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Chapter Twenty Five. Lipid Metabolism. Outline. 25.1 Digestion of Triacylglycerols 25.2 Lipoproteins for Lipid Transport 25.3 Triacylglycerol Metabolism: An Overview 25.4 Storage and Mobilization of Triacylglycerols 25.5 Oxidation of Fatty Acids 25.6 Energy from Fatty Acid Oxidation

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chapter twenty five

Chapter Twenty Five

Lipid Metabolism

outline
Outline
  • 25.1 Digestion of Triacylglycerols
  • 25.2 Lipoproteins for Lipid Transport
  • 25.3 Triacylglycerol Metabolism: An Overview
  • 25.4 Storage and Mobilization of Triacylglycerols
  • 25.5 Oxidation of Fatty Acids
  • 25.6 Energy from Fatty Acid Oxidation
  • 25.7 Ketone Bodies and Ketoacidosis
  • 25.8 Biosynthesis of Fatty Acids

Chapter Twenty Five

25 1 digestion of triacylglycerols
25.1 Digestion of Triacylglycerols
  • Triacylglycerols (TAGs) pass through the mouth unchanged and enter the stomach. The heat and churning action of the stomach break lipids into smaller droplets.
  • The presence of lipids in consumed food slows down the rate at which the mixture of partially digested foods leaves the stomach because they take longer to digest.
  • When partially digested food leaves the stomach, it enters the upper end of the small intestine (the duodenum), where its arrival triggers the release of pancreatic lipases, enzymes for the hydrolysis of lipids. The gallbladder simultaneously releases bile.

Chapter Twenty Five

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Bile contains bile acids and cholesterol, which are steroids, and phospholipids. Cholic acid is the major bile acid. These molecules use their hydrophilic and hydrophobic regions to emulsify the lipid droplets so they can be acted on by the pancreatic lipases.

Chapter Twenty Five

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Pancreatic lipase partially hydrolyzes the emulsified triacylglycerols, producing mainly mono- and diacylglycerols, plus fatty acids and a small amount of glycerol.

Chapter Twenty Five

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Smaller fatty acids and glycerol are water-soluble and are absorbed directly through the surface of the villi that line the small intestine and enter the bloodstream through capillaries.
  • The insoluble acylglycerols and larger fatty acids within the intestine packaged into the lipoproteins known as chylomicrons. Too large to enter through capillary walls, they are absorbed into the lymphatic system through lacteals within the villi.

Chapter Twenty Five

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Summary of pathways of lipids through the villi and into the transport systems of the bloodstream and the lymphatic system.

Chapter Twenty Five

25 2 lipoproteins for lipid transport
25.2 Lipoproteins for Lipid Transport
  • Lipids enter metabolism from three different sources:
    • (1) the diet
    • (2) storage in adipose tissue
    • (3) synthesis in the liver
  • Whatever their source, these lipids must eventually be transported in blood.
  • To become water-soluble, fatty acids released from adipose tissue associate with albumin, a very large protein that binds up to 10 fatty acid molecules. All other lipids are carried by lipoproteins of various types.

Chapter Twenty Five

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A lipoprotein: A lipoprotein contains a core of neutral lipids, including triacylglycerols and cholesteryl esters.
  • Surrounding the core is a layer of phospholipids in which varying proportions of proteins and cholesterol are embedded.

Chapter Twenty Five

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Lipids are less dense than proteins, the density of lipoproteins depends on the ratio of lipids to proteins.
  • Chylomicrons, which are the only lipoproteins devoted to transport of lipids from the diet, are the lowest-density lipoproteins (specific gravity < 0.95 ).
  • Very-low-density lipoproteins (VLDLs) carry TAGs from the liver to peripheral tissues for storage or energy generation (0.96 < s. g. < 1.006).
  • Intermediate-density lipoproteins (IDLs) carry remnants of the VLDLs from peripheral tissues back to the liver for use in synthesis (1.006 < s. g. < 1.019).

Chapter Twenty Five

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Low-density lipoproteins (LDLs) transport cholesterol from the liver to peripheral tissues, where it is used in cell membranes or for steroid synthesis. LDL cholesterol can also cause formation of arterial plaque (1.019 < s. g. < 1.063).
  • High-density lipoproteins (HDLs) transport cholesterol fromdead or dying cells back to the liver, where it is converted to bile acids. The bile acids are then available for use in digestion or are excreted when in excess (1.063 < s. g. < 1.210).

