carnitine palmitoyltransferase I

**Function and location** - CPT-I is on the outer mitochondrial membrane. It catalyzes: long-chain acyl-CoA + carnitine → acylcarnitine + CoA. - Long-chain fatty acids (≥C12) can't cross the inner mitochondrial membrane on their own. They need the carnitine shuttle. - Steps of the shuttle: 1. Acyl-CoA synthetase (outer membrane) activates the fatty acid to acyl-CoA. 2. **CPT-I** (outer membrane) converts acyl-CoA to acylcarnitine. 3. Carnitine-acylcarnitine translocase (CACT) moves acylcarnitine across the inner membrane in exchange for free carnitine. 4. **CPT-II** (inner membrane, matrix side) regenerates acyl-CoA and releases carnitine. 5. Acyl-CoA enters β-oxidation, which produces acetyl-CoA, NADH, and FADH2. - Medium- and short-chain fatty acids (<C12) enter mitochondria without the carnitine shuttle.

**Regulation** - CPT-I is the **rate-limiting step of fatty acid oxidation**. - **Malonyl-CoA** inhibits it. Malonyl-CoA is the product of acetyl-CoA carboxylase (ACC), the committed step of fatty acid synthesis. In the fed state, insulin activates ACC, malonyl-CoA rises, and CPT-I is inhibited. This prevents a futile cycle of synthesis and oxidation. - In the fasted state, glucagon and epinephrine activate AMPK, which phosphorylates and 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 the brain isoform.

**CPT-I deficiency (CPT1A deficiency)** - Inheritance is autosomal recessive. It is a fatty acid oxidation disorder of the liver. - Presentation: fasting-induced **hypoketotic hypoglycemia**, hepatic encephalopathy, hepatomegaly, and elevated transaminases, often in infancy or early childhood. - Labs: - Elevated free carnitine, because it can't be esterified. - Low acylcarnitines. - Elevated C0/(C16+C18) ratio on the newborn screen. - Treatment: - Avoid fasting. - Eat frequent meals high in carbohydrate. - Supplement with medium-chain triglycerides (MCTs), which bypass CPT-I. - Contrast with other disorders: - **CPT-II deficiency** is the most common inherited disorder of lipid metabolism affecting skeletal muscle. It causes exercise-induced rhabdomyolysis with myoglobinuria, and acylcarnitines are elevated. - **Primary carnitine deficiency** is a defect in the carnitine transporter OCTN2. It causes cardiomyopathy, hypoketotic hypoglycemia, and low serum carnitine. - **MCAD deficiency** is the most common fatty acid oxidation disorder. It causes hypoketotic hypoglycemia with dicarboxylic aciduria, and CPT-I deficiency does not.

**Pharmacology** - Etomoxir and oxfenicine are experimental CPT-I inhibitors. - Perhexiline is a CPT-I inhibitor (used for angina in some countries). - Perhexiline and the antianginal trimetazidine (which inhibits 3-ketoacyl-CoA thiolase, not CPT-I) shift the heart from fatty acid to glucose oxidation. This is more oxygen-efficient. - Metformin and AMPK activators lower malonyl-CoA and so increase CPT-I activity.

**Key exam points** - CPT-I is rate-limiting. Malonyl-CoA inhibits it. - The result of a defect is **hypoketotic hypoglycemia**, because fatty acid oxidation is needed to make ketones and to fuel gluconeogenesis. - CPT-I deficiency mainly affects the liver. CPT-II deficiency mainly affects muscle.