RESUMEN
Proprotein convertase subtilisin/kexin 9 (PCSK9), a protein regulating the number of cell-surface LDL receptors (LDLR), circulates partially associated to plasma lipoproteins. How this interaction alters PCSK9 plasma levels is still unclear. In the present study, we took advantage of the availability of a large cohort of carriers of genetic HDL disorders to evaluate how HDL defects affect plasma PCSK9 levels and its distribution among lipoproteins. Plasma PCSK9 concentrations were determined by ELISA in carriers of mutations in LCAT, ABCA1, or APOAI genes, and lipoprotein distribution was analyzed by FPLC. Carriers of one or two mutations in the LCAT gene show plasma PCSK9 levels comparable to that of unaffected family controls (homozygotes, 159.4â¯ng/mL (124.9;243.3); heterozygotes, 180.3â¯ng/mL (127.6;251.5) and controls, 190.4â¯ng/mL (146.7;264.4); P for trendâ¯=â¯0.33). Measurement of PCSK9 in plasma of subjects carrying mutations in ABCA1 or APOAI genes confirmed normal values. When fractionated by FPLC, PCSK9 peaked in a region between LDL and HDL in control subjects. In carriers of all HDL defects, lipoprotein profile shows a strong reduction of HDL, but the distribution of PCSK9 was superimposable to that of controls. In conclusion, the present study demonstrates that in genetically determined low HDL states plasma PCSK9 concentrations and lipoprotein distribution are preserved, thus suggesting that HDL may not be involved in PCSK9 transport in plasma.
Asunto(s)
Transportador 1 de Casete de Unión a ATP/sangre , Apolipoproteína A-I/sangre , Hipolipoproteinemias/sangre , Fosfatidilcolina-Esterol O-Aciltransferasa/sangre , Proproteína Convertasa 9/sangre , Transportador 1 de Casete de Unión a ATP/deficiencia , Transportador 1 de Casete de Unión a ATP/genética , Adulto , Anciano , Apolipoproteína A-I/deficiencia , Apolipoproteína A-I/genética , Estudios de Casos y Controles , Femenino , Regulación de la Expresión Génica , Heterocigoto , Homocigoto , Humanos , Hipolipoproteinemias/genética , Hipolipoproteinemias/patología , Lipoproteínas HDL/sangre , Lipoproteínas HDL/genética , Lipoproteínas LDL/sangre , Lipoproteínas LDL/genética , Masculino , Persona de Mediana Edad , Fosfatidilcolina-Esterol O-Aciltransferasa/genética , Proproteína Convertasa 9/genéticaRESUMEN
p.R375W (Fibrinogen Aguadilla) is one out of seven identified mutations (Brescia, Aguadilla, Angers, Al du Pont, Pisa, Beograd, and Ankara) causing hepatic storage of the mutant fibrinogen γ. The Aguadilla mutation has been reported in children from the Caribbean, Europe, Japan, Saudi Arabia, Turkey, and China. All reported children presented with a variable degree of histologically proven chronic liver disease and low plasma fibrinogen levels. In addition, one Japanese and one Turkish child had concomitant hypo-APOB-lipoproteinemia of unknown origin. We report here on an additional child from Turkey with hypofibrinogenemia due to the Aguadilla mutation, massive hepatic storage of the mutant protein, and severe hypo-APOB-lipoproteinemia. The liver biopsy of the patient was studied by light microscopy, electron microscopy (EM), and immunohistochemistry. The investigation included the DNA sequencing of the three fibrinogen and APOB-lipoprotein regulatory genes and the analysis of the encoded protein structures. Six additional Fibrinogen Storage Disease (FSD) patients with either the Aguadilla, Ankara, or Brescia mutations were investigated with the same methodology. A molecular analysis revealed the fibrinogen gamma p.R375W mutation (Aguadilla) but no changes in the APOB and MTTP genes. APOB and MTTP genes showed no abnormalities in the other study cases. Light microscopy and EM studies of liver tissue samples from the child led to the demonstration of the simultaneous accumulation of both fibrinogen and APOB in the same inclusions. Interestingly enough, APOB-containing lipid droplets were entrapped within the fibrinogen inclusions in the hepatocytic Endoplasmic Reticulum (ER). Similar histological, immunohistochemical, EM, and molecular genetics findings were found in the other six FSD cases associated with the Aguadilla, as well as with the Ankara and Brescia mutations. The simultaneous retention of fibrinogen and APOB-lipoproteins in FSD can be detected in routinely stained histological sections. The analysis of protein structures unraveled the pathomorphogenesis of this unexpected phenomenon. Fibrinogen gamma chain mutations provoke conformational changes in the region of the globular domain involved in the "end-to-end" interaction, thus impairing the D-dimer formation. Each monomeric fibrinogen gamma chain is left with an abnormal exposure of hydrophobic patches that become available for interactions with APOB and lipids, causing their intracellular retention and impairment of export as a secondary unavoidable phenomenon.
