Lipid Metabolism Exam Review

24.1 Digestion of Triacylglycerols

• Learning Objective: List the steps in the digestion of dietary triacylglycerols and their transport into the bloodstream.
• The digestion of dietary triacylglycerols is not as straightforward as that of carbohydrates.
• When eating, triacylglycerols pass through the mouth unchanged and enter the stomach.
• The heat and churning action of the stomach break triacylglycerols into small droplets, a process that takes longer than the physical breakdown and digestion of other food.
• No catabolism of triacylglycerols takes place in the stomach, only preparation for this step by breaking the fats into microscopic droplets.
• Triacylglycerols are not water-soluble but must enter an aqueous environment.
• They are packaged in lipoproteins, which consist of droplets of hydrophobic lipids surrounded by phospholipids, proteins, and other molecules with their hydrophilic ends to the outside.
• Lipoproteins are special forms of micelles.
• 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.
• When food leaves the stomach, it enters the duodenum, triggering the release of pancreatic lipases.
• The gallbladder releases bile, a mixture of cholesterol, phospholipids, and bile acids that is manufactured in the liver and stored in the gallbladder until needed.
• It is the job of bile acids and phospholipids to emulsify the triacylglycerols by forming micelles.
• The major bile acid is cholic acid.
• It resembles soaps and detergents because it contains both hydrophilic and hydrophobic regions.
• Pancreatic lipase partially hydrolyzes the emulsified triacylglycerols, producing mono- and diacylglycerols plus fatty acids and a small amount of glycerol.
• Small fatty acids and glycerol are absorbed through the villi that line the small intestine, then carried by the blood to the liver (via the hepatic portal vein).
• Water-insoluble acylglycerols and larger fatty acids are again emulsified, then absorbed by the cells lining the intestine.
• To enter the aqueous bloodstream for transport, they are packaged into lipoproteins known as chylomicrons.
• Chylomicrons are absorbed into the lymphatic system through lacteals, small vessels analogous to capillaries within villi.
• They are carried to the thoracic duct, where the lymphatic system empties into the bloodstream. At this point, the lipids are ready to be used for either energy generation or storage.
• From the thoracic duct, the chylomicrons are carried directly to the liver.

24.2 Lipoproteins for Lipid Transport

• The lipids used in the body’s metabolic pathways have three sources:
  • From the digestive tract as food is broken down
  • From adipose tissue, where excess lipids have been stored
  • From the liver, where lipids are synthesized
• Whatever their source, these lipids must eventually be transported in blood.
• Fatty acids released from adipose tissue associate with albumin, a protein found in blood plasma that binds up to 10 fatty acid molecules per protein molecule.
• All other lipids are carried by lipoproteins.
• Because lipids are less dense than proteins, the density of lipoproteins depends on the ratio of lipids to proteins.
• Lipoproteins can be arbitrarily divided into five major types.
  • Chylomicrons are devoted to transport of lipids from the diet. They carry triacylglycerols through the lymphatic system into the blood and to the liver for processing. These are the lowest-density lipoproteins (less than 0.95 g/cm3) because they carry the highest ratio of lipid to protein.
  • Very-low-density lipoproteins (VLDLs) (0.96–1.006 g/cm3) carry triacylglycerols from the liver (where they are synthesized) to tissues for storage or energy generation.
  • Intermediate-density lipoproteins (IDLs) (1.007–1.019 g/cm3) carry remnants of the VLDLs from peripheral tissues back to the liver for use in synthesis.
  • Low-density lipoproteins (LDLs) (1.020–1.062 g/cm3) transport cholesterol from the liver to peripheral tissues, where it is used in cell membranes or for steroid synthesis.
  • High-density lipoproteins (HDLs) (1.063–1.210 g/cm3) transport cholesterol from dead or dying cells back to the liver, where it is converted to bile acids.
• According to the U.S. Food and Drug Administration (FDA), there is “strong, convincing, and consistent evidence” for the connection between heart disease and diets high in saturated fats and cholesterol.
• A diet rich in saturated animal fats leads to an increase in blood-serum cholesterol, while a diet low in saturated fat and higher in unsaturated fat can lower the serum cholesterol level.
• High levels of cholesterol are correlated with atherosclerosis and an increased risk of coronary artery disease and heart attack or stroke.
• Risk factors for heart disease: High blood levels of cholesterol and low levels of high-density lipoproteins, cigarette smoking, high blood pressure, diabetes, obesity, low level of physical activity, family history of early heart disease.
• The ideal ratio of total cholesterol/HDL is considered to be 3.5. A ratio of 4.5 indicates an average risk, and a ratio of 5 or higher shows a high and potentially dangerous risk.
• Worked Example 24.1: Description of how fat in an ice cream cone gets to a liver cell
  • Dietary fat from animal sources (like whole milk in ice cream) is primarily triacylglycerols with some cholesterol.
  • Cholesterol isn't degraded in the digestive system.
  • Fat-digesting enzymes are secreted by the pancreas and delivered to the small intestine with bile acids.
  • Only free fatty acids and mono- and diacylglycerols can cross the intestinal cell wall to reach the bloodstream.
  • Smaller molecules like some free fatty acids and glycerol diffuse into the bloodstream; larger ones need lipoproteins for transport.
  • In the stomach, mixing forms triacylglycerols into small droplets, but no enzymatic digestion occurs there.
  • In the small intestine, bile acids and pancreatic lipases are secreted.
  • Bile acids help emulsify fat droplets into micelles.
  • Lipases hydrolyze the triacylglycerols into mono- and diacylglycerols and fatty acids.
  • These products enter the cells lining the small intestine, are resynthesized into triacylglycerides, then secreted into the bloodstream as chylomicrons.
  • Chylomicrons travel to the liver and enter cells for processing.
  • Cholesterol is absorbed, packaged into chylomicrons, and also sent to the liver.

