Lipid Metabolism & Fatty Acid Oxidation
A board-focused walkthrough of fatty acid oxidation and synthesis: the carnitine shuttle, reciprocal malonyl-CoA/CPT-I regulation, and the FAO disorders (MCAD, primary carnitine deficiency, CPT-II) that present as hypoketotic hypoglycemia, plus why the liver makes but cannot use ketone bodies.
The Big Picture
Lipid metabolism on Step 1 is tested on where each pathway runs and what breaks when an enzyme fails. Fatty acid oxidation (β-oxidation) degrades fatty acids to acetyl-CoA in the mitochondrial matrix to generate ATP and ketones during fasting; fatty acid synthesis builds palmitate in the cytosol during the fed state. The two are reciprocally regulated, so a cell never runs both at once. The linchpin is malonyl-CoA — the first committed product of synthesis, which simultaneously inhibits CPT-I to shut off oxidation. Board favorites cluster around three themes: the carnitine shuttle, the enzyme defects that cause hypoketotic hypoglycemia (especially MCAD), and the fact that the liver makes but cannot use ketone bodies.
- β-oxidation occurs in the mitochondrial matrix; each round yields 1 NADH + 1 FADH₂ + 1 acetyl-CoA and shortens the chain by 2 carbons
- Long-chain fatty acids cannot cross the inner membrane alone — they require the carnitine shuttle
- CPT-I (outer membrane) is the rate-limiting step and is inhibited by malonyl-CoA, linking fed-state synthesis to switched-off oxidation
- CACT (translocase) swaps acylcarnitine inward for free carnitine; CPT-II (inner membrane) regenerates acyl-CoA in the matrix
- Acetyl-CoA produced feeds ketogenesis (liver) and the TCA cycle
- Odd-chain fatty acids yield propionyl-CoA → methylmalonyl-CoA (biotin) → succinyl-CoA (B₁₂) — the only glucogenic portion
Synthesis vs. Oxidation
| Feature | Fatty acid synthesis | Fatty acid oxidation |
|---|---|---|
| Location | Cytosol | Mitochondrial matrix |
| Metabolic state | Fed (↑ insulin) | Fasting (↑ glucagon) |
| Rate-limiting enzyme | Acetyl-CoA carboxylase | CPT-I |
| Key regulation | Activated by citrate & insulin | Malonyl-CoA inhibits CPT-I |
| Cofactors | NADPH, biotin | FAD, NAD⁺ |
| Transport shuttle | Citrate (out of mito) | Carnitine (into mito) |
| Net | Builds palmitate (C16) | Yields acetyl-CoA + ketones |
- All FAO defects → hypoketotic hypoglycemia with fasting: no fatty-acid–derived acetyl-CoA means no ketones and impaired gluconeogenesis (acetyl-CoA normally activates pyruvate carboxylase)
- MCAD deficiency — most common FAO disorder, autosomal recessive; ↑ C8–C10 acylcarnitines and dicarboxylic aciduria; caught on newborn screening; can mimic SIDS or Reye syndrome
- Primary carnitine deficiency (OCTN2 / SLC22A5 transporter) — low plasma carnitine, dilated cardiomyopathy, hypotonia, weakness
- CPT-II deficiency — adolescent/adult with muscle pain + myoglobinuria (rhabdomyolysis) after prolonged exercise, fasting, or cold
- Management of all: avoid fasting, give IV dextrose during illness, frequent carbohydrate-rich feeds
Vignette: An 11-month-old, previously healthy, is brought in lethargic and vomiting the morning after poor intake during a viral illness. Exam shows hepatomegaly; urine dipstick shows no ketones. Labs: glucose 32 mg/dL, low/absent ketones, elevated C8 (octanoyl) acylcarnitine.
- Diagnosis: MCAD deficiency (medium-chain acyl-CoA dehydrogenase)
- Why hypoketotic: blocked β-oxidation → no acetyl-CoA substrate for ketogenesis, so hypoglycemia occurs without the expected compensatory ketosis
- Next best step: IV dextrose to correct hypoglycemia and halt lipolysis; confirm with a plasma acylcarnitine profile ± genetic testing
- Long-term: frequent feeding and avoid fasting, especially during illness
- Ketogenesis occurs in liver mitochondria; the rate-limiting enzyme is HMG-CoA synthase (mitochondrial — distinct from HMG-CoA reductase of cholesterol synthesis)
- Ketone bodies are acetoacetate and β-hydroxybutyrate (acetone is a minor, breath-detectable byproduct)
- The liver makes ketones but cannot use them — it lacks thiophorase (succinyl-CoA:acetoacetate CoA transferase / SCOT)
- Brain shifts to ketones in prolonged starvation; RBCs never can (no mitochondria)
- A high NADH/NAD⁺ ratio (DKA, alcoholism) shifts the balance toward β-hydroxybutyrate
- Urine nitroprusside detects acetoacetate but NOT β-hydroxybutyrate, so it can underestimate early DKA ketosis
- CPT-I = Inhibited — the I cues that CPT-I is the fed-state brake on β-oxidation, inhibited by malonyl-CoA
- Citrate → Cytosol — the citrate shuttle exports acetyl-CoA to the cytosol, where fatty-acid synthesis runs (both start with C)
- Carnitine carries — carnitine carries long-chain fatty acids into the mitochondrion; no shuttle, no β-oxidation
- Liver "can't eat what it cooks" — it synthesizes ketones but lacks thiophorase (SCOT), so it cannot oxidize them for its own fuel
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