Asunto(s)
Afibrinogenemia/genética , Apolipoproteína B-100/genética , Fibrinógeno/genética , Hipolipoproteinemias/genética , Hepatopatías/sangre , Afibrinogenemia/sangre , Afibrinogenemia/patología , Apolipoproteína B-100/sangre , Preescolar , Retículo Endoplásmico/genética , Retículo Endoplásmico/metabolismo , Femenino , Fibrinógeno/química , Fibrinógeno/metabolismo , Hepatocitos/química , Hepatocitos/metabolismo , Hepatocitos/patología , Humanos , Hipolipoproteinemias/metabolismo , Hipolipoproteinemias/patología , Hígado/metabolismo , Hígado/patología , Hepatopatías/genética , Hepatopatías/patología , Masculino , Persona de Mediana Edad , Mutación , Conformación Proteica , Relación Estructura-ActividadRESUMEN
Hyperlipidemia has been extensively studied in the context of atherosclerosis, whereas the potential health consequences of the opposite extreme, hypolipidemia, remain largely uninvestigated. Circulating lipoproteins are essential carriers of insoluble lipid molecules and are increasingly recognized as innate immune effectors. Importantly, severe hypolipidemia, which may occur with trauma or critical illness, is clinically associated with bacterial pneumonia. To test the hypothesis that circulating lipoproteins are essential for optimal host innate defense in the lung, we used lipoprotein-deficient mice and a mouse model of Staphylococcus aureus pneumonia in which invasive infection requires virulence factor expression controlled by the accessory gene regulator (agr) operon. Activation of agr and subsequent virulence factor expression is inhibited by apolipoprotein B, the structural protein of low-density lipoprotein, which binds and sequesters the secreted agr-signaling peptide (AIP). In this article, we report that lipoprotein deficiency impairs early pulmonary innate defense against S. aureus quorum-sensing-dependent pathogenesis. Specifically, apolipoprotein B levels in the lung early postinfection are significantly reduced with lipoprotein deficiency, coinciding with impaired host control of S. aureus agr-signaling and increased agr-dependent morbidity (weight loss) and inflammation. Given that lipoproteins also inhibit LTA- and LPS-mediated inflammation, these results suggest that hypolipidemia may broadly impact posttrauma pneumonia susceptibility to both Gram-positive and -negative pathogens. Together with previous reports demonstrating that hyperlipidemia also impairs lung innate defense, these results suggest that maintenance of normal serum lipoprotein levels is necessary for optimal host innate defense in the lung.