24.3 Triacylglycerol Metabolism: An Overview

• Learning Objective: Name the major pathways for the synthesis and breakdown of triacylglycerols and fatty acids, and identify their connections to other metabolic pathways.
• Triacylglycerols are essential for long-term energy storage, insulation, and cushioning of internal organs.
• Dietary Triacylglycerols
  • Hydrolysis occurs when chylomicrons encounter lipoprotein lipase anchored in capillary walls.
  • When energy is in good supply, they are converted back to triacylglycerols for storage in adipose tissue.
  • When cells need energy, the fatty acid carbon atoms are activated and then oxidized as acetyl-CoA.
  • Acetyl-CoA generates energy via the citric acid cycle and oxidative phosphorylation.
  • Acetyl-CoA serves as the starting material for lipogenesis, ketogenesis, and the synthesis of cholesterol, from which all other steroids are made.
• Triacylglycerols from Adipocytes
  • When stored triacylglycerols are needed as an energy source, lipases within fat cells are activated by hormone level variation—low insulin and high glucagon.
  • Stored triacylglycerols are hydrolyzed to fatty acids, and free fatty acids and glycerol are released into the bloodstream.
  • These fatty acids travel in association with albumins (blood plasma proteins) to cells (primarily muscle and liver cells), where they are converted to acetyl-CoA for energy generation.
• Glycerol from Triacylglycerols
  • Glycerol produced from triacylglycerol hydrolysis is carried to the liver or kidneys, where it is converted to glyceraldehyde 3-phosphate and dihydroxyacetone phosphate (DHAP).
  • DHAP enters the glycolysis/gluconeogenesis pathways, linking lipid and carbohydrate paths.
  • CH₂OH HO-C-H CH₂OH (Glycerol) is converted to CH₂-O-PO32- HO-C-H C=O (Glycerol-3-phosphate) and CH₂-O-PO32- CH₂OH (Dihydroxyacetone phosphate (DHAP))
• Fate of Dietary Triacylglycerols
  • Triacylglycerols undergo hydrolysis to fatty acids and glycerol.
  • Fatty acids undergo:
    • Resynthesis of triacylglycerols for storage
    • Conversion to acetyl-CoA
  • Glycerol is converted to glyceraldehyde 3-phosphate and DHAP, which participate in:
    • Glycolysis—energy generation
    • Gluconeogenesis—glucose formation
    • Triacylglycerol synthesis—energy storage
  • Acetyl-CoA participates in:
    • Triacylglycerol synthesis
    • Ketone body synthesis (ketogenesis)
    • Synthesis of sterols and other lipids
    • Citric acid cycle and oxidative phosphorylation

