RESUMEN
Lecithin cholesterol acyltransferase (LCAT) is a lipid-modification enzyme that catalyzes the transfer of the acyl chain from the second position of lecithin to the hydroxyl group of cholesterol (FC) on plasma lipoproteins to form cholesteryl acylester and lysolecithin. Familial LCAT deficiency is an intractable autosomal recessive disorder caused by inherited dysfunction of the LCAT enzyme. The disease appears in two different phenotypes depending on the position of the gene mutation: familial LCAT deficiency (FLD, OMIM 245900) that lacks esterification activity on both HDL and ApoB-containing lipoproteins, and fish-eye disease (FED, OMIM 136120) that lacks activity only on HDL. Impaired metabolism of cholesterol and phospholipids due to LCAT dysfunction results in abnormal concentrations, composition and morphology of plasma lipoproteins and further causes ectopic lipid accumulation and/or abnormal lipid composition in certain tissues/cells, and serious dysfunction and complications in certain organs. Marked reduction of plasma HDL-cholesterol (HDL-C) and corneal opacity are common clinical manifestations of FLD and FED. FLD is also accompanied by anemia, proteinuria and progressive renal failure that eventually requires hemodialysis. Replacement therapy with the LCAT enzyme should prevent progression of serious complications, particularly renal dysfunction and corneal opacity. A clinical research project aiming at gene/cell therapy is currently underway.
Asunto(s)
Terapia de Reemplazo Enzimático/métodos , Deficiencia de la Lecitina Colesterol Aciltransferasa , Lipoproteínas , Fosfatidilcolina-Esterol O-Aciltransferasa/genética , Opacidad de la Córnea/etiología , Opacidad de la Córnea/prevención & control , Humanos , Japón/epidemiología , Deficiencia de la Lecitina Colesterol Aciltransferasa/sangre , Deficiencia de la Lecitina Colesterol Aciltransferasa/epidemiología , Deficiencia de la Lecitina Colesterol Aciltransferasa/fisiopatología , Deficiencia de la Lecitina Colesterol Aciltransferasa/terapia , Lipoproteínas/sangre , Lipoproteínas/metabolismo , Mutación , Fosfatidilcolina-Esterol O-Aciltransferasa/farmacología , Fosfolípidos/sangre , Fosfolípidos/metabolismo , Insuficiencia Renal/etiología , Insuficiencia Renal/prevención & controlRESUMEN
BACKGROUND: We investigated the reaction specificity toward cholesterol in lipoprotein X (Lp-X) and abnormal LDL among 6 homogeneous assays for low-density lipoprotein cholesterol (LDL-C) based on different measurement principles. METHODS: The homogeneous LDL-C assays used were based on the liquid selective detergent, selective solubilization, elimination, enzyme-selective protection, calixarene complex, and phosphate complex inhibition methods. The fraction with a density of 1.006-1.063 kg/l was isolated from cholestatic sera, and the reactivity of cholesterol in the lipoprotein fractions by gel filtration for each homogeneous LDL-C assay was determined. RESULTS: The liquid selective detergent and elimination methods showed increased cholesterol reactivity in the Lp-X fraction in a concentration-dependent manner, while the selective solubilization and phosphate complex inhibition methods were less reactive toward Lp-X cholesterol. Meanwhile, the homogeneous LDL-C assays showed decreased reactivity against cholesterol in abnormal LDL, with increased ratios of phospholipids and triglycerides against cholesterol. CONCLUSION: The homogeneous LDL-C assays showed differential reactivity toward Lp-X and abnormal LDL. Our findings enable accurate interpretation of the LDL-C values in these homogeneous assays, and suggest that these methods should be improved to distinguish between normal LDL and abnormal LDL or Lp-X.