Fatty Acid Degradation PDF

Chapter 27 Fatty Acid Degradation Fat as Fuel Triacylglycerols (TAG) – Fatty acids linked to glycerol with ester linkages – Most efficient fuel Highly reduced, high storage capacity (no water) BUT must have O2 – Most stored in adipose...

Chapter 27 Fatty Acid Degradation Fat as Fuel Triacylglycerols (TAG) – Fatty acids linked to glycerol with ester linkages – Most efficient fuel Highly reduced, high storage capacity (no water) BUT must have O2 – Most stored in adipose Throughout the body – Subcutaneous (below the skin) – Visceral (around the internal organs) – There is intramuscular TAG  Using Fat as Fuel 3 stages to release energy from adipose tissue 1. Degradation of adipose TAG to release fatty acids and glycerol into the blood for transport to energy- requiring tissues Loading… 2. Activation of the fatty acids and transport into the mitochondria for oxidation 3. Degradation of the fatty acids to acetyl CoA for processing by the citric acid cycle  Stage 1. “Release the Fatty Acids” Epinephrine or glucagon – Fight or flight or low blood glucose signal Stimulate lipid breakdown or lipolysis – Protein kinase A activated Perilipin phosphorylated – Organizes fat droplet so TAG is accessible – Releases coactivator (CA) for adipose triglyceride lipase (ATGL) » Remove 1st fatty acid Hormone-sensitive lipase phosphorylated » Remove 2nd fatty acid 3rd fatty acid and glycerol released by monoacylglycerol lipase – Needs MAG as a substrate Clinical Insight: Chanarin-Dorfmam Syndrome and Impaired Triacylglycerol Hydrolyzation CLINICAL INSIGHT Triacylglycerols Are Hydrolyzed by Hormone-Stimulated Lipases Phosphorylation of perilipin results in the activation of adipocyte Loading… triglyceride lipase (ATGL) through a coactivator. In Chanarin-Dorfmam syndrome, the coactivator is defective or missing and lipid breakdown is compromised. This results in fat accumulation throughout the body as well as dry skin, enlarged liver and muscle, and mild cognitive disability Results of Fatty Acid/Glycerol Release Triacylglycerol * 3 fatty acids and glycerol – Glycerol (soluble in plasma) Taken up by liver Enter glycolysis or gluconeogenesis – Fatty acids transported in blood by albumin Taken up by tissues requiring energy Fatty acids converted to acetyl-CoA  Glycerol Backbone is Gluconeogenic Glycerol (3 carbons) is phosphorylated and oxidized into dihydroxyacetone phosphate (DHAP) – DHAP is part of the glycolysis/gluconeogenesis pathway  Stage 2A - “Activate the Fatty Acids” Fatty acids enter the cell by “flip-flop” or a transport protein Once in the cell – CoA is added to the fatty acids Acyl-CoA Synthetase Traps fatty acid in cell – similar to phosphate being added to glucose It is a 2-step reaction with acyl adenylate intermediate formed then CoA exchanged – NOTE: That ATP is converted to AMP and PPi This counts as 2 high energy phosphates (2ATP equivalents) – Another ATP is needed to add to the AMP to get back to ADP – ATP + AMP = 2ADP  Stage 2B – “Get the Fatty Acid into The Matrix” For oxidation, fatty acids need to get into the mitochondrial matrix – BUT no Acyl-CoA transporter Need to exchange CoA for carnitine – Catalyzed by carnitine acyltransferase I (CAT I) A translocase can then transport acyl-carnitine into the matrix In matrix, fatty acid transferred back to CoA – Catalyzed by carnitine acyltransferase II (CAT II)  Stage 3 (4 Steps) – “Degrade the Fatty Acids” Known as β-oxidation Four reactions that are repeated 1. Oxidation of the β carbon 2. Hydration of trans-Δ2-enoyl CoA “alpha” carbon is first 3. Oxidation of L-3-hydroxyacyl CoA carbon attached to a 4. Cleavage of the 3-ketoacyl CoA functional group  The 4 Steps of Degradation acyl CoA enoyl CoA dehydrogenase hydratase Loading… L-3-hydroxyacyl CoA dehydrogenase thiolase The 4 Steps Repeat Depending on Length of Fatty Acid Each round – Generates an acetyl CoA – Acyl CoA gets