24.4 Storage and Mobilization of Triacylglycerols

• Learning Objective: Explain the reactions by which triacylglycerols are stored and mobilized, and describe how these reactions are regulated.
• The passage of fatty acids in and out of storage in adipose tissue is a continuous process essential to maintaining homeostasis.
• Our bodies regulate the storage and mobilization of triacylglycerols through the same hormones that regulate blood glucose concentration, insulin, and glucagon.
• Mobilization (of triacylglycerols) is the hydrolysis of triacylglycerols in adipose tissue and release of fatty acids into the bloodstream.
• After a meal, blood glucose levels increase, insulin levels rise, and glucagon levels drop.
• Glucose enters cells, and the rate of glycolysis increases.
• Insulin activates the synthesis of triacylglycerols for storage.
• The reactants in triacylglycerol synthesis are glycerol 3-phosphate and fatty acid acyl groups carried by coenzyme A.
• Triacylglycerol synthesis proceeds by transfer of first one and then another fatty acid acyl group from coenzyme A to glycerol 3-phosphate.
• The reaction is catalyzed by acyl transferase, and the product is phosphatidic acid.
• Next, the phosphate group is removed from phosphatidic acid to produce 1,2-diacylglycerol. The third fatty acid group is then added to give a triacylglycerol.
• Adipocytes cannot synthesize glycerol 3-phosphate from glycerol.
• Glycerol 3-phosphate can be synthesized from dihydroxyacetone phosphate (DHAP), so adipocytes can synthesize triacylglycerols as long as there is available DHAP.
• This pathway is called glyceroneogenesis, and it supplies the DHAP necessary to become glycerol 3-phosphate.
• When digestion of a meal is finished, blood glucose levels return to normal; insulin levels drop and glucagon levels rise.
• The lower insulin level and higher glucagon level activate triacylglycerol lipase, the enzyme that controls hydrolysis of stored triacylglycerols.
• When glycerol 3-phosphate is in short supply, fatty acids and glycerol produced by hydrolysis of stored triacylglycerols are released to the bloodstream for transport to energy-generating cells.
• Otherwise, the fatty acids and glycerol are cycled back into new TAGs for storage.

