RESUMO
BACKGROUND: Lecithin-cholesterol acyltransferase (LCAT) is a plasma enzyme that esterifies cholesterol in high