U01.01.127 Fatty acid metabolism

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Learning Objectives

  • Distinguish between the locations of Fatty Acid Synthesis (cytoplasm) and Degradation (mitochondria).
  • Master the “shuttle” mechanisms: Citrate for synthesis and Carnitine for degradation.
  • Explain the clinical consequences of Primary Carnitine Deficiency and MCAD Deficiency.
  • Identify the rate-limiting enzymes and their hormonal regulators.

1. Fatty Acid Synthesis (Lipogenesis)

Synthesis occurs predominantly in the liver, lactating mammary glands, and adipose tissue. It requires the transport of acetyl-CoA units out of the mitochondria.

  • The “Sytrate” Shuttle: Acetyl-CoA cannot cross the mitochondrial membrane. It joins oxaloacetate to form Citrate, which is then shuttled into the cytoplasm.
  • Rate-Limiting Step: Acetyl-CoA Carboxylase (ACC). This enzyme requires Biotin (B_{7}) and CO_{2}.
  • Regulation:
    • ↑ Insulin stimulates synthesis.
    • ↑ Glucagon/Epinephrine inhibits synthesis.
  • Product: Palmitate (a 16-carbon fatty acid).

2. Fatty Acid Degradation (\beta-Oxidation)

This process breaks down long-chain fatty acids (LCFA) into acetyl-CoA to fuel the TCA cycle or ketone body production.

  • The Carnitine Shuttle: LCFAs are converted to Fatty Acyl-CoA in the cytoplasm, then linked to Carnitine by Carnitine Palmitoyltransferase I (CPT-I) to enter the mitochondrial matrix.
  • Inhibition: Malonyl-CoA (an intermediate of synthesis) inhibits CPT-I to prevent a “futile cycle” (preventing breakdown while synthesis is active).
  • Product: Acetyl-CoA, NADH, and FADH_{2}.

 

Activity

3. Clinical Correlates

Disorder Pathophysiology Clinical Findings
Systemic 1° Carnitine Deficiency Defect in carnitine transporter; no LCFA transport into mitochondria. Weakness, hypotonia, hypoketotic hypoglycemia, and dilated cardiomyopathy.
MCAD Deficiency ↓ Medium-chain acyl-CoA dehydrogenase. Accumulation of fatty acyl carnitines. Vomiting, seizures, coma, and sudden infant death. Hypoketotic hypoglycemia during fasting.

Clinical Notes & Corrections:

  • Hypoketotic Hypoglycemia: This is the hallmark of fatty acid oxidation defects. If you can’t break down fats, you can’t make Ketones, and you use up all your Glucose trying to compensate.
  • Treatment for MCAD: The most critical intervention is avoiding fasting. Patients must maintain a consistent intake of carbohydrates to prevent metabolic crisis.

Activity: Fatty Acid Metabolism Vignette

Memory Hooks: “Sytrate” = Synthesis. Carnitine = Carnage of fatty acids (breakdown).

Activity: