Harvey's Garden

Fatty acid oxidation

4 min read

Pathophysiology/Etiology

  • Function: Breaks down fatty acids (FAs) into acetyl-CoA, generating NADH and FADH₂. This is a crucial energy source during fasting, starvation, and prolonged exercise, especially for the heart and skeletal muscle.
  • Location: Primarily in the mitochondrial matrix.
  • Process Overview: A cyclical process that sequentially cleaves two-carbon units (as acetyl-CoA) from the fatty acyl-CoA molecule.

Key Steps:

  1. Activation: In the cytoplasm, long-chain fatty acids (LCFAs) are activated to fatty acyl-CoA by fatty acyl-CoA synthetase, requiring ATP.
  2. Transport (Rate-Limiting Step): LCFAs require the carnitine shuttle to enter the mitochondria.
    • CPT1 (Carnitine Palmitoyltransferase I): Fatty acyl-CoA is converted to acylcarnitine on the outer mitochondrial membrane. Inhibited by Malonyl-CoA (an intermediate in FA synthesis).
    • Translocase: Acylcarnitine is transported into the mitochondrial matrix.
    • CPT2 (Carnitine Palmitoyltransferase II): Acylcarnitine is converted back to fatty acyl-CoA in the matrix.
    • Note: Short and medium-chain FAs do not require the carnitine shuttle.
  3. β-Oxidation Spiral: In the mitochondrial matrix, a four-reaction sequence is repeated:
    • Oxidation by acyl-CoA dehydrogenase (produces FADH₂).
    • Hydration.
    • Oxidation by β-hydroxyacyl-CoA dehydrogenase (produces NADH).
    • Thiolysis (cleavage) to release acetyl-CoA and a fatty acyl-CoA that is two carbons shorter.
  • Fates of Acetyl-CoA:
    • Enters the TCA cycle in muscle and other tissues for ATP production.
    • Used for ketone body synthesis in the liver, especially during fasting.

Clinical Presentation of Defects

  • Disorders typically present during periods of catabolic stress (e.g., fasting, illness, prolonged exercise).
  • Classic presentation: Hypoketotic hypoglycemia. The hypoglycemia occurs because gluconeogenesis requires ATP and NADH, which are supplied by β-oxidation. Without β-oxidation, gluconeogenesis is impaired. Ketone body production is also deficient.
  • Other common symptoms include lethargy, vomiting, seizures, coma, hyperammonemia, and myopathy.

Key Disorders

Carnitine Shuttle Defects

  • Primary Carnitine Deficiency: Defect in the carnitine transporter.
    • Dx: Low plasma carnitine levels, reduced carnitine uptake by cells.
    • Presentation: Weakness, hypotonia, cardiomyopathy, hypoketotic hypoglycemia.
  • Carnitine Palmitoyltransferase (CPT) I Deficiency: Affects the liver.
    • Dx: Elevated plasma carnitine, acylcarnitine profile shows ↑ free carnitine.
    • Presentation: Primarily hepatic symptoms with hypoketotic hypoglycemia and risk of liver failure.
  • Carnitine Palmitoyltransferase (CPT) II Deficiency: Most common inherited disorder of lipid metabolism in adults.
    • Dx: Acylcarnitine profile shows elevated C16, C18:1 acylcarnitines during an attack.
    • Presentation: Classic adult form involves myalgia, muscle weakness, and myoglobinuria (red-brown urine) triggered by prolonged exercise, fasting, or illness.

Acyl-CoA Dehydrogenase Deficiencies

  • Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency: Most common inborn error of FA oxidation.
    • Dx: Elevated C8-C10 acylcarnitines in plasma, dicarboxylic acids in urine. Now part of newborn screening.
    • Presentation: Presents in infancy or early childhood. Vomiting, lethargy, seizures, coma, liver dysfunction, hypoketotic hypoglycemia following a period of fasting (e.g., viral illness).
  • Very Long-Chain Acyl-CoA Dehydrogenase (VLCAD) Deficiency:
    • Dx: Elevated C14-C18 acylcarnitines.
    • Presentation: Can present with severe cardiomyopathy in infancy, hypoketotic hypoglycemia, or later-onset myopathy.

Management/Treatment

  • Acute: IV dextrose to correct hypoglycemia and reverse catabolism.
  • Long-term:
    • Avoid fasting and prolonged exercise.
    • Provide frequent meals with a high-carbohydrate, low-fat diet.
    • Carnitine supplementation for carnitine deficiencies.
    • Medium-chain triglyceride (MCT) oil can be used as a supplement in LCHAD/VLCAD deficiency, as MCTs bypass the carnitine shuttle.

Key Associations/Buzzwords

  • Buzzwords: Hypoketotic hypoglycemia, myoglobinuria after exercise, dicarboxylic aciduria.
  • Jamaican Vomiting Sickness: Caused by eating unripe ackee fruit, which contains hypoglycin A. This toxin irreversibly inhibits MCAD, leading to symptoms mimicking MCAD deficiency.
  • Odd-Chain Fatty Acids: Undergo β-oxidation to yield acetyl-CoA and one molecule of propionyl-CoA. Propionyl-CoA enters the TCA cycle after being converted to succinyl-CoA.
  • Peroxisomal Oxidation: Very-long-chain fatty acids (>20 carbons) are initially oxidized in peroxisomes. Defects lead to conditions like Zellweger syndrome or X-linked adrenoleukodystrophy.

Rate-limiting enzyme

Tip

Very long chain fatty acids (VLCFAs) and certain branched-chain fatty acids (eg, phytanic acid) cannot undergo mitochondrial beta-oxidation; these fatty acids are metabolized by a special form of beta-oxidation (VLCFAs) or by alpha-oxidation (branched-chain fatty acids) within peroxisomes.

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