CPT-I

**Function and location** - CPT-I is on the outer mitochondrial membrane. It is part of the carnitine shuttle. - Long-chain fatty acids (≥12 carbons) are activated to acyl-CoA in the cytosol by acyl-CoA synthetase. Acyl-CoA cannot cross the inner mitochondrial membrane. - CPT-I transfers the acyl group from CoA to carnitine, forming acylcarnitine. - Carnitine-acylcarnitine translocase (CACT) moves acylcarnitine across the inner membrane in exchange for free carnitine. - CPT-II is on the inner membrane. It converts acylcarnitine back to acyl-CoA and carnitine in the matrix, and the acyl-CoA then enters β-oxidation. - Medium- and short-chain fatty acids enter mitochondria without the carnitine shuttle.

**Regulation (high-yield)** - CPT-I is the rate-limiting step of β-oxidation. - Malonyl-CoA inhibits it. Malonyl-CoA is the product of acetyl-CoA carboxylase (ACC), the rate-limiting step of fatty acid synthesis. - This stops newly synthesized fatty acids from being immediately oxidized (a futile cycle). - Fed state: insulin activates ACC, so malonyl-CoA rises and CPT-I is inhibited. - Fasting: glucagon and epinephrine act through AMPK, which inhibits ACC. Malonyl-CoA falls, CPT-I is disinhibited, and β-oxidation increases.

**Isoforms** - CPT1A is the liver isoform. - CPT1B is the muscle and heart isoform. It is more sensitive to malonyl-CoA. - CPT1C is in the brain.

**Clinical correlations** - *CPT-I deficiency (CPT1A):* - Autosomal recessive. - It causes hypoketotic hypoglycemia during fasting or illness, because fatty acid oxidation and ketogenesis fail. - Other findings are hepatomegaly, elevated liver enzymes, and sometimes renal tubular acidosis. - Acylcarnitines are low, and free carnitine is normal or elevated. - Management is frequent feeding, avoiding fasting, and a diet with medium-chain triglycerides (MCTs), which bypass CPT-I. - *CPT-II deficiency:* - This is the more common adult form. - It causes exercise-induced myalgia, rhabdomyolysis, and myoglobinuria. - Long-chain acylcarnitines accumulate. - *Carnitine deficiency:* - Causes include malnutrition, valproate use, dialysis, and organic acidemias. - It causes hypoketotic hypoglycemia, weakness, and cardiomyopathy. - Treatment is carnitine supplementation. - *Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency* is a downstream β-oxidation defect. It also causes hypoketotic hypoglycemia, but with dicarboxylic aciduria.

**Pharmacology** - Etomoxir is a CPT-I inhibitor used in research. - Perhexiline is a CPT-1 inhibitor used as an antianginal outside the US. - Metformin and AMPK activation indirectly increase fatty acid oxidation by lowering malonyl-CoA.

**Board pearls** - Think "CPT-I = rate-limiting, inhibited by malonyl-CoA." - Hypoketotic hypoglycemia points to a fatty acid oxidation defect. - Hypoglycemia with low or absent ketones also occurs with hyperinsulinism, so look for other clues.