shorter by 2 carbons – 1 FADH2 made – 1 NADH made  Note the Final Round of β-oxidation: A 4-carbon fatty Acyl-CoA Split into 2 Acetyl-CoA Butryl-CoA (C4) – Last round of Oxidation/Hydration/Oxidation The ketoacyl formed is acetoacetyl-CoA Removeing and acetyl-CoA from acetoacetyl-CoA leaves acetyl-CoA – Net result of last round: O 2 Acetyl-CoA Only 1 FADH2 FAD + Only 1 NADH O NAD+ C -S- H3 CoA C C -S- C O C C CoA C -S- FADH2 + NADH + H3 CoA H+ C Stage 2A Stage 2B Stage 3  Energy Yield from Fatty Acid Oxidation Palmitic acid (16:0) (palmitate) ATP Cost 2 ATP → 2 ADP to make fatty acyl-CoA AMP + PPi (need another ATP to form 2 ADP) -2 7 rounds of β-oxidation (Rounds = [#carbons/2]-1) 7 FADH2 (1.5 ATP per FADH2) 10.5 7 NADH (2.5 ATP per NADH) 17.5 8 acetyl Co-A – enter TCA cycle (Acetyl cCoA = #carbons/2) 80 1 TCA round 3 NADH, 1 FADH2, 1 ATP → (7.5 + 1.5 + 1) = 10 Total 106  Oxidation of Unsaturated Fat C=C bonds – Not fully reduced No FADH2 made Theoretically slightly less energy generated Some of the oxidation steps not needed – Some FADH2 not generated – Sometimes the double-bond is in the wrong location for the reactions Isomerases – Can rearrange the molecule Reductase NADPH used – Used to oxidize to reorganize 2 bonds in wrong place to one in correct place » Uses an NADPH + H+  Adapting to Starvation Normal Conditions – Glucose is the predominant fuel for the brain Initially with starvation – Gluconeogenesis in the liver fueled by protein degradation Glucose released into the blood for the brain – Tissues (skeletal muscle) shift to fatty acid oxidation Continued starvation – Shift to fatty acid oxidation and ketone bodies (from fat) use increases Liver exports ketones, brain begins to use them – Gluconeogenesis is slowed and protein degradation slowed  Ketone Bodies Acetoacetate, D-3-hydroxybutyrate, and acetone Enzymes catalyzing these reactions are: – Formed from acetyl CoA primarily in the liver 1. 3-ketothiolase – Liver taking on metabolic load of fatty acid 2. hydroxymethylglutaryl CoA synthase oxidation 3. hydroxymethylglutaryl CoA cleavage enzyme Ketones are more soluble in water than fatty acids 4. D-3-hydroxybutyrate dehydrogenase – Acetoacetate spontaneously decarboxylates to form acetone  Ketone Production Also Supports Fatty Acid Oxidation Fatty acid oxidation in liver generates more Ketone production releases CoA acetyl CoA than liver can use – 3 Acetyl CoA are used, 2 free CoA released – Increased Acetyl CoA build up can also tie up all There is also some reoxidation of NADH back to the CoA (limited pool) NAD+ – Need for 3rd step of fatty acid oxidation  Ketone Use for Energy Ketones in blood taken up by tissues – Converted back into Acetyl CoA Can enter local tissue TCA Cycle to produce energy Clinical Insight: Ketogenic Diets May Have Therapeutic Properties CLINICAL INSIGHT Ketogenic Diets May Have Therapeutic Properties Ketogenic diets – Rich in fats and low in carbohydrates but with adequate proteins – Lead to formation of substantial amounts of ketone bodies Frequently used to reduce the seizures in children suffering from drug-resistant epilepsy – Recent research in mice suggests that ketogenic diets alter the intestinal flora (the microbiome) – This alters neurotransmitter levels that may be responsible for the diet’s therapeutic effects  Diabetic Ketosis Ketone bodies – Can cause acidosis – With starvation, tissues gradually adapt Increase the ability to metabolize ketones Type I Diabetes – Rapid increase in ketones can occur as a result of no insulin Adipose releases free fatty acids resulting in increased production of acetyl CoA TCA cycle limited as no ability to handle excess acetyl CoA without glucose to top up the oxaloacetate in cycle – Acetyl CoA gets shunted to ketones and released and tissues not able to metabolize efficiently yet Acidosis results causing low pH – Impairs tissue function and can lead to coma or death