Chapter Twenty Five

25 3 triacylglycerol metabolism an overview
25.3 Triacylglycerol Metabolism:An Overview
  • Triacylglycerols undergo hydrolysis to fatty acids and glycerol.
  • Fatty acids undergo
    • Resynthesis of triacylglycerols for storage
    • Conversion to acetyl-SCoA
  • Glycerol is converted to glyceraldehyde 3-phosphate and DHAP, which participate in
    • Glycolysis—energy generation
    • Gluconeogenesis—glucose formation
    • Triacylglycerol synthesis

Chapter Twenty Five

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Metabolism of triacylglycerols. Pathways that break down molecules (catabolism) are shown in light brown, and synthetic pathways (anabolism) are shown in blue. Connections to other pathways or intermediates of metabolism are shown in green.

Chapter Twenty Five

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Acetyl-SCoA participates in
    • Triacylglycerol synthesis
    • Ketone body synthesis
    • Synthesis of steroids and other lipids
    • Citric acid cycle and oxidative phosphorylation

Chapter Twenty Five

25 4 storage and mobilization of triacylglycerols
25.4 Storage and Mobilization of Triacylglycerols
  • The passage of fatty acids in and out of storage in adipose tissue is a continuous process essential to maintaining homeostasis.
  • After a meal, blood glucose levels are high and insulin activates the synthesis of TAGs for storage.
  • The metabolism of glucose is needed to supply dihydroxyacetone phosphate that isomerizes to give the necessary glycerol 3-phosphate because adipocytes do not have the enzyme needed to convert glycerol to glycerol 3-phosphate.

Chapter Twenty Five

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The reactants in TAG synthesis are glycerol 3-phosphate and fatty acid acyl groups carried by coenzyme A.
  • TAG synthesis proceeds by transfer of first one and then another fatty acid acyl group from coenzyme A to glycerol 3-phosphate.

Chapter Twenty Five

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Next, the phosphate group is removed and the third fatty acid group is added to give a triacylglycerol.
  • When digestion of a meal is finished, blood glucose levels are low; consequently insulin levels drop and glucagon levels rise.

Chapter Twenty Five

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The lower insulin level and higher glucagon level together activate triacylglycerol lipase, the enzyme within adipocytes that controls hydrolysis of stored TAGs.
  • When glycerol 3-phosphate is in short supply, an indication that glycolysis is not producing sufficient energy, the fatty acids and glycerol produced by hydrolysis of the stored TAGs are released to the bloodstream for transport to energy-generating cells.
  • Mobilization (of triacylglycerols): Hydrolysis of triacylglycerols in adipose tissue and release of fatty acids into the bloodstream.

Chapter Twenty Five

25 5 oxidation of fatty acids
25.5 Oxidation of Fatty Acids
  • Once a fatty acid enters the cytosol of a cell that needs energy, three successive processes must occur.
  • 1. Activation: The fatty acid must be activated by conversion to fatty acyl-SCoA. Some energy from ATP must initially be invested in converting the fatty acid to fatty acyl-SCoA, a form that breaks down more easily.

Chapter Twenty Five

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2. Transport: The fatty acyl-SCoA must be transported into the mitochondrial matrix where energy generation will occur. Carnitine, a transmembrane protein found only in the mitochondrial membrane, specifically moves fatty acyl-SCoA across the membrane into the mitochondria.
  • 3. Oxidation: The fatty acyl-SCoA must be oxidized by enzymes in the mitochondrial matrix to produce acetyl-SCoA plus the reduced coenzymes to be used in ATP generation. The oxidation occurs by repeating the series of four reactions which make up the b-oxidation pathway.

Chapter Twenty Five

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b-Oxidation refers to the oxidation of the carbon atom b to the thioester linkage in two steps of the pathway.
  • STEP 1: The first b-oxidation: The oxidizing agent FAD removes hydrogen atoms from the carbon atoms a and b to the C=O group in the fatty acyl-SCoA, forming a carbon–carbon double bond.

Chapter Twenty Five

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STEP 2: Hydration: A water molecule adds across the newly created double bond to give an alcohol with the –OH group on the b-carbon.
  • STEP 3: The second b-oxidation: NAD+is the oxidizing agent for conversion of the b-OH group to a carbonyl group.
  • STEP 4: Cleavage to remove an acetyl group: An acetyl group is split off and attached to a new coenzyme A molecule, leaving behind an acyl-SCoA that is two carbon atoms shorter.