Asunto(s)
Proteínas Bacterianas/metabolismo , Hipolipoproteinemias/inmunología , Lipoproteínas LDL/sangre , Neumonía Estafilocócica/inmunología , Percepción de Quorum/inmunología , Staphylococcus aureus/inmunología , Transactivadores/metabolismo , Animales , Apolipoproteínas B/inmunología , Proteínas Bacterianas/genética , Línea Celular , Modelos Animales de Enfermedad , Humanos , Hipolipoproteinemias/genética , Inmunidad Innata/inmunología , Lipoproteínas LDL/inmunología , Pulmón/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Transducción de Señal/genética , Transactivadores/genéticaRESUMEN
CONTEXT: Familial combined hypolipidemia causes a global reduction of plasma lipoproteins. Its clinical correlates and metabolic implications have not been well defined. OBJECTIVE: The objective of the study was to investigate the genetic, clinical, and metabolic characteristics of a cohort of subjects with familial combined hypolipidemia. DESIGN: The design of the study included candidate gene screening and the comparison of the clinical and metabolic characteristics between carrier and noncarrier individuals. SETTING: The study was conducted in a general community. SUBJECTS: Participants in the study included individuals belonging to nine families with familial combined hypolipidemia identified in a small town (Campodimele) as well as from other 352 subjects living in the same community. MAIN OUTCOMES MEASURES: Serum concentrations of lipoproteins, Angiopoietin-like 3 (Angptl3) proteins, and noncholesterol sterols were measured. RESULTS: The ANGPTL3 S17X mutation was found in all probands, 20 affected family members, and 32 individuals of the community. Two additional frame shift mutations, FsE96del and FsS122, were also identified in two hypocholesterolemic individuals. Homozygotes for the ANGPTL3 S17X mutation had no circulating Angptl3 and a marked reduction of all plasma lipids (P < 0.001). Heterozygotes had 42% reduction in Angptl3 level compared with noncarriers (P < 0.0001) but a significant reduction of only total cholesterol and high-density lipoprotein cholesterol. No differences were observed in the plasma noncholesterol sterols between carriers and noncarriers. No association between familial combined hypolipidemia and the risk of hepatic or cardiovascular diseases were detected. CONCLUSIONS: Familial combined hypolipidemia segregates as a recessive trait so that apolipoprotein B- and apolipoprotein A-I-containing lipoproteins are comprehensively affected only by the total deficiency of Angptl3. Familial combined hypolipidemia does not perturb whole-body cholesterol homeostasis and is not associated with adverse clinical sequelae.
Asunto(s)
Angiopoyetinas/genética , Hipolipoproteinemias/genética , Mutación , Adulto , Anciano , Proteína 3 Similar a la Angiopoyetina , Proteínas Similares a la Angiopoyetina , Angiopoyetinas/sangre , Apolipoproteína A-I/sangre , Apolipoproteína A-I/metabolismo , Apolipoproteínas B/sangre , Apolipoproteínas B/metabolismo , Estudios de Casos y Controles , Colesterol/sangre , Estudios de Cohortes , Análisis Mutacional de ADN , Familia , Femenino , Genotipo , Humanos , Hipolipoproteinemias/sangre , Hipolipoproteinemias/diagnóstico , Hipolipoproteinemias/epidemiología , Italia/epidemiología , Masculino , Persona de Mediana Edad , Mutación/fisiología , Linaje , FenotipoAsunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Aterosclerosis/genética , Hipolipoproteinemias/genética , Lipoproteínas HDL/genética , Mutación/genética , Transportador 1 de Casete de Unión a ATP , Disnea/etiología , Femenino , Heterocigoto , Humanos , Lipoproteínas HDL/sangre , Persona de Mediana EdadRESUMEN
OBJECTIVE: Alterations of lipid metabolism play a pivotal role in the development of atherosclerosis and its complications, today's major mortality risks. The predominant regulators controlling cholesterol- and fatty acids synthesis in liver are the sterol regulatory element-binding proteins (SREBPs), a family of transcription factors that were formerly identified as cholesterol sensor for LDLR gene expression. Variation of gene structure in these genes might therefore indicate a predisposition to develop complications like myocardial infarction and stroke. METHODS: We investigated 190 unrelated German subjects, including 69 subjects with LDL-cholesterol <55mg/dl, for mutations in SREBP genes SREBF-1 and SREBF-2 by direct sequencing. The impact on SREBP functionality was analyzed by protein biochemical analyses, promoter reporter gene assays and gene expression studies. RESULTS: A missense mutation in SREBF-1 (c.332 C>T; P111L) was identified in a subject with LDL-cholesterol <5mg/dl. Examination of the subject's family confirmed the mutation in two of three siblings. Detailed clinical evaluation of these subjects disclose a novel form of primary combined hypolipidemia only in SREBP-1a P111L carriers, characterized by low levels of apoB and apoA1, low triglyceride, LDL-cholesterol and HDL-cholesterol levels. Functional analyses indicated that the mutation abolishes phosphorylation of SREBP-1. As a consequence transcriptional activation of classical target genes, i.e. LDLR, HMG-CoAR, FAS, ABCA1, but also MTTP, was dramatically reduced. CONCLUSIONS: Phosphorylation of SREBP-1, the master regulator of genes for central rate limiting enzymes of cholesterol and lipid metabolism, appears to be a biological principle with clinical implications.
