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Section 12: Fatty Acid and Lipid Metabolism Chapter 27: Fatty Acid Degradation Chapter 28: Fatty Acid Synthesis

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Section 12: Fatty Acid and Lipid Metabolism Chapter 27: Fatty Acid Degradation Chapter 28: Fatty Acid Synthesis Section 12: Fatty Acid and Lipid Metabolism Chapter 27: Fatty Acid Degradation Chapter 28: Fatty Acid Synthesis By the end of this section, you should be able to: Ø Identify the repeated steps of fatty acid degradation. Ø Describe ketone bodies and their role in metabolism. Ø Explain how fatty acids are synthesized. Ø Explain how fatty acid metabolism is regulated. Lecture: Ch27-28-29 CHAPTER 27 Fatty Acid Synthesis CHAPTER 28 Fatty Acid Degradation Chapter 27 Outline Fatty acid degradation is a key energy source for mammals during hibernation. • Fatty acids are stored in adipose tissue as triacylglycerols (TAG) in which fatty acids are linked to glycerol with ester linkages. • Adipose tissue is located throughout the body, with subcutaneous (below the skin) and visceral (around the internal organs) deposits being most prominent. Lipid degradation The fatty acids incorporated into triacylglycerols in adipose tissue are made accessible in three stages. 1. Degradation of TAG to release fatty acids and glycerol into the blood for transport to energy-requiring tissues. 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. • Triacylglycerols are stored in adipocytes as a lipid droplet. • Epinephrine and glucagon, acting through 7TM receptors, stimulate lipid breakdown or lipolysis. • Protein kinase A phosphorylates perilipin, which is associated with the lipid droplet, and hormone-sensitive lipase. • Phosphorylation of perilipin results in the activation of adipocyte triacylglyceride lipase (ATGL). • ATGL initiates the breakdown of lipids. Chanarin-Dorfmam syndrome, characterized by dry skin, enlarged liver and muscle, and mild cognitive disability, results if ATGL activity is compromised. • The glycerol released during lipolysis is absorbed by the liver for use in glycolysis or gluconeogenesis. Triacylglycerols in adipose tissue are converted into free fatty acids in response to hormonal signals The phosphorylation of perilipin restructures the lipid droplet and releases the coactivator of ATGL. The activation of ATGL by binding with its coactivator initiates the mobilization. Hormone-sensitive lipase releases a fatty acid from diacylglycerol. Monoacylglycerol lipase completes the mobilization process. Abbreviations: 7TM, seven transmembrane; ATGL, adipose triglyceride lipase; CA, coactivator; HS lipase, hormone-sensitive lipase; MAG lipase, monoacylglycerol lipase; DAG, diacylglycerol; TAG, triacylglycerol. Lipolysis generates fatty acids and glycerol Acyl CoA is an activated form of fatty acid Acyl carnitine translocase After being activated by linkage to CoA, the fatty acid is transferred to carnitine, a reaction catalyzed by carnitine acyltransferase I, for transport into the mitochondria. A translocase transports the acyl carnitine into the mitochondria. In the mitochondria, carnitine acyltransferase II transfers the fatty acid to CoA. The fatty acyl CoA is now ready to be degraded. Clinical Insights: Muscle, kidney, and heart use fatty acids as a fuel. Pathological conditions results if the acyltransferase or the translocase are deficient. Carnitine deficiencies can be treated by carnitine supplementation. Fatty acid degradation consists of four steps that are repeated. 1. Oxidation of the β carbon, catalyzed by acyl CoA dehydrogenase, generates trans-Δ2-enoyl CoA and FADH2. 2. Hydration of trans-Δ2-enoyl CoA by enoyl CoA hydratase yields L-3-hydroxyacyl CoA. 3. Oxidation of L-3-hydroxyacyl CoA by L-3- hydroxyacyl dehydrogenase generates 2- ketoacyl CoA and NADH. 4. Cleavage of the 3-ketoacyl CoA by thiolase forms acetyl CoA and a fatty acid chain two carbons shorter. Fatty acid degradation is also called β-oxidation. The reaction seQuence for the degradation of fatty acids Fatty acids are degraded by the repetition of a four-reaction sequence consisting of oxidation, hydration, oxidation, and thiolysis. Two carbon units are sequentially removed from the carboxyl end of the fatty acid The reaction for one round of β-oxidation is: The complete reaction for C16 palmitoyl CoA is: Processing of the products of the complete reaction by cellular respiration would generate 106 molecules of ATP. Answer: The steps are (1) oxidation by FAD; (2) hydration; (3) oxidation by NAD+; (4) thiolysis to yield acetyl CoA. In symbolic notation, the β-carbon atom is oxidized. • β-oxidation alone cannot degrade unsaturated fatty acids. When monounsaturated fatty acids are degraded by β-oxidation, cis-Δ3-enoyl CoA is formed, which cannot be processed by acyl CoA dehydrogenase. • Cis-Δ3-enoyl CoA isomerase converts the double bond into trans-Δ2-enoyl CoA, a normal substrate for β-oxidation. • When polyunsaturated fatty acids are degraded by β-oxidation, cis-Δ3-enoyl CoA isomerase is also required. 