Chapter Twenty Five

25 6 energy from fatty acid oxidation
25.6 Energy from Fatty Acid Oxidation
  • The total energy output from fatty acid catabolism is measured by the total number of ATPs produced. Current best estimates are that 2.5 ATPs result from each NADH and 1.5 ATPs from each FADH2.
  • The b-oxidation pathway produces 1 NADH and 1 FADH2 or 4 ATPs per cycle.
  • Each acetyl-SCoA produces 3 NADH, 1 FADH2 and 1 ATP or 10 ATPs per acetyl-SCoA.
  • Lauric acid, CH3(CH2)10COOH, has 12 carbons.

Chapter Twenty Five

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After initial activation (-2 ATP), five b-oxidations (5x4 ATP = +20 ATP) will change lauric acid into 6 acetyl-SCoA molecules (6x10 ATP = + 60 ATP). The total energy yield is 78 ATP per lauric acid.
  • 1 mole (200g) lauric acid yields 78 moles ATP
  • 1 mole (180g) glucose yields 30-32 moles ATP
  • Fats and oils yield 9 Calories per gram
  • Carbohydrates yield 4 Calories per gram
  • Each gram of glycogen can hold as much as 2 grams of water so fats are almost 7 times more energy dense than carbohydrates in the body.

Chapter Twenty Five

25 7 ketone bodies and ketoacidosis
25.7 Ketone Bodies and Ketoacidosis
  • When there is too much acetyl-SCoA for the citric acid cycle to process, ketone bodies are formed.
  • Ketone bodies: Compounds produced in the liver that can be used as fuel by muscle and brain tissue:
    • 3-hydroxybutyrate
    • acetoacetate
    • acetone.
  • Ketogenesis: The synthesis of ketone bodies from acetyl-SCoA.

Chapter Twenty Five

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In Step 1, two acetyl-SCoA molecules combine in a reversible reaction to produce acetoacetyl-SCoA.
  • In Step 2, a third acetyl-SCoA and a water molecule react with acetoacetyl-SCoA to give 3-hydroxy-3-methylglutaryl-SCoA.

Chapter Twenty Five

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In Step 3, removal of acetyl-SCoA from the product of Step 2 produces the first of the ketone bodies, acetoacetate, the precursor of the other two ketone bodies produced by ketogenesis, 3-hydroxybutyrate and acetone.
  • In Step 4, the acetoacetate produced in Step 3 is reduced to 3-hydroxybutyrate. (Note that 3-hydroxybutyrate and acetoacetate are connected by a reversible reaction. In tissues that need energy, acetoacetate is produced by different enzymes than those used for ketogenesis. Acetyl-SCoA can then be produced from the acetoacetate.)
  • Acetone is then formed in the bloodstream by the decomposition of acetoacetate and is excreted primarily by exhalation.

Chapter Twenty Five

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Under well-fed, healthy conditions, skeletal muscles derive a small portion of their daily energy needs from acetoacetate, and heart muscles use it in preference to glucose.
  • During the early stages of starvation, heart and muscle tissues burn larger quantities of acetoacetate, thereby preserving glucose for use in the brain. In prolonged starvation, even the brain can switch to ketone bodies to meet up to 75% of its energy needs.
  • The condition in which ketone bodies are produced faster than they are utilized (ketosis) occurs in diabetes. It is indicated by the odor of acetone (a highly volatile ketone) on the patient’s breath and the presence of ketone bodies in the urine (ketonuria) and the blood (ketonemia).

Chapter Twenty Five

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Two of the ketone bodies are carboxylic acids. Ketoacidosis results from increased concentrations of ketone bodies in the blood. The blood’s buffers are overwhelmed and blood pH drops. Ketoacidosis causes dehydration due to increased urine flow, labored breathing because acidic blood is a poor oxygen carrier, depression, and ultimately, if untreated, the condition leads to coma and death.

Chapter Twenty Five

25 8 biosynthesis of fatty acids
25.8 Biosynthesis of Fatty Acids
  • The biosynthesis of fatty acids from acetyl-SCoA, a process known as lipogenesis, provides a link between carbohydrate, lipid, and protein metabolism.
  • Acetyl-SCoA is an end product of carbohydrate and amino acid catabolism, using it to make fatty acids allows the body to divert the energy of excess carbohydrates and amino acids into storage as TAGs.
  • Fatty acid synthesis and catabolism are similar in that they both proceed two carbon atoms at a time.

Chapter Twenty Five

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Lipogenesis, the biochemical pathway for synthesis of fatty acids from acetyl-SCoA, is not the exact reverse of the b-oxidation pathway. The reverse of an energetically favorable pathway is energetically unfavorable.

