmitoyl-CoA CoA Figure 3 (bottom). Mitochondrial uptake via of palmitoylcarnitine via the carnitine-acylcarnitine translocase (CAT) (step 5 in Fig. 2). ATP + CoA AMP + PP i palmitate Cytoplasm palmitoyl-CoA ACS [1] OUTER MITOCHONDRIAL MEMBRANE CPT-I [2] CoA palmitoyl-CoA carnitine Intermembrane Space palmitoyl-carnitine CAT [3] INNER MITOCHONDRIAL MEMBRANE CPT-II Matrix carnitine palmitoyl-carnitine [4] palmitoyl-CoA CoA Palmitoylcarnitine Carnitine translocase inner mitochondrial membrane matrix side respiratory chain Palmitoylcarnitine 2 ATP 3 ATP Palmitoyl-CoA FAD oxidation FADH2 H2O hydration recycle 6 times oxidation NAD+ Figure 4. Processing and -oxidation of palmitoyl CoA NADH cleavage CoA CH3-(CH)12-C-S-CoA + Acetyl CoA O Citric acid cycle 2 CO2 Beta Oxidation Reaction Sequence Acyl CoA H Dehydrogenase R-CH2 -C-C-COSCoA R-CH2 -C=C-COSCoA H H H H FAD -Ketoacyl CoA H FADH2 L--Hydroxyacyl CoA Dehydrogenase NADH + H+ CoASH trans- 2 -enoyl CoA H2 O Enoyl CoA Hydratase H H R-CH2 -C-C-COSCoA R-CH2 -C-C-COSCoA OH H NAD+ HO H L--Hydroxyacyl CoA Thiolase (-ketothiolase) CH 3 -C-SCoA R-CH2 -C-SCoA + O O Occurs in Mitochondria Repeat Sequence 15 Energetics of Complete Oxidation of Fatty Acids High Energy Phosphate Bonds Generated Palmitic Acid Palmitoyl CoA -2 TCA Cycle CH3COSCoA CO2 + H2O 108 Net 106 106 High Energy Phosphate Bonds For Palmitic Acid CO2: G0’ = - 9,790 KJ/Mole G0’ = 3,233 KJ/Mole Efficiency of -Oxidation = 33% 16 Energetics of beta oxidation • • • • • • • • • Palmitic acid yield 8 acetyl coA molecules 7 NADH and 7FADH 2 are formed 1 acetyl coA in TCA cycle gives 12 ATPs 12 x 8 = 96 1 NADH = 3 ATP 1 FADH2 =2 ATP 7 x 5 =35 96+35 =131 -2 =129 ATP Net gain Stearic acid yield 9 acetyl coA ,8 NADH, 8 FADH2 • 9 x 12 =108, • 8 x 5 =40 • 148 – 2 = 146 ATP Net gain OXIDATION OF ODD-CHAIN FATTY ACIDS Final step of -oxidation produces: propionyl CoA + acetyl CoA propionyl CoA carboxylase: (biotin-dependent) propionyl CoA + ATP + CO2 methylmalonyl CoA + AMP + PPi methylmalonyl CoA mutase: (adenosyl cobalamin-dependent) methylmalonyl CoA succinyl CoA Figure 5. Reactions in the metabolism of propionyl CoA derived from odd-chain fatty acids Thanks & Best Wishes