Asunto(s)
Hipolipoproteinemias/genética , Metabolismo de los Lípidos , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/genética , Adulto , Colesterol/metabolismo , LDL-Colesterol/metabolismo , Salud de la Familia , Femenino , Regulación de la Expresión Génica , Genes Reporteros , Variación Genética , Células Hep G2 , Humanos , Masculino , Microscopía Fluorescente/métodos , Persona de Mediana Edad , Mutación , Mutación Missense , Linaje , Análisis de Secuencia de ADN , Proteína 2 de Unión a Elementos Reguladores de Esteroles/genéticaRESUMEN
We report a novel apolipoprotein A-I (apoA-I) mutation identified in a 64-year-old patient with marked plasma high density lipoprotein (HDL) cholesterol (4 mg/dl) and apoA-I (5mg/dl) deficiency, prior myocardial infarction, and moderate corneal opacities. Coronary angiography revealed extensive atherosclerosis in all three major vessels. Genomic DNA sequencing of the proband revealed a homozygous novel deletion of two successive adenine residues in codon 138 in the apoA-I gene, resulting in a frameshift mutation at amino acid residues 138-178, which we have designated as apoA-I Tomioka. His elder brother was also homozygous for apoA-I Tomioka with marked HDL cholesterol and apoA-I deficiency, but had no clinical evidence of coronary heart disease. Other family members including three siblings and two sons were heterozygous for the mutation, and had approximately 50% of normal plasma HDL cholesterol, and apoA-I. Analysis of apoA-I-containing HDL particles by two-dimensional gel electrophoresis revealed undetectable apoA-I HDL particles in the homozygotes, while in heterozygotes, the mean concentrations of apoA-I in large alpha-1 and very small prebeta-1 HDL subpopulations were significantly decreased at about 35% of normal. Thus, apoA-I Tomioka, a novel deletion mutation in codon 138 of the apoA-I gene, is the causative defect in this case of HDL deficiency.
Asunto(s)
Apolipoproteína A-I/genética , HDL-Colesterol/sangre , Enfermedad de la Arteria Coronaria/genética , Mutación del Sistema de Lectura , Hipolipoproteinemias/genética , Eliminación de Secuencia , Apolipoproteína A-I/sangre , LDL-Colesterol/sangre , Codón , Opacidad de la Córnea/genética , Angiografía Coronaria , Enfermedad de la Arteria Coronaria/sangre , Análisis Mutacional de ADN , Regulación hacia Abajo , Electroforesis en Gel Bidimensional , Predisposición Genética a la Enfermedad , Aneurisma Cardíaco/genética , Heterocigoto , Homocigoto , Humanos , Hipolipoproteinemias/sangre , Hipolipoproteinemias/complicaciones , Masculino , Persona de Mediana Edad , Infarto del Miocardio/genética , Linaje , Fenotipo , Índice de Severidad de la Enfermedad , Triglicéridos/sangreRESUMEN
Monogenic disorders that cause abnormal levels of plasma cholesterol and triglycerides have received much attention due to their role in metabolic dysfunction and cardiovascular disease. While these disorders often present clinically during adulthood, some present most commonly in the pediatric population and can have serious consequences if misdiagnosed or untreated. This review provides an overview of monogenic lipid disorders that present with unusually high or low levels of plasma cholesterol and/or triglycerides during infancy, childhood and adolescence. Biochemical and genetic findings, clinical presentation and treatment options are discussed with an emphasis upon recent advances in our understanding and management of these monogenic disorders.
