9-Fatty+Acid+Nomenclature%2C+Oxidation+and+Ketone+Bodies+-+MBS602+-+2025

Page 1: Introduction to Fatty Acid Metabolism

• Title: Fatty Acid Nomenclature, Oxidation and Ketone Bodies

• Date: March 5th, 2025

• Presenter: Gino Cingolani, Ph.D., University of Alabama at Birmingham

Page 2: Learning Objectives Overview

Section 1: Fatty Acid Nomenclature

• Learning Objective 1 (LO1): Interpret common chemical notations (e.g., C18:2, Δ9, ω-3, ω-6).

• Compare saturated vs mono- and polyunsaturated fatty acids; cis vs trans configurations.

Section 2: Lipolysis and Regulation

• Learning Objective 2 (LO2): Understanding body fats; define lipolysis; describe lipase types; hormonal regulation.

Section 3: Transport of Fatty Acids

• Learning Objective 3 (LO3): Explain fatty acid movement, blood transport, and mitochondrial uptake mechanisms (role of CoA, Carnitine, Malonyl-CoA).

Section 4: Fatty Acid β-Oxidation

• Learning Objective 4 (LO4): Purpose, reactants, products, location, distribution, and regulation of β-oxidation.

Section 5: Ketone Body Synthesis

• Learning Objective 5 (LO5): Sources of Acetyl-CoA, purpose of synthesis, reactants, products, and regulation.

Section 6: Oxidation of Ketone Bodies

• Learning Objective 6 (LO6): Purpose, reactants, products, and regulation of ketone oxidation.

Section 7: Ketosis and Ketoacidosis

• Learning Objective 7 (LO7): Compare ketosis and ketoacidosis.

Section 8: Ketone Bodies and Hypoglycemia

• Learning Objective 8 (LO8): Correlate ketone bodies with hypoglycemia and differentiate between ketotic and non-ketotic hypoglycemia.

Page 3: Fatty Acid Use and Nomenclature

• Learning Objectives:

  • LO1: Interpret notations for fatty acids C18:2, Δ9, ω-3, and ω-6.

  • Compare structures/properties of saturated vs unsaturated fatty acids.

Page 4: Fatty Acids in Biological Use

• Molecular Structure:

  • Hydrophobic Tail: Non-polar, associated with lipid membranes.

  • Hydrophilic Head: Polar, interacts with water.

• Fatty Acid Examples:

  • Saturated Fatty Acids: No double bonds.

  • Unsaturated Fatty Acids: One or more double bonds, includes phospholipids and triglycerides.

Page 5: Overview of Human Triglycerides

• Most Abundant Fatty Acids:

  • Palmitate (16:0)

  • Stearate (18:0)

  • Oleate (18:1-cis)

Page 6: Fatty Acid Nomenclature

• Standard Nomenclature: Count carbon atoms from carboxyl end (C1)

  • Example: C18:1 (18 carbons, 1 double bond).

• Alternate Omega Nomenclature: Counts from methyl end (CH3)

  • Examples: ω-(n)-3, ω-6.

Page 7: Comparing Saturated and Unsaturated Fats

• Characteristics:

  • Saturated at room temperature (solid, animal sources).

  • Unsaturated commonly liquid (plant sources).

Page 8: Trans Fatty Acids

• Configurations:

  • Cis: Natural form produced in body.

  • Trans: Synthetically produced, can affect health.

Page 9: Essential Fatty Acids

• Examples:

  • Linoleate (18:2, ω-6), Linolenate (18:3, ω-3), Arachidonate (20:4, can be synthesized from linoleate).

Page 10: Fatty Acids as Membrane Anchors

• Post-Translational Modifications:

  • Important for membrane anchoring.

  • Examples: Myristoate (14:0), Palmitate (16:0).

Page 11: Lipolysis and Its Regulation

• Learning Objectives:

  • LO2: Two fat types; define lipolysis; describe lipase types; hormonal regulation.

Page 12: Triglycerides and Lipases

• Triglycerides: Main dietary fat (TG = triacylglycerol).

• Lipases: Catalyze hydrolysis of TG to fatty acids and glycerol.

Page 13: Body Fat Types & Definition of Lipolysis

• Fat Types:

  • Dietary fat: ~20-35% calories.

  • Adipose tissue: 25-30% body weight.

• Lipolysis Definition: Breakdown of triglycerides into free fatty acids and glycerol, important for energy.

Page 14: Lipolysis Mechanism

• Function: Provides energy during fasting/exercise; occurs mostly in adipocytes triggered by low insulin.

• By-products: Fatty acids used for energy; glycerol for gluconeogenesis in the liver.

