Advanced Cellular Biochemistry: Fatty Acid Metabolism

Advanced Cellular Biochemistry: Fatty Acid Metabolism

Lecture Objectives

  • Objective 1: Understand basic steps in lipolysis and mobilization of fatty acids.
  • Objective 2: Define steps for fatty acid transport into mitochondria (carnitine, CPT-I, CPT II) and associated metabolic disorders.
  • Objective 3: Gain knowledge of the four steps in β-oxidation spiral.
  • Objective 4: Comprehend the basis of MCAD deficiency.
  • Objective 5: Understand various levels of regulation in β-oxidation.

Fatty Acids as Fuel

  • Energy Supply:
    • Fatty acids are a major energy source between meals and during exertion.
    • During overnight fasting, they become the primary fuel for cardiac and skeletal muscles as well as the liver.
    • Note: Erythrocytes and brain cannot use fatty acids as energy sources.
    • One molecule of fatty acid produces more ATP than a molecule of glucose (greater than 3-fold yield).

Metabolic Profiles

  • Postabsorptive State:

    • Hormonal Control: Glucagon predominates.
    • Major metabolic events:
    • Breakdown of stored fats (lipolysis).
    • Fatty acids enter the bloodstream, affecting muscle and liver metabolism.

  • Postprandial State:

    • Hormonal Control: Insulin predominates.
    • Major metabolic events:
    • Increased uptake of glucose and fatty acids by tissue, stored as fat and glycogen.

Mobilization of Fatty Acids from Adipose Tissue

  • Mechanism: Lipolysis releases free fatty acids from triglycerides in adipose tissue, which then travel in blood complexed with albumin.
  • Key Enzymes: Lipases.

Cellular Uptake of Fatty Acids

  • Routes:
    • Diffusion through the plasma membrane.
    • Transport via fatty acid binding proteins (FaBP) on the plasma membrane helps transport into cells.

Oxidation of Fatty Acids

  • Fatty acids are oxidized to CO2 and water to produce ATP.
  • Acetyl-CoA:
    • Generated through β-oxidation in the liver can either:
    • Enter the TCA cycle.
    • Be converted into ketone bodies.
  • Glycerol:
    • Generated from triglyceride lipolysis, used by the liver for gluconeogenesis.

Fatty Acid Uptake and Mitochondrial β-Oxidation Process

  1. Activation:

    • Fatty acyl CoA synthetase synthesizes fatty acyl-CoA, using ATP.

  2. Transport:

    • CPT I: Transfers fatty acyl to carnitine, forming fatty acyl-carnitine.
    • CPT II: Reforms fatty acyl-CoA in the mitochondria after transport.

Diseases Related to Carnitine and Fatty Acid Metabolism

  • Carnitine Deficiency:

    • Sources from the body (25% synthesized from lysine in liver and kidneys; requires SAM and vitamin C).
    • Primary deficiency: Faulty plasma membrane carnitine transporter.
    • Secondary deficiency: Caused by metabolic disorders or organic acidemias.

  • Symptoms:

    • Varying age of onset (1 month to 7 years): Hypoketotic hypoglycemia, skeletal myopathies, cardiomyopathies, encephalopathy, hepatomegaly.

  • CPT I Deficiency:

    • Autosomal recessive; affects fatty acid oxidation in the liver.
    • Symptoms: hypoglycemia, lethargy, seizures, coma.

  • CPT II Deficiency:

    • Symptoms appear after puberty: recurrent myalgia, muscle stiffness, exacerbated by prolonged exercise, fasting, or high-fat diets.

The β-Oxidation Spiral

  • Fatty acyl groups are cleaved sequentially into 2-carbon acetyl-CoA units.
  • Enzymatic Steps in the Spiral:
    • 1. Oxidation: Fatty acyl CoA dehydrogenase action.
    • 2. Hydration: Enoyl CoA hydratase action.
    • 3. Oxidation: 3-Hydroxy acyl CoA dehydrogenase action.
    • 4. Cleavage: β-Keto thiolase action, producing acetyl-CoA.

Enzyme Specificity in β-Oxidation

  • Acyl-CoA Dehydrogenases: Categorized based on specificity for fatty acid chain lengths:
    • Very Long Chain (VLCAD): 14-26 carbons.
    • Long Chain (LCAD): 12-20 carbons.
    • Medium Chain (MCAD): 6-12 carbons.
    • Short Chain (SCAD): <6 carbons.

MCAD Deficiency

  • The most frequently diagnosed fatty acid oxidation disorder; autosomal recessive with an incidence of 1 in 20,000.
  • Symptoms include fasting hypoglycemia, low ketones, and potential for sudden infant death syndrome (SIDS).
  • Treatment includes intravenous glucose and dietary adjustments (frequent feeding, high-carb/low-fat diet).

Regulation of β-Oxidation

  • Influences include hormones (glucagon, epinephrine), malonyl CoA, and ATP utilization.
  • Activation and inhibition dependent on substrate availability and hormonal signals.

Special Cases in Fatty Acid Oxidation

  1. Oxidation of Unsaturated Fatty Acids:

    • Dietary fatty acids with cis double bonds must be converted to trans for β-oxidation.

  2. Odd-chain Length Fatty Acids:

    • The β-oxidation spiral continues until 5 carbons remain, producing propionyl CoA.

  3. Peroxisomal and Microsomal Fatty Acid Oxidation:

    • Occurs for detoxifying compounds and specific lipid processing. Not feedback regulated.

  4. Ketone Body Production:

    • Occurs under fasting conditions when excess acetyl-CoA production overwhelms the TCA cycle, providing alternate energy sources during prolonged fasting/states of starvation.

Gas Exchange of Ketone Bodies

  • Ketone bodies can supply two-thirds of the brain's energy during starvation.
  • Brain relies on ketone bodies during fasting as they cannot use fatty acids.
  • Provides spare amino acids by reducing muscle protein breakdown.

Summary

  • Fatty acid metabolism integrates energy storage and utilization, providing significant fuel in various states, particularly fasting and during high energy demand. It involves complex biochemical pathways regulated at multiple levels, highlighting the significance of understanding related metabolic disorders such as MCAD deficiency and carnitine-related diseases.