Asunto(s)
Dislipidemias , Serina Endopeptidasas/genética , Adolescente , Ácidos y Sales Biliares/metabolismo , Niño , Dislipidemias/clasificación , Dislipidemias/genética , Dislipidemias/metabolismo , Dislipidemias/terapia , Humanos , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo II/metabolismo , Hiperlipoproteinemia Tipo II/terapia , Hiperlipoproteinemia Tipo IV/genética , Hiperlipoproteinemia Tipo IV/metabolismo , Hiperlipoproteinemia Tipo IV/terapia , Hipolipoproteinemias/genética , Hipolipoproteinemias/metabolismo , Hipolipoproteinemias/terapia , Mutación , Proproteína Convertasa 9 , Proproteína ConvertasasRESUMEN
Our aim was to characterize HDL subspecies and fat-soluble vitamin levels in a kindred with familial apolipoprotein A-I (apoA-I) deficiency. Sequencing of the APOA1 gene revealed a nonsense mutation at codon -2, Q[-2]X, with two documented homozygotes, eight heterozygotes, and two normal subjects in the kindred. Homozygotes presented markedly decreased HDL cholesterol levels, undetectable plasma apoA-1, tuboeruptive and planar xanthomas, mild corneal arcus and opacification, and severe premature coronary artery disease. In both homozygotes, analysis of HDL particles by two-dimensional gel electrophoresis revealed undetectable apoA-I, decreased amounts of small alpha-3 migrating apoA-II particles, and only modestly decreased normal amounts of slow alpha migrating apoA-IV- and apoE-containing HDL, while in the eight heterozygotes, there was loss of large alpha-1 HDL particles. There were no significant decreases in plasma fat-soluble vitamin levels noted in either homozygotes or heterozygotes compared with normal control subjects. Our data indicate that isolated apoA-I deficiency results in marked HDL deficiency with very low apoA-II alpha-3 HDL particles, modest reductions in the separate and distinct plasma apoA-IV and apoE HDL particles, tuboeruptive xanthomas, premature coronary atherosclerosis, and no evidence of fat malabsorption.
Asunto(s)
Apolipoproteína A-I/deficiencia , Apolipoproteína A-I/genética , Hipolipoproteinemias/genética , Hipolipoproteinemias/metabolismo , Lipoproteínas HDL/química , Adulto , Anciano , Apolipoproteína A-I/sangre , Niño , Preescolar , HDL-Colesterol/sangre , Femenino , Humanos , Hipolipoproteinemias/sangre , Lipoproteínas HDL/sangre , Masculino , Tamaño de la Partícula , Linaje , Xantomatosis/metabolismoRESUMEN
PURPOSE OF REVIEW: Proprotein convertase subtilisin kexin type 9 (PCSK9) has emerged as a potential target for lowering plasma LDL cholesterol levels. This review summarizes recent studies published in print or online before January 2007 which have investigated the functional significance of this intriguing protease. RECENT FINDINGS: Increasing interest in PCSK9 has given rise to landmark epidemiological studies, the generation of animal models, the discovery of new human mutations, as well as numerous in-vitro studies. These studies have helped to unravel the molecular functions of PCSK9. SUMMARY: Mutations of PCSK9 are associated either with hypercholesterolemia or with hypocholesterolemia. In the latter case, the incidence of coronary heart disease is reduced, thereby demonstrating that low LDL cholesterol levels from birth are highly beneficial. PCSK9 promotes the degradation of the LDL receptor in hepatocytes apparently both intracellularly and by being a secreted protein that can bind the LDL receptor and be internalized. By virtue of its role as a major inhibitor of the LDL receptor, PCSK9 is a promising therapeutic target. Specific PCSK9 pharmacological inhibitors may prove to be useful in amplifying the well documented benefits of statins.