Page 15: Types of Lipases

• Adipose Triglyceride Lipase (ATGL): First step in hydrolysis.

• Hormone-Sensitive Lipase (HSL): Hydrolyzes diacylglycerol.

• Monoacylglycerol Lipase (MGL): Hydrolyzes monoacylglycerol; inhibited by insulin.

Page 16: Lipolysis Regulation

• Regulators:

  • Hormonal (glucagon, epinephrine stimulate, insulin inhibits).

• Lipolysis leads to β-oxidation and energy production.

Page 17: Fatty Acid Transport and Uptake

• Learning Objectives:

  • LO3: Explain fatty acid transport in blood and uptake into mitochondria; focus on CoA, Carnitine, Malonyl-CoA roles.

Page 18: Movement of Fatty Acids

• Fed State: Triglycerides from food go to adipose tissue.

• Fasting State: Fatty acids mobilized from adipose tissue to liver/muscle.

Page 19: Fatty Acids as Detergents

• Nature: Amphipathic molecules with hydrophilic and hydrophobic components.

Page 20: Toxicity of Fatty Acids

• Toxic Concentrations: Free fatty acids can be hazardous at high levels.

• Binding Proteins: Bound to albumin in blood; fatty acid binding proteins (FABPs) inside cells.

Page 21: Daily Plasma Fatty Acid Variation

• Levels: Plasma fatty acid concentrations fluctuate post-meals and during lipolysis.

Page 22: Fatty Acids Entry into Cells

• Transport Mechanisms:

  • Plasma membrane transporters; intracellular binding to FABPs.

  • Mitochondrial uptake via carrier systems.

Page 23: Key Principles of Fatty Acid Uptake

1. Cross both mitochondrial membranes to enter catabolism as fatty acyl-CoA.

2. Carnitine facilitates fatty acid transport.

3. Uptake regulated by cytoplasmic Malonyl-CoA levels.

Page 24: Steps for Mitochondrial Uptake

• Mechanisms:

  • (A) Activation of fatty acids by CoA.

  • (B) Translocation to intermembrane space.

  • (C) Conversion to fatty acyl-carnitine.

  • (D) Import inside mitochondria.

  • (E) Re-activation with CoA.

Page 25: Carnitine Sources

• Dietary Sources: Comes from trimethyl-lysine; involved in fatty acid metabolism.

Page 26: Insulin Effects on Fatty Acid Uptake

• Regulators: Insulin inhibits fatty acid uptake via Malonyl-CoA while energy needs increase AMP concentration.

Page 27: Fatty Acid β-Oxidation

• Learning Objectives:

  • LO4: Understand β-oxidation functions, reactants, products, tissue distribution, and regulation.

Page 28: Overview of β-Oxidation

• Process: Fatty acids broken down into Acetyl-CoA, FADH2, and NADH; cyclic reaction in mitochondria; typically proceeds until 2 carbons remain.

Page 29: Palmitate β-Oxidation Example

• Palmitate (C16):

  • 7 cycles yield 8 Acetyl-CoA (cost 1 ATP for CoA attachment).

Page 30: Tissue Distribution for β-Oxidation

• Sites: Occurs in liver, kidney, heart, but not in brain or red blood cells.

Page 31: Regulation of β-Oxidation

• Hormonal Influences:

  • Insulin inhibits while epinephrine promotes β-oxidation.

• Malonyl-CoA: Inhibits transport into mitochondria, thus suppressing β-oxidation.

Page 32: ATP Production Comparison

• Fuels Comparison:

  • Glucose yields 36/38 ATP; Palmitate yields 129 ATP, indicating higher energy in fats.

Page 33: Break Time

• 8-minute break

Page 34: Synthesis of Ketone Bodies

• Learning Objectives:

  • LO5: Compare Acetyl-CoA sources; describe ketone body synthesis purpose and regulation.

Page 35: Acetyl-CoA Sources

• Metabolism: [Acetyl-CoA] is higher in fasting than fed state, primarily from fatty acid β-oxidation.

Page 36: Ketone Bodies Production

• Pathway: Overflow pathway for excess Acetyl-CoA synthesis in liver mitochondria.

Page 37: Types of Ketone Bodies

• Examples:

  • Acetoacetate, β-Hydroxybutyrate, Acetone (spontaneous conversion).

Page 38: Ketone Body Synthesis Trigger

• Circumstances: Occurs during prolonged fasting with high lipolysis rates; blood ketone levels can surge significantly.

Page 39: Ketone Body Production Step Diagram

• Synthesis Steps: Transition from Acetyl-CoA to acetoacetate and β-hydroxybutyrate; spontaneous conversion to acetone.

