lecithin-cholesterol acyltransferase

**Function / biochemistry** - Synthesized by the liver and secreted into plasma, where it associates mainly with HDL. - Cofactor/activator: apolipoprotein A-I (apoA-I), the main HDL apolipoprotein. - Reaction: lecithin (phosphatidylcholine) + free cholesterol → cholesteryl ester + lysolecithin. The enzyme transfers the sn-2 fatty acid (usually linoleate) from lecithin to the 3-OH group of cholesterol. - Nascent (discoidal) HDL picks up free cholesterol from peripheral cells and other lipoproteins through ABCA1 (and later ABCG1/SR-B1). LCAT esterifies this cholesterol. The cholesteryl esters are hydrophobic and move into the HDL core, so the particle becomes spherical, mature HDL (HDL3 → HDL2). - Esterification removes free cholesterol from the surface. This maintains the gradient for further cholesterol efflux from cells and drives reverse cholesterol transport. - Mature HDL cholesteryl esters then: 1. Go to the liver directly via SR-B1. 2. Transfer to VLDL/IDL/LDL via CETP in exchange for triglycerides, and are then cleared by the liver via LDL receptors.

**Related proteins (commonly tested together)** - ApoA-I activates LCAT. - ApoC-II activates lipoprotein lipase (LPL). - ApoB-100 is the ligand for the LDL receptor. - ApoE mediates remnant and chylomicron remnant uptake. - ABCA1 is defective in Tangier disease. - CETP transfers cholesteryl esters from HDL to VLDL/LDL.

**Clinical significance** - Familial LCAT deficiency (autosomal recessive; complete deficiency): - Cholesterol can't be esterified, so HDL is very low and free cholesterol and lecithin accumulate in tissues and membranes. - Corneal opacities ("fish-eye"), normochromic hemolytic anemia (RBC membrane lipid abnormalities, target cells), and proteinuria progressing to renal failure (the main cause of mortality). - Labs: low HDL, low cholesteryl esters, high free cholesterol:total cholesterol ratio, often high triglycerides. - Fish-eye disease (partial LCAT deficiency): corneal opacities and low HDL, but typically no hemolytic anemia or renal failure. - Acquired low LCAT activity occurs in severe liver disease because of decreased hepatic synthesis. - Because LCAT activity increases HDL cholesteryl ester content, it helps determine HDL structure and maturation. Its direct antiatherogenic role in humans is unclear, and LCAT deficiency doesn't consistently cause premature atherosclerosis. - Recombinant LCAT (and other LCAT-targeted therapies) have been investigated for LCAT deficiency and acute coronary syndromes. These are not standard board-relevant treatments.

**High-yield mnemonic/tips** - "LCAT = Lecithin Cholesterol AcylTransferase → makes cholesteryl esters in HDL, activated by apoA-I." - LCAT deficiency triad: corneal clouding, hemolytic anemia, and renal failure. - Low HDL plus corneal opacities on boards: think Tangier disease (orange tonsils, hepatosplenomegaly, neuropathy, ABCA1 defect) versus LCAT deficiency (hemolytic anemia, renal disease).