Asunto(s)
Serina Endopeptidasas/fisiología , Animales , Humanos , Hipercolesterolemia/genética , Hipercolesterolemia/metabolismo , Hipolipoproteinemias/genética , Hipolipoproteinemias/metabolismo , Lipoproteínas LDL/sangre , Modelos Biológicos , Mutación , Fenotipo , Polimorfismo Genético , Proproteína Convertasa 9 , Proproteína Convertasas , Estructura Terciaria de Proteína , Receptores de LDL/metabolismo , Serina Endopeptidasas/metabolismoRESUMEN
HDL promotes cholesterol efflux from peripheral cells via ABCA1 in the first step of reverse cholesterol transport (RCT). We investigated whether the early steps of RCT were disturbed in subjects with familial low HDL and an increased risk for early atherosclerosis. Cholesterol efflux from monocyte-derived macrophages to lipid-free apolipoprotein A-I (apoA-I; %) was measured in 22 patients with familial low HDL without Tangier disease mutations and in 21 healthy controls. In addition, we defined the different alleles of ABCA1 using single-nucleotide polymorphism haplotypes and measured ABCA1 and ABCG1 mRNA transcript levels in cholesterol-loaded macrophages. Similar ABCA1-mediated cholesterol efflux levels were observed for macrophages derived from control subjects and from low-HDL subjects. However, when efflux of cholesterol was estimated as cholesterol efflux to apoA-I (%)/relative ABCA1 mRNA expression level, cholesterol removal was significantly (P = 0.001) lower in the low-HDL group. Cholesterol-loaded macrophages from low-HDL subjects showed significantly increased levels of ABCA1 mRNA but not of ABCG1 mRNA and were more often carriers of the rare ABCA1 alleles L158 and R219K. These results suggest that defective ABCA1 function in cholesterol-loaded macrophages is one potential contributor to the impaired RCT process and the increased coronary heart disease risk in subjects with familial low HDL.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Colesterol/metabolismo , Lipoproteínas HDL/metabolismo , Polimorfismo Genético , Transportador 1 de Casete de Unión a ATP , Transportadoras de Casetes de Unión a ATP/metabolismo , Apolipoproteína A-I/metabolismo , Células Cultivadas , Femenino , Frecuencia de los Genes , Humanos , Hipolipoproteinemias/genética , Hipolipoproteinemias/metabolismo , Macrófagos/metabolismo , Masculino , Persona de Mediana Edad , Análisis Multivariante , ARN Mensajero/genética , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
OBJECTIVE: Reduced plasma concentrations of high-density lipoprotein-cholesterol (HDL-C) are a significant risk factor for cardiovascular disease. Mechanisms that regulate HDL-C concentrations represent an important area of investigation. METHODS AND RESULTS: Comparative transcriptome analyses of monocyte-derived macrophages (MDM) from a large population of low HDL-C subjects and age- and sex-matched controls revealed a cluster of inflammatory genes highly expressed in low HDL-C subjects. The expression levels of peroxisome proliferator activated receptor (PPAR) gamma and several antioxidant metallothionein genes were decreased in MDM from all low HDL-C groups compared with controls, as was the expression of other genes regulated by PPARgamma, including CD36, adipocyte fatty acid binding protein (FABP4), and adipophilin (ADFP). In contrast, PPARdelta expression was increased in MDM from low HDL-C groups. Quantitative RT-PCR corroborated all major findings from the microarray analysis in two separate patient cohorts. Expression of several inflammatory cytokine genes including interleukin 1beta, interleukin 8, and tumor necrosis factor alpha were highly increased in low HDL-C subjects. CONCLUSIONS: The activated proinflammatory state of monocytes and MDM in low HDL-C subjects constitutes a novel parameter of risk associated with HDL deficiency, related to altered expression of metallothionein genes and the reciprocal regulation of PPARgamma and PPARdelta.
