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BIOC 460 - DR. TISCHLER LECTURE 33 LIPOLYSIS: FAT OXIDATION & KETONES OBJECTIVES 1. Lipolysis a) describe the pathway; b) location c) principal enzyme d) role e) role of albumin and FABP in transport/metabolism of FFA 2. Degradation of fatty acyl CoA a) roles of acyl CoA synthetase, CPT-I and CPT-II, and CAT b) relationship of -oxidation products to energy production. c) degradation of odd- vs even-chain FA d) vitamins for metabolizing propionyl CoA to succinyl CoA 3. Ketone body metabolism a) where ketogenesis occurs b) when ketogenesis occurs c) role of keotgenesis d) why normal individuals do not usually develop ketacidosis even when producing ketone bodies. FAT FACTS fat (lipid) makes up 37% of the calories in the American diet 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 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 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 Fatty acid -oxidation MITOCHONDRION oxidation to CO2 Thiolase 2 Acetyl CoA (excess acetyl CoA) Citric acid cycle CoA Acetoacetyl CoA acetyl CoA Figure 6. Ketone HMG-CoA synthase body formation CoA (ketogenesis) in liver Hydroxymethylglutaryl CoA mitochondria from excess acetyl CoA HMG-CoA-lyase derived from the - acetyl CoA oxidation of fatty Acetoacetate acids NADH (non-enzymatic) -Hydroxybutyrate dehydrogenase Acetone NAD+ -Hydroxybutyrate KETONE BODY OXIDATION high rates of lipolysis (e.g., long-term starvation or in uncontrolled diabetes) produce sufficient ketones in the blood to be effective as a fuel ketones are the preferred fuel if glucose, ketones, fatty acids all available in the blood primary tissues: using ketones, when available, are brain, muscle, kidney and intestine, but NOT the liver. -Hydroxybutyrate + NAD+ acetoacetate + NADH -hydroxybutyrate dehydrogenase in mitochondria; reverse of ketogenesis KETOACIDOSIS Excessive build-up of ketone bodies results in ketosis eventually leading to a fall in blood pH due to the acidic ketone bodies. In diabetic patients the events that can lead to ketosis are: Relative or absolute (most common cause) deficiency of insulin Mobilization of free fatty acids (from adipose lipolysis) Increased delivery of free fatty acids to the liver Increased uptake and oxidation of free fatty acids by the liver Accelerated production of ketone bodies by the liver Adipose Tissue X Free fatty acids Liver Ketone Bodies Insulin Pancreas Figure 7. Mechanism for prevention of ketosis due to excess ketone body production that can lead to ketoacidosis