lecture 19b Fatty Acid Oxidation Review

Fatty Acid Oxidation (Degradation)

Lecture Overview

  • Instructor: J. Scott Pattison, Ph.D.

  • Date: March 7th, 2025

Objectives

  1. Hormonal mobilization of fatty acids (FAs) from stored triglycerides and their transport in blood.

  2. Activation of FAs (attachment to CoA) and transport into mitochondrial matrix; regulation by malonyl CoA.

  3. Mechanism of beta-oxidation: location, sequence of reactions, and redox coenzymes required.

  4. Hormonal vs. allosteric control of fatty acid oxidation during fed vs. fasted states.

  5. Introduction to ketone body synthesis in the liver.

Fat Storage and Mobilization

  • Storage: Fatty acids are primarily stored as Triacylglycerols in lipid droplets within adipocytes (fat cells).

    • Lipid droplets can fill most of an adipocyte's volume.

    • Perilipin: A protein regulating TAG metabolism; helps in mobilizing stored fats.

    • TAGs can provide energy for 2-6 months in typical individuals.

  • Mobilization: Fatty acids are released from adipocytes when blood glucose is low (high glucagon levels).

  • The liver uses β-oxidation of FAs for energy and glycerol for gluconeogenesis during starvation.

Fates of Triacylglycerol Components

  • ATP Utilization:

    • Heart, skeletal muscle, and liver primarily use FAs for fuel.

    • Red blood cells (RBCs) and the brain predominantly utilize glucose.

TAG Degradation Activation

  • Hormonal Regulation: Initiated by Hormone-Sensitive Lipase (HSL) in adipocytes.

  • Phosphorylation of Perilipin by PKA is necessary for HSL activation.

TAG Degradation Process

  • HSL cleaves fatty acids from the glycerol backbone.

  • Monoacylglycerol lipase hydrolyzes Monoacylglycerol into one fatty acid and one glycerol.

Glycerol Metabolism

  • Glycerol is transported to the liver and utilized for gluconeogenesis or glycolysis.

Transport of Free Fatty Acids

  • Transport Mechanism:

    • Free fatty acids diffuse out of adipocytes.

    • FAs are hydrophobic and must be carried in blood by Albumin (7+ FAs per albumin).

Glucagon Signaling

  • Fasted State: Glucagon signaling in adipocytes initiates FA release into the bloodstream.

  • The cascade includes:

    1. Glucagon binds to receptor.

    2. Activation of cAMP and PKA.

    3. HSL leads to FA liberation.

Mitochondrial Fatty Acid Metabolism

  1. Transport: FABPs transport FAs across the plasma membrane.

  2. Activation: Fatty acyl CoA synthetase adds CoA to make Fatty Acyl CoAs (requires ATP).

  3. Carnitine Shuttling:

    • Carnitine Acyl Transferase-I (CAT-1) swaps CoA with Carnitine.

    • Transport via Carnitine Acyl Translocase into the mitochondrial matrix.

    • Carnitine Acyl Transferase-II (CAT-2) reattaches CoA.

  4. Beta-Oxidation: Occurs in the mitochondrial matrix, yielding NADH, FADH2, and Acetyl CoA.

Fatty Acid Activation

  • Fatty Acyl CoA Synthetase activates FAs, costing 2 high-energy phosphates (ATP to AMP).

Conditions for Metabolism

  • Low Energy Charge: Fatty acyl-CoA undergoes beta-oxidation.

  • High Energy Charge: Synthesis of fatty acids is favored, inhibited by Malonyl-CoA.

Diet and Fatty Acid Composition

  • 38% of the average North American diet is fat.

  • Common fatty acids ingested include Palmitate (C16), Stearate (C18), Oleate (C18:1), and Linoleate (C18:2).

Triacylglycerol Mobilization

  • Stored as Triacylglycerols; provides energy for months.

  • Mobilized under low blood glucose (glucagon) or stress (epinephrine and cortisol).

Beta-Oxidation Overview

  • Main Components: Generates NADH, FADH2, and Acetyl CoA through 4 steps:

    1. Acyl-CoA Dehydrogenase (oxidation) - FADH2 and trans C=C.

    2. Enoyl-CoA Hydratase (hydration) - adds water.

    3. 3-Hydroxyacyl-CoA Dehydrogenase (oxidation) - produces NADH.

    4. Beta-Ketoacyl-CoA Thiolase (thiolysis) - produces Acetyl-CoA.

Energy Yield from Beta-Oxidation

  • Example: Palmitoyl-CoA (C16):

    • Yields 8 Acetyl CoA (80 ATP), 7 FADH2 (10.5 ATP), and 7 NADH (17.5 ATP).

    • Activation cost: 2 ATP.

    • Total ATP yield: 106 ATP from Palmitate.

Oxidation of Odd Carbon Fatty Acids

  • Last three carbons released as Propionyl CoA.

  • Process requires Biotin (for Propionyl-CoA carboxylase) and Vitamin B12 (for Succinyl CoA formation).

Role of Peroxisomes

  • Peroxisomes oxidize very long-chain fatty acids, shortening them for mitochondrial β-oxidation.

  • Produce H2O2 from FADH2; catalase converts H2O2 to water and oxygen.

Ketone Body Synthesis

  • Occurs in the liver during starvation and high ATP levels when Acetyl CoA accumulates beyond TCA cycle requirements.

Summary of Fatty Acid Oxidation

  1. Hormonal regulation (insulin inhibits HSL) governs FA release from adipose tissue.

  2. Blood transport bound to serum albumin, influenced by malonyl CoA for mitochondrial entry.

  3. FAs serve as primary fuel during rest, fasting, and prolonged exercise (except brain/RBCs).

  4. Liver saves glucose through gluconeogenesis powered by FFAs during fasting.

  5. The process yields high-energy ATP through beta-oxidation and potential ketone body synthesis.