Asunto(s)
HDL-Colesterol/deficiencia , Expresión Génica , Hipolipoproteinemias/sangre , Macrófagos/metabolismo , PPAR delta/genética , PPAR gamma/genética , ARN/genética , Aterosclerosis/sangre , Aterosclerosis/etiología , Biomarcadores/sangre , HDL-Colesterol/sangre , Proteínas de Unión a Ácidos Grasos/biosíntesis , Proteínas de Unión a Ácidos Grasos/genética , Genotipo , Humanos , Hipolipoproteinemias/complicaciones , Hipolipoproteinemias/genética , Interleucina-1beta/biosíntesis , Interleucina-1beta/genética , Interleucina-8/biosíntesis , Interleucina-8/genética , Proteínas de la Membrana/biosíntesis , Proteínas de la Membrana/genética , Análisis por Micromatrices , Mutación , PPAR delta/biosíntesis , PPAR gamma/biosíntesis , Perilipina-2 , Fenotipo , Reacción en Cadena de la Polimerasa , Factores de Riesgo , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
Proprotein convertase subtilisin-like kexin type 9 (PCSK9) is a newly discovered serine protease that destroys low density lipoprotein (LDL) receptors in liver and thereby controls the level of LDL in plasma. Mutations that increase PCSK9 activity cause hypercholesterolemia and coronary heart disease (CHD); mutations that inactivate PCSK9 have the opposite effect, lowering LDL levels and reducing CHD. Although the mechanism of PCSK9 action is not yet clear, the protease provides a new therapeutic target to lower plasma levels of LDL and prevent CHD.
Asunto(s)
LDL-Colesterol/metabolismo , Enfermedad Coronaria/genética , Hipolipoproteinemias/genética , Serina Endopeptidasas/genética , Enfermedad Coronaria/sangre , Enfermedad Coronaria/epidemiología , Variación Genética , Humanos , Biología Molecular , Proproteína Convertasa 9 , Proproteína ConvertasasRESUMEN
Cholesterol and its metabolites play a variety of essential roles in living systems. Virtually all animal cells require cholesterol, which they acquire through synthesis or uptake, but only the liver can degrade cholesterol. The ABCA1 gene product regulates the rate-controlling step in the removal of cellular cholesterol: the efflux of cellular cholesterol and phospholipids to an apolipoprotein acceptor. Mutations in ABCA1, as seen in Tangier disease, result in accumulation of cellular cholesterol, reduced plasma high-density lipoprotein cholesterol, and increased risk for coronary artery disease. To date, more than 100 coding variants have been identified in ABCA1, and these variants result in a broad spectrum of biochemical and clinical phenotypes. Here we review genetic variation in ABCA1 and its critical role in cholesterol metabolism and atherosclerosis in the general population.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Aterosclerosis/genética , HDL-Colesterol/sangre , Colesterol/metabolismo , Variación Genética , Hipolipoproteinemias/genética , Transportador 1 de Casete de Unión a ATP , Aterosclerosis/sangre , Aterosclerosis/metabolismo , Humanos , Hipolipoproteinemias/metabolismo , MutaciónRESUMEN
BACKGROUND: A low plasma level of low-density lipoprotein (LDL) cholesterol is associated with reduced risk of coronary heart disease (CHD), but the effect of lifelong reductions in plasma LDL cholesterol is not known. We examined the effect of DNA-sequence variations that reduce plasma levels of LDL cholesterol on the incidence of coronary events in a large population. METHODS: We compared the incidence of CHD (myocardial infarction, fatal CHD, or coronary revascularization) over a 15-year interval in the Atherosclerosis Risk in Communities study according to the presence or absence of sequence variants in the proprotein convertase subtilisin/kexin type 9 serine protease gene (PCSK9) that are associated with reduced plasma levels of LDL cholesterol. RESULTS: Of the 3363 black subjects examined, 2.6 percent had nonsense mutations in PCSK9; these mutations were associated with a 28 percent reduction in mean LDL cholesterol and an 88 percent reduction in the risk of CHD (P=0.008 for the reduction; hazard ratio, 0.11; 95 percent confidence interval, 0.02 to 0.81; P=0.03). Of the 9524 white subjects examined, 3.2 percent had a sequence variation in PCSK9 that was associated with a 15 percent reduction in LDL cholesterol and a 47 percent reduction in the risk of CHD (hazard ratio, 0.50; 95 percent confidence interval, 0.32 to 0.79; P=0.003). CONCLUSIONS: These data indicate that moderate lifelong reduction in the plasma level of LDL cholesterol is associated with a substantial reduction in the incidence of coronary events, even in populations with a high prevalence of non-lipid-related cardiovascular risk factors.
