STEPTRACKERBIOCHEMISTRY + PEDIATRICS | LIPID METABOLISM | HIGH-YIELD REVIEW

Fatty Acid Synthesis & Oxidation

Synthesis in the cytosol (citrate out, malonyl-CoA built up); oxidation in mitochondria (carnitine in, acetyl-CoA chopped off) — and the infant who can't burn fat.

FOCUS ON
Synthesis: citrate shuttle exports acetyl-CoA → acetyl-CoA carboxylase (biotin, rate-limiting) → malonyl-CoA → fatty acid synthase (NADPH) → palmitate. Oxidation: carnitine shuttle (CPT I, rate-limiting; malonyl-CoA blocks it) → β-oxidation. Defects → hypoketotic hypoglycemia with fasting: MCAD deficiency (↑ C8–C10 acylcarnitines; sudden death after a viral illness) and carnitine deficiency (weakness, cardiomyopathy).
STEP · DISORDER
WHAT HAPPENS
REGULATION · FEATURES
CLUE
Citrate shuttle
Mitochondrial acetyl-CoA + OAA → citrate → cytosol → ATP-citrate lyase → acetyl-CoA
Fed state
Citrate also activates ACC
Acetyl-CoA carboxylase
rate-limiting · synthesis
Acetyl-CoA → malonyl-CoA (biotin, ATP)
+ Insulin, citrate · − glucagon, palmitoyl-CoA, AMPK
Malonyl-CoA blocks CPT I
Fatty acid synthase
Adds 2-carbon units from malonyl-CoA → palmitate (C16)
Uses NADPH (HMP shunt, malic enzyme)
Pantothenate (B5) in its acyl carrier
Essential fatty acids
Linoleic (ω-6) and α-linolenic (ω-3) can't be made
Deficiency: scaly dermatitis, alopecia, poor healing
Long-term fat-free TPN
Carnitine shuttle
CPT I rate-limiting · oxidation
Acyl-CoA → acylcarnitine (CPT I) → across inner membrane → acyl-CoA (CPT II)
Inhibited by malonyl-CoA
Short/medium-chain FAs enter without carnitine
β-Oxidation
Each turn removes acetyl-CoA, makes 1 FADH₂ + 1 NADH; palmitate → 8 acetyl-CoA (~106 ATP)
Fasting; glucagon
Liver uses acetyl-CoA for ketones
MCAD deficiency
AR · most common FAO defect
Medium-chain acyl-CoA DH ↓ → can't oxidize C6–C12
Fasting/illness → vomiting, lethargy, hypoketotic hypoglycemia, liver dysfunction, ↑ ammonia, sudden death
↑ C8–C10 acylcarnitines, dicarboxylic acids · avoid fasting, cornstarch
Systemic primary carnitine deficiency
AR
OCTN2 carnitine transporter ↓ → no long-chain FA entry
Weakness, hypotonia, cardiomyopathy, hypoketotic hypoglycemia
↓ Serum carnitine · oral carnitine
CPT II deficiency (adult)
Long-chain FAs can't be processed
Exercise- or fasting-induced rhabdomyolysis, myoglobinuria
Contrast McArdle (short burst exercise)
Odd-chain fatty acids
Final product propionyl-CoA → methylmalonyl-CoA (biotin) → succinyl-CoA (B12)
Can contribute to glucose
B12 deficiency → ↑ MMA → abnormal myelin FAs

Mechanism — synthesis and oxidation never run together

Fed: insulin
→
ACC on → malonyl-CoA
→
Fatty acid synthasePalmitate
Malonyl-CoA
→
Blocks CPT I
→
New FAs can't enter mitochondria to be burned
Fasting: glucagon
→
ACC off → malonyl-CoA ↓
→
CPT I free → β-oxidation, ketones

Synthesis vs oxidation

FEATURE
SYNTHESIS
OXIDATION
Location
Cytosol
Mitochondria
Rate-limiting
Acetyl-CoA carboxylase
CPT I
Carrier
Citrate (out)
Carnitine (in)
Cofactor
NADPH, biotin
FAD, NAD⁺
Hormone
Insulin
Glucagon, epinephrine

How it's tested

COMMON CONFUSIONHypoglycemia with LOW ketones points to a fatty acid oxidation defect (or hyperinsulinism); hypoglycemia with high ketones points to glycogen/gluconeogenesis problems or normal fasting.
THE TRAPA previously well infant dies suddenly after a day of vomiting and poor feeding — MCAD deficiency, often missed until the fasting stress.
YOUR APPROACHFasting hypoglycemia → ketones? → acylcarnitine profile (C8 = MCAD; low carnitine = transport) → organ involvement (heart, muscle, liver).

If you see… think…

Rate-limiting enzyme of fatty acid synthesis → acetyl-CoA carboxylase
Molecule that prevents futile cycling of fat → malonyl-CoA (blocks CPT I)
Shuttle carrying acetyl-CoA out of mitochondria → citrate
Toddler with hypoketotic hypoglycemia after a stomach bug → MCAD deficiency
↑ C8 acylcarnitine on newborn screen → MCAD deficiency
Weakness, cardiomyopathy, low serum carnitine → primary carnitine deficiency
Rhabdomyolysis after prolonged exercise or fasting → CPT II deficiency
Scaly dermatitis on fat-free TPN → essential fatty acid deficiency
Reducing cofactor for fatty acid synthesis → NADPH
Acetyl-CoA yield of palmitate → 8 acetyl-CoA