Page 40: Feedback Regulation in Ketogenesis

• Regulatory Mechanism: Ketone bodies stimulate insulin production, reducing lipolysis.

• Diabetes Impact: Impaired regulation in Type I diabetes.

Page 41: Ketogenesis in Fasting and Diets

• Timing: Starts after 1-2 days of fasting; high speed in ketogenic diets.

Page 42: Feedback Mechanism of Ketone Bodies

• Hormonal Response: Insulin secretion is stimulated; maintains ketogenesis without ketoacidosis.

Page 43: Oxidation of Ketone Bodies

• Learning Objectives:

  • LO6: Understand ketone oxidation location, reactants, products, and importance.

Page 44: Ketolysis Mechanics

• Usage: Brain, heart, skeletal muscle, kidneys utilize ketone bodies for conversion back to Acetyl-CoA for metabolism.

Page 45: Energy Sources in Different States

• Nutritional States: Fed state relies on glucose; prolonged fasting shifts to high reliance on ketone bodies.

Page 46: Liver and Ketone Body Oxidation

• Limitation: Liver cannot use ketone bodies for gluconeogenesis; Acetyl-CoA is not a precursor for glucose.

Page 47: Tissues Excluding Ketone Body Utilization

• Non-Participants: Liver and red blood cells cannot utilize ketone bodies for energy.

Page 48: Metabolic Interplay

• Glycolysis Inhibition: β-oxidation and ketolysis inhibit glycolysis to conserve glucose, essential for survival during starvation.

Page 49: Ketosis vs. Ketoacidosis

• Learning Objectives:

  • LO7: Define and differentiate ketosis from ketoacidosis.

Page 50: Understanding Ketosis

• Definition: Increased ketone body production (visible after ~2-3 days fasting or low-carb diets); helps restore metabolic balance.

Page 51: Understanding Ketoacidosis

• Definition: Abnormal state when ketone production exceeds utilization; associated with significant health risks (e.g., in Type I diabetes).

Page 52: Diabetic Ketoacidosis (DKA)

• Condition Characterization: Extreme hyperglycemia, severe insulin deficiency, danger of serious outcomes without treatment.

Page 53: Detection of Ketone Bodies

• Self-Testing: Urine tests (Ketostix) reflect blood ketone levels, important for monitoring.

Page 54: Correlating Ketone Bodies and Hypoglycemia

• Learning Objectives:

  • LO8: Distinction between ketotic and non-ketotic hypoglycemia.

Page 55: Overview of Hypoglycemic Conditions

• Types:

  • Ketotic: Low glucose with high ketones.

  • Non-ketotic: Low glucose with low ketones.

Page 56: Ketotic Hypoglycemia Overview

• Condition Attributes: Caused by low insulin; symptoms could lead to serious health issues if untreated.

Page 57: Non-Ketotic Hypoglycemia Overview

• Identification: Marked by low glucose and ketone levels; potential causes and recommended behavior for management.

Page 58: Review of Learning Objectives

• Section Summary: Reiterate goals concerning fatty acid nomenclature, lipolysis, transport, oxidation, and ketone body metabolism.

Applications of Fatty Acids in Metabolism

1. Energy Production

• Fatty acids are a primary energy source, especially during fasting and prolonged exercise.

• Oxidized in the mitochondria to produce Acetyl-CoA, FADH2, and NADH, which enter the TCA cycle.

2. Membrane Structure

• Fatty acids contribute to the phospholipid bilayer of cell membranes, affecting fluidity and functionality.

• Role in anchoring membrane proteins through post-translational modifications (e.g., myristoylation, palmitoylation).

3. Hormone Production

• Precursor for eicosanoids (hormone-like substances) that play roles in inflammation, blood pressure regulation, and immunity.

• Polyunsaturated fatty acids, especially omega-3 and omega-6, are crucial for synthesis.

4. Insulation and Protection

• Stored in adipose tissue as triglycerides, fatty acids provide insulation against temperature fluctuations and cushion organs.

5. Ketone Body Synthesis

• During prolonged fasting, fatty acids are converted to ketone bodies in the liver, serving as an alternative energy source for the brain and muscles.

6. Regulation of Gene Expression

• Lipid-derived signaling molecules affect gene transcription related to metabolism and energy homeostasis (e.g., PPARs).

7. Nutrient Transport

• Fatty acids modulate the transport of other nutrients across membranes, influencing nutrient absorption and usage.

Summary

Fatty acids are versatile molecules with essential roles in energy production, structural components of membranes, hormone synthesis, nutrient utilization, and signaling pathways in various metabolic processes.