2,4-Dienoyl CoA is also generated, but cannot be processed by the normal enzymes. • 2,4-Dienoyl CoA is converted into trans-Δ3-enoyl CoA by 2,4-dienoyl CoA reductase, and the isomerase converts this product to trans-Δ2-enoyl CoA, a normal substrate. • Unsaturated fatty acids with odd numbers of double bonds require only the isomerase. Even number of double bonds require both the isomerase and reductase. β-Oxidation of fatty acids with odd numbers of carbons generates propionyl CoA in the last thiolysis reaction. Propionyl carboxylase, a biotin enzyme, adds a carbon to propionyl CoA to form methylmalonyl CoA Succinyl CoA, a citric acid cycle component, is subsequently formed from methylmalonyl CoA by methylmalonyl CoA mutase, a vitamin B12 requiring enzyme. • Ketone bodies —acetoacetate, 3-hydroxybutyrate, and acetone— are synthesized from acetyl CoA in liver mitochondria and secreted into the blood for use as a fuel by some tissues such as heart muscle. • 3-Hydroxybutyrate is formed upon the reduction of acetoacetate. Acetone is generated by the spontaneous decarboxylation of acetoacetate. • In tissues using ketone bodies, 3-hydroxybutyrate is oxidized to acetoacetate, which is ultimately metabolized to two molecules of acetyl CoA. The formation of ketone bodies The utilization of D-3- hydroxybutyrate and acetoacetate as a fuel The ketone bodies—acetoacetate, D-3-hydroxybutyrate, and acetone—are formed from acetyl CoA primarily in the liver. Enzymes catalyzing these reactions are (1) 3-ketothiolase, (2) hydroxymethylglutaryl CoA synthase, (3) hydroxymethylglutaryl CoA cleavage enzyme, and (4) D-3-hydroxybutyrate dehydrogenase. Acetoacetate spontaneously decarboxylates to form acetone Ketogenic diets, rich in fats and low in carbohydrates but with adequate proteins, lead to formation of substantial amounts of ketone bodies. Ketogenic diets may have therapeutic properties: For reasons not yet established, such diets reduce the seizures in children suffering from drug-resistant epilepsy. Fats are converted into acetyl CoA, which is then processed by the citric acid cycle. Oxaloacetate, a citric acid cycle intermediate, is a precursor to glucose. However, acetyl CoA derived from fats cannot lead to the net synthesis of oxaloacetate or glucose because although two carbons enter the cycle when acetyl CoA condenses with oxaloacetate, two carbons are lost as CO2 before oxaloacetate is regenerated. High levels of acetoacetate in the blood signify an abundance of acetyl units and lead to a decrease in the rate of lipolysis in adipose tissue. Answer: D-3-Hydroxybutyrate is more energy rich because its oxidation potential is greater than that of acetoacetate. After having been absorbed by a cell, d-3-hydroxybutyrate is oxidized to acetoacetate, generating high- energy electrons in the form of NADH. The acetoacetate is then cleaved to yield to acetyl CoA. • Ketone bodies are moderately strong acids, and excess production can lead to acidosis. • An overproduction of ketone bodies can occur when diabetes, a condition resulting from a lack of insulin function, is untreated. The resulting acidosis is called diabetic ketosis. • If insulin is absent or not functioning, glucose cannot enter cells. All energy must be derived from fats, leading to the production of acetyl CoA. • Acetyl CoA builds up because oxaloacetate, which can be generated from glucose, is not available to replenish the citric acid cycle. • Moreover, fatty acid released from adipose tissue is enhanced in the absence of insulin function. Diabetic ketosis results when insulin is absent In the absence of insulin, fats are released from adipose tissue, and glucose cannot be absorbed by the liver or adipose tissue. The liver degrades the fatty acids by b-oxidation, but cannot process the acetyl CoA because of a lack of glucose-derived oxaloacetate (OAA). Excess ketone bodies are formed and released into the blood. Abbreviation: CAC, citric acid cycle. • Glucose is the predominant fuel for the brain. • During starvation, protein degradation is initially the source of carbons for gluconeogenesis in the liver. The glucose is then released into the blood for the brain to use. • After several days of fasting, the brain begins to use ketone bodies as a fuel. • Ketone body use curtails (reduces) protein degradation and thus prevents tissue failure. Moreover, ketone bodies are synthesized from fats, the largest energy store in the body. Fuel choice during starvation Saturated and trans unsaturated fatty acids are synthesized commercially to enhance the shelf life and heat stability of fats for food preparation. Studies suggest that excess consumption of these fats results in obesity, heart disease
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