24.5 Oxidation of Fatty Acids

• Learning Objectives:
  • Describe fatty acid oxidation.
  • Calculate the energy yield from fatty acid oxidation.
• Once a fatty acid enters the cytosol of a cell that needs energy, three successive processes occur.
  1. Activation
     • The fatty acid must be activated by conversion to fatty acyl-CoA.
     • This serves the same purpose as the first few steps in oxidation of glucose by glycolysis.
     • Some energy from ATP must be invested in converting the fatty acid to fatty acyl-CoA, a form that breaks down more easily.
     • R-C-O + HSCOA + ATP → R-C-SCOA + AMP + P2O74-
  2. Transport
     • Fatty acyl-CoA must be transported from the cytosol into the mitochondrial matrix, where energy generation will occur.
     • Carnitine undergoes an ester formation exchange reaction with the fatty acyl-CoA, resulting in a fatty acyl-carnitine ester that moves into the mitochondria by facilitated diffusion.
     • In the mitochondria, another ester formation exchange reaction regenerates the fatty acyl-CoA and carnitine.
  3. Oxidation
     • Fatty acyl-CoA must be oxidized in the mitochondrial matrix to produce acetyl-CoA plus the reduced coenzymes used in ATP generation.
     • The oxidation occurs by repeating four reactions, which make up the b-oxidation pathway.
     • Each repetition of these reactions cleaves a 2-carbon acetyl group from the end of a fatty acid acyl group and produces one acetyl-CoA.
     • The acyl group must continue to return to the pathway until each pair of carbon atoms is removed.
• b-oxidation refers to the oxidation of the carbon atom b to the thioester linkage in two steps of the pathway:
• The b-Oxidation Pathway
  • STEP 1: The first b -oxidation
    • Acyl-CoA dehydrogenase and FAD remove hydrogen atoms from the carbon atoms a and b to the carbonyl group in the fatty acyl- CoA, forming a carbon–carbon double bond.
    • These hydrogen atoms and their electrons are passed directly from FADH2 to coenzyme Q so that the electrons can enter the electron transport chain.
    • CH3(CH2)-CH2-CH2-C-S-CoA + FAD → CH3(CH2)-C=C-C-S-CoA + FADH2
  • STEP 2: Hydration
    • Enoyl-CoA hydratase adds a water molecule across the newly created double bond to give an alcohol with the –OH group on the b carbon.
  • STEP 3: The second b-oxidation
    • The coenzyme NAD+ is the oxidizing agent for conversion of the b–OH group to a carbonyl group by b-hydroxyacyl-CoA dehydrogenase.
  • STEP 4: Cleavage to remove an acetyl group
    • An acetyl group is split off by thiolase (acyl- CoA acetyltransferase) and attached to a new coenzyme A molecule, leaving behind an acyl-CoA that is 2 carbon atoms shorter.
    • For a fatty acid with an even number of carbon atoms, all of the carbons are transferred to acetyl-CoA molecules through the b-oxidation spiral. Additional steps are required to oxidize fatty acids with odd numbers of carbon atoms and double bonds.
    • Ultimately, all fatty acid carbons are released for further oxidation in the citric acid cycle.
• The total energy output from fatty acid catabolism, like that from glucose catabolism, is measured by the total number of ATP molecules produced.
• For fatty acids, this is the total number of ATP molecules from acetyl-CoA oxidation through the citric acid cycle, including those produced from the reduced coenzymes NADH and FADH2 during oxidative phosphorylation, plus those produced by the reduced coenzymes during fatty acid oxidation.
• Worked Example 24.2: How many times does stearic acid (CH3(CH2)16COOH) spiral through the b -oxidation pathway to produce acetyl-CoA?
  • Each turn of the b-oxidation spiral pathway produces one acetyl-CoA. To determine the number of turns, divide the total number of carbon atoms in the fatty acid, 18 in this case, by 2 because an acetyl group contains 2 carbon atoms and they come from the fatty acid. Subtract one turn, because the last turn produces two acetyl-CoA molecules.
  • Stearic acid contains 18 carbon atoms; the acetyl group contains 2 carbon atoms. Therefore, eight b-oxidation turns occur, and nine molecules of acetyl-CoA are produced.
• Worked Example 24.3: How much energy is released as ATP from the complete oxidation of lauric acid (CH3(CH2)10COOH)?
  • Complete oxidation of a molecule includes conversion of any energy released in oxidation pathways, as NADH or FADH2 is also converted to ATP by passage through the electron transport system. To calculate the ATP yield from lauric acid:
    • Determine the number of acetyl groups and number of turns of the b-oxidation spiral needed.
    • Determine the ATP, NADH, and FADH2 yield from one turn of the b-oxidation spiral.
    • Determine the ATP, NADH, and FADH2 yield from oxidation of acetyl-CoA in the citric acid cycle.
    • Convert NADH and FADH2 yields to ATP yields from oxidative phosphorylation.
    • Adjust the b-oxidation ATP yield for number of turns of the spiral.
    • Adjust the citric acid cycle ATP yield for number of acetyl-CoA molecules oxidized.
    • Add the ATP yield and subtract 2 ATP molecules used to prime the start of b oxidation.
  • From the citric acid cycle:
    • 12 C atoms/2 = 6 acetyl-CoA molecules
    • 12 ATP molecules × 6 acetyl-CoA molecules = 72 ATP molecules
  • Activation of the fatty acid: = -2 ATP molecules
  • From the 5 ẞ oxidations:
    • 5 ATP molecules × 5 ẞ oxidations = 25 ATP molecules
  • Summation of the ATP used and produced:
    • Total = (722 + 25) ATP molecules = 95 ATP molecules
• Best estimates show that 1 mol of glucose (180 g) generates 38 mol of ATP.
• 1 mol of lauric acid (200 g) generates 95 mol of ATP.
• Fatty acids yield nearly three times as much energy per gram as carbohydrates.
• Carbohydrates yield 4 Cal/g (16.7 kJ/g), whereas fats and oils yield 9 Cal/g (37.7 kJ/g).