Chapter Twenty Five

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The stage is set for lipogenesis by two reactions:
    • (1) transfer of an acetyl group from acetyl-SCoA to an acyl carrier protein (ACP)
    • (2) conversion of acetyl- SCoA to malonyl-SCoA in a reaction that requires investment of energy from ATP. The malonyl-SCoA is then transferred to the acyl carrier protein (ACP).

Chapter Twenty Five

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Fatty acids with up to 16 carbon atoms (palmitic acid) are produced by a series of 4 reactions that lengthen the growing fatty acid chain by 2 C atoms with each repetition.
  • STEP 1: Condensation: The malonyl group from malonyl-SACP transfers to acetyl-SACP with the loss of CO2.
  • STEPS 2–4: Reduction, Dehydration, and Reduction: These three reactions accomplish the reverse of Steps 3, 2, and 1 in b oxidation of fatty acids. The carbonyl group is reduced to an –OH group, dehydration yields a C=C double bond, and the double bond is reduced by addition of hydrogen.

Chapter Twenty Five

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The result of the first cycle in fatty acid synthesis is the addition of 2 C atoms to an acetyl group to give a 4-carbon acyl group.

Chapter Twenty Five

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The next cycle then adds two more carbon atoms to give a 6-carbon acyl group.
  • After seven trips through the elongation spiral, a 16-carbon palmitoyl group is produced. Larger fatty acids are synthesized from palmitoyl-SCoA with the aid of specific enzymes.

Chapter Twenty Five

chapter summary
Chapter Summary
  • Triacylglycerols (TAGs) from the diet are broken into droplets in the stomach and enter the small intestine, where they are emulsified by bile acids.
  • Pancreatic lipases partially hydrolyze the TAGs, small fatty acids and glycerol from TAG hydrolysis are absorbed directly into the bloodstream at the intestinal surface.
  • Insoluble hydrolysis products are carried to the lining in micelles, where they are absorbed, reassembled into TAGs, then assembled into chylomicrons (which are lipoproteins) and absorbed into the lymph system for transport to the bloodstream.

Chapter Twenty Five

chapter summary cont
Chapter Summary Cont.
  • VLDLs carry TAGs synthesized in the liver to peripheral tissues for energy generation or storage. LDLs transport cholesterol from the liver to peripheral tissues for cell membranes or steroid synthesis. HDLs transport cholesterol from peripheral tissues back to the liver for conversion to bile acids.
  • The fatty acids undergo b oxidation to acetyl-SCoA or resynthesis into TAGs for storage. Acetyl-SCoA can participate in lipogenesis, ketogenesis, steroid synthesis, or energy generation via the citric acid cycle and oxidative phosphorylation. Glycerol can participate in glycolysis, gluconeogenesis, or TAG synthesis.

Chapter Twenty Five

chapter summary cont1
Chapter Summary Cont.
  • Synthesis of TAGs for storage is activated by insulin when glucose levels are high. Glycerol 3-phosphate adds fatty acyl groups one at a time to yield TAGs. Hydrolysis of TAGs stored in adipocytes is activated by glucagon when glucose levels drop.
  • Fatty acids are activated (in the cytosol) by conversion to fatty acyl-CoA, a reaction that requires the equivalent of two ATPs, transported into the mitochondrial matrix and oxidized two carbon atoms at a time to acetyl-SCoA by repeated trips through the b-oxidation spiral.

Chapter Twenty Five

chapter summary cont2
Chapter Summary Cont.
  • The ketone bodies are 3-hydroxybutyrate, acetoacetate, and acetone. They are produced from acetyl-SCoA when the citric acid cycle cannot keep pace with the quantity of acetyl-SCoA available.
  • This occurs during the early stages of starvation and in unregulated diabetes. The ketone bodies are water-soluble and can travel unassisted in the bloodstream to tissues where acetyl-SCoA is produced from acetoacetate and 3-hydroxybutyrate. In this way, acetyl-SCoA is made available for energy generation when glucose is in short supply.

Chapter Twenty Five

chapter summary cont3
Chapter Summary Cont.
  • Fatty acid synthesis (lipogenesis), like b oxidation, proceeds two carbon atoms at a time in a four-step pathway. The pathways utilize different enzymes and coenzymes. In synthesis, the initial two carbons are transferred from acetyl-SCoA to the malonyl carrier protein.
  • Each additional pair of carbons is then added to the growing chain bonded to the carrier protein, with the final three steps of the four step synthesis sequence the reverse of the first three steps in b oxidation.

Chapter Twenty Five

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End of Chapter 25

Chapter Twenty Five