carnitine palmitoyltransferase

**Function (carnitine shuttle):** Long-chain fatty acids (≥C12) cannot cross the inner mitochondrial membrane as acyl-CoA. Steps: (1) Fatty acid is activated to fatty acyl-CoA by acyl-CoA synthetase (fatty acid CoA ligase) on the outer mitochondrial membrane. (2) CPT-I (CPT1, outer membrane) transfers the acyl group from CoA to carnitine, forming acylcarnitine. (3) Carnitine-acylcarnitine translocase (CACT) moves acylcarnitine into the matrix in exchange for free carnitine. (4) CPT-II (inner membrane, matrix side) transfers the acyl group back to CoA, regenerating fatty acyl-CoA and releasing carnitine. (5) Fatty acyl-CoA then enters β-oxidation, producing acetyl-CoA, NADH, and FADH2. Medium- and short-chain fatty acids enter mitochondria independent of carnitine.

**Regulation:** CPT-I is the rate-limiting enzyme of fatty acid oxidation. It is inhibited by malonyl-CoA, the first intermediate of fatty acid synthesis (made by acetyl-CoA carboxylase, ACC). This prevents a futile cycle of simultaneous synthesis and oxidation. In the fed state, insulin activates ACC, malonyl-CoA rises, and CPT-I is inhibited. In fasting, glucagon and AMPK inhibit ACC, malonyl-CoA falls, and oxidation increases. CPT-I isoforms: CPT1A (liver), CPT1B (muscle, heart), CPT1C (brain).

**Clinical correlates:** - **CPT-II deficiency (adult/muscular form):** The most common cause of recurrent myoglobinuria and the most common inherited disorder of lipid metabolism affecting skeletal muscle. It is autosomal recessive. Presents in adolescence or adulthood with muscle pain, weakness, and rhabdomyolysis (dark urine from myoglobinuria) triggered by prolonged exercise, fasting, cold, or infection. Between episodes, the patient is normal. Labs: ↑ CK, ↑ long-chain acylcarnitines (C16, C18:1) on acylcarnitine profile, and myoglobinuria. Treatment: avoid fasting and prolonged exertion, high-carbohydrate diet, and medium-chain triglycerides (MCT), which bypass the carnitine shuttle. Severe neonatal and infantile hepatocardiomuscular forms also exist, with hypoketotic hypoglycemia, cardiomyopathy, and liver failure. - **CPT-I deficiency (liver form, CPT1A):** Causes hypoketotic hypoglycemia, hepatomegaly, and elevated free carnitine, usually presenting during fasting or illness in infancy. Low ketones in the setting of hypoglycemia are a key clue. Common in some Arctic populations (the P479L variant). - **Differentials for fatty-acid oxidation defects:** Systemic primary carnitine deficiency (OCTN2 transporter defect, which causes cardiomyopathy and hypoketotic hypoglycemia), and MCAD deficiency (the most common FAO disorder overall, with hypoketotic hypoglycemia, vomiting, and lethargy after fasting, and ↑ C8-C10 acylcarnitines). - **Pharmacology:** Etomoxir is a CPT-I inhibitor. Perhexiline and trimetazidine affect myocardial fatty acid metabolism. Valproate can cause secondary carnitine deficiency. Pivalate-containing antibiotics can too. Metformin and AMPK activation lower malonyl-CoA and so promote CPT-I activity.

**High-yield pearls:** - CPT-I = rate-limiting step, inhibited by malonyl-CoA. - Carnitine shuttle is needed only for long-chain fatty acids. - Low ketones with hypoglycemia suggest a fatty acid oxidation defect (compare with high ketones in hypoglycemia from other causes). - Exercise-induced rhabdomyolysis with normal findings between episodes suggests CPT-II deficiency. - Differentiate from McArdle disease (glycogen phosphorylase deficiency): in McArdle disease, there are cramps with short intense exercise and a "second wind" phenomenon, and no rise in lactate with ischemic forearm exercise. In CPT-II deficiency, symptoms come with prolonged, endurance-type exercise and fasting, and the ischemic forearm test is normal.