24.6 Ketone Bodies and Ketoacidosis

• Learning Objective: Identify ketone bodies, describe their properties and synthesis, and explain their role in metabolism.
• What happens if lipid catabolism produces more acetyl-CoA than the citric acid cycle can handle?
• b-oxidation produces several acetyl-CoA from each molecule of fatty acid, and the enzymes in the b-oxidation pathway catalyze reactions more rapidly than the enzymes in the citric acid cycle.
• Excess acetyl-CoA is converted by liver mitochondria to 3-hydroxybutyrate and acetoacetate. Acetoacetate spontaneously decomposes to acetone.
• 3-hydroxybutyrate, acetoacetate, and acetone are known as ketone bodies.
• They are water-soluble, so once formed, they are available to all body tissues.
• Ketogenesis: The synthesis of ketone bodies from acetyl-CoA
• Ketogenesis occurs in four enzyme-catalyzed steps plus the spontaneous decomposition of acetoacetate.
• STEPS 1 and 2 of Ketogenesis: Assembly of 6-Carbon Intermediate
  • Step 1 is the reverse of the final step of b-oxidation: Two acetyl-CoA molecules combine in a reaction catalyzed by thiolase to produce acetoacetyl-CoA.
  • In step 2, a third acetyl-CoA and a water molecule react with acetoacetyl-CoA to give 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA).
• STEPS 3 and 4 of Ketogenesis: Formation of the Ketone Bodies
  • In step 3, removal of acetyl-CoA from the product of step 2 produces acetoacetate.
  • Acetoacetate is the precursor of 3-hydroxybutyrate and acetone.
  • In step 4, the acetoacetate produced in step 3 is reduced to 3-hydroxybutyrate by 3-hydroxybutyrate dehydrogenase.
  • As acetoacetate and 3-hydroxybutyrate are synthesized, they are released to the bloodstream. Acetone is then formed in the bloodstream by the decomposition of acetoacetate and is excreted primarily by exhalation.
• When energy production from glucose is inadequate, the body must respond by providing other energy sources, and the production of ketone bodies accelerates.
• During the early stages of starvation, heart and muscle burn acetoacetate, preserving glucose for the brain.
• In prolonged starvation, the brain can switch to ketone bodies to meet up to 75% of its energy needs.
• Ketone bodies are produced faster than they are utilized in diabetes. This is indicated by acetone on the patient’s breath and ketone bodies in the urine (ketonuria) and blood (ketonemia).
• Because two of the ketone bodies are carboxylic acids, continued ketosis leads to ketoacidosis.
• The blood’s buffers are overwhelmed and blood pH drops. Dehydration due to increased urine flow, labored breathing (acidic blood is a poor oxygen carrier), and depression ensue. Untreated, the condition leads to coma and death.

24.7 Biosynthesis of Fatty Acids

• Learning Objective: Compare the pathways for fatty acid synthesis and oxidation, and describe the reactions of the synthesis pathway.
• Lipogenesis: The biochemical pathway for synthesis of fatty acids from acetyl-CoA
• Lipogenesis provides a link between carbohydrate, lipid, and protein metabolism.
• Because acetyl-CoA 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 triacylglycerols.
• Fatty acid synthesis and catabolism are similar in that they both proceed 2 carbon atoms at a time and in that they are both recursive, spiral pathways.
• The biochemical pathway in one direction is not the exact reverse of the pathway in the other direction.
• The stage is set for lipogenesis by two separate reactions:
  • Transfer of an acetyl group from acetyl-CoA to a carrier enzyme in the fatty acid synthase complex (S-enzyme 1)
  • Conversion of acetyl-CoA to malonyl-CoA, followed by transfer of the malonyl group to acyl carrier protein (ACP) and regeneration of coenzyme A
    • CH3-C-SCOA + H-S-enzyme-1 → CH3-C-S-enzyme-1 + H-SCOA
    • CH3-C-SCOA + HCO3- → -0-C-CH2-C-SCOA → ¯0—C—CH₂—C-SACP + HS-COA
• Chain elongation in the biosynthesis of fatty acids
  • Acetyl-ACP + Malonyl-ACP
    • Step 1. Condensation The malonyl group from malonyl-ACP transfers to acetyl-ACP with the loss of CO2. Loss of CO2 releases energy to drive the reaction.
    • Step 2. Reduction. This reaction uses the coenzyme NADPH to reduce the carbonyl group of the original acetyl group to a hydroxyl group.
    • Step 3. Dehydration Removal of H_2O at the C atoms a and ẞ to the remaining carbonyl group introduces a double bond.
    • Step 4. Reduction The coenzyme NADPH is used to add H atoms to the double bond, converting it to a single bond.
• The result of the first cycle in fatty acid synthesis is the addition of 2 carbon atoms to an acetyl group to give a 4-carbon acyl group still attached to the carrier protein in fatty acid synthase.
• The next cycle adds 2 more carbon atoms to give a 6-carbon acyl group by repeating the four steps of chain elongation shown here up to 16 carbon palmitoyl groups.