In-depth Notes on Fatty Acid Metabolism

Physiological Roles of Fatty Acids
  • Fatty acids have four major physiological roles:
    • Fuel molecules: Serve as a major source of energy.
    • Building blocks: Form phospholipids and glycolipids essential for cell membranes.
    • Protein modification: Fatty acids attach to proteins, helping target them to membranes.
    • Hormones/Messengers: Serve as derivatives that function as hormones and intracellular messengers.
Triacylglycerols (TAGs)
  • TAGs are neutral fats (triglycerides) composed of fatty acids and glycerol.
  • Storage:
    • Primarily stored in adipose tissue (under the skin - subcutaneous fat, and around internal organs - visceral fat).
    • Muscle tissue also stores TAGs for energy needs.
Importance of TAGs as Energy Sources
  • TAGs are energy-rich, reduced, and anhydrous.
  • Energy density:
    • Complete oxidation of fatty acids yields 38 kJ/g compared to 17 kJ/g for carbohydrates and proteins.
    • A gram of fat stores 6.75 times as much energy as a gram of hydrated glycogen.
  • Dietary lipids are hydrolyzed by pancreatic lipases for digestion.
Role of Bile Acids and Colipase
  • Bile acids: Amphipathic molecules synthesized from cholesterol, aid lipid digestion by lipases; secreted from the gallbladder.
  • Colipase: A protein that helps lipases bind to lipid particles for degradation.
Transport of Dietary Lipids in Chylomicrons
  • Free fatty acids and monoacylglycerols are transported in micelles to intestinal epithelial cells.
  • FATP: Transports free fatty acids and monoacylglycerols inside cells.
  • Fatty acid binding proteins (FABPs) ferry fatty acids to the smooth ER, where they are resynthesized into TAGs.
  • Newly synthesized TAGs are packaged into chylomicrons for blood transport.
Three Stages of Fatty Acid Fuel Processing
  1. Mobilization: TAG degradation from adipose tissue.
  2. Activation and Transport: Fatty acids are activated and transported into mitochondria.
  3. Breakdown: Fatty acids are converted to Acetyl-CoA for entry into the citric acid cycle.
Stage 1: Mobilization
  • Lipolysis is hormonally controlled, involving processes that phosphorylate proteins, enhancing TAG accessibility for mobilization.
  • Regulatory hormones: Glucagon and Epinephrine trigger lipase activation.
Lipid Metabolism in the Liver
  • Hepatocytes are crucial in lipid import, synthesis, storage, and secretion, responsive to diet and energy needs.
  • Ethanol can disrupt lipolysis.
Stage 2: Activation and Transport
  • Activation: Fatty acids form thioester linkages with CoA via acyl CoA synthetase, requiring ATP.
  • Transport: Fatty acids are conjugated to carnitine for transport across the mitochondrial membrane.
Breakdown of Fatty Acids into Acetyl-CoA
  • β-Oxidation Pathway (four repeating steps):
    1. Oxidation by FAD to form trans-enoyl-CoA.
    2. Hydration to form 3-hydroxyacyl-CoA.
    3. Oxidation by NAD+ to form β-ketoacyl-CoA.
    4. Thiolysis by CoA to release Acetyl-CoA and a shortened acyl-CoA.
ATP Yield Calculations for Fatty Acids
  • Formula derived to calculate ATP from the oxidation of even-chain saturated fatty acids.
Metabolism of Monounsaturated and Polyunsaturated Fatty Acids
  • β-Oxidation cannot degrade unsaturated fatty acids directly; special enzymes convert the double bonds into substrates suitable for oxidation.
  • Different enzymes are needed for various unsaturation patterns.
Odd-chain Fatty Acids
  • Odd-chain fatty acids generate propionyl CoA, which is converted into succinyl CoA, an intermediary that may enter the citric acid cycle or participate in glucose biosynthesis.
Fatty Acids in Peroxisomes
  • Long-chain and branched fatty acids undergo initial oxidation in peroxisomes, with a focus on reducing very long chains for mitochondrial β-oxidation.
Ketone Bodies and Their Importance
  • In fasting or diabetes, oxaloacetate is depleted and acetyl-CoA is diverted to produce ketone bodies, which serve as an alternative energy source, especially for the brain.
Fatty Acid Synthesis
  • FA Synthase: Complex enzyme system that synthesizes fatty acids, functioning under certain physiological conditions (e.g., lactation).
  • The synthesis process mirrors β-oxidation in reverse, requiring NADPH as a reducing agent.
  • Acetyl-CoA is converted into malonyl-CoA, and further elongation occurs through multiple enzyme-catalyzed steps until longer fatty acids are formed.
Regulatory Roles in Fatty Acid Metabolism
  • Acetyl-CoA Carboxylase (ACC) plays a key role in regulating FA metabolism by catalyzing malonyl-CoA production, influencing both synthesis and degradation based on hormonal signaling (insulin, glucagon).