Asunto(s)
LDL-Colesterol/sangre , Codón sin Sentido , Enfermedad Coronaria/genética , Variación Genética , Hipolipoproteinemias/genética , Serina Endopeptidasas/genética , Población Negra/genética , Arterias Carótidas/anatomía & histología , Estudios de Cohortes , Enfermedad Coronaria/sangre , Enfermedad Coronaria/epidemiología , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Proproteína Convertasa 9 , Proproteína Convertasas , Riesgo , Estados Unidos , Población Blanca/genéticaAsunto(s)
LDL-Colesterol/sangre , Enfermedad Coronaria/genética , Hipolipoproteinemias/genética , Serina Endopeptidasas/genética , Animales , Codón sin Sentido , Enfermedad Coronaria/sangre , Regulación de la Expresión Génica , Variación Genética , Humanos , Hiperlipoproteinemia Tipo II/genética , Ratones , Mutación Missense , Proproteína Convertasa 9 , Proproteína Convertasas , Receptores de LDL/genética , Receptores de LDL/metabolismo , Serina Endopeptidasas/metabolismoRESUMEN
Monogenic high density lipoprotein (HDL) deficiency, because of defects in the genes of apolipoprotein A-I (apoA-I), adenosine triphosphate binding cassette transporter A1 (ABCA1) or lecithin:cholesterol acyltransferase (LCAT), can be assumed in patients with HDL cholesterol levels below the fifth percentile within a given population. As in a first step underlying diseases should be excluded. Patients with a virtual absence of HDL must undergo careful physical examination to unravel the clinical hallmarks of certain HDL deficiency syndromes. In addition, family studies should be initiated, to demonstrate the vertical transmission of the low HDL cholesterol phenotype. Definitive diagnosis requires specialized biochemical tests and the demonstration of a functionally-relevant mutation in one of the three discussed candidate genes. As yet no routinely used drug is able to increase HDL cholesterol levels in patients with familial low HDL cholesterol so that prevention of cardiovascular disease in these patients must be focused on the avoidance and treatment of additional risk factors.
Asunto(s)
Dislipidemias/genética , Dislipidemias/metabolismo , Hipolipoproteinemias/genética , Hipolipoproteinemias/metabolismo , HDL-Colesterol/sangre , HDL-Colesterol/deficiencia , HDL-Colesterol/genética , Diagnóstico Diferencial , Dislipidemias/sangre , Dislipidemias/patología , Humanos , Hipolipoproteinemias/sangre , Hipolipoproteinemias/patología , SíndromeRESUMEN
Familial hypobetalipoproteinemia (FHBL) is a co-dominant disorder either linked or not linked to apolipoprotein (apo) B gene. Abetalipoproteinemia (ABL) is a recessive disorder due to mutations of microsomal triglyceride transfer protein (MTP) gene. We investigated a patient with apparently recessive hypobetalipoproteinemia consistent with symptomatic heterozygous FHBL or a "mild" form of ABL. The proband had fatty liver associated with LDL-cholesterol (LDL-C) and apo B levels <5th percentile but no truncated apo B forms detectable in plasma. MTP gene sequence revealed that he was a carrier of the I128T polymorphism and an unreported amino acid substitution (V168I) unlikely to be the cause of hypobetalipoproteinemia. Apo B gene sequence showed that he was heterozygous for two single base substitutions in exon 9 and 22 resulting in a nonsense (Q294X) and a missense (R1101H) mutation, respectively. Neither of his parents carried the Q294X; his father and paternal grandmother carried the R1101H mutation. Analysis of polymorphic genetic markers excluded non-paternity. In conclusion, the proband has a "de novo" mutation of apo B gene resulting in a short truncated apo B form (apo B-6.46). Sporadic cases of FHBL with an apparently recessive transmission may be caused by "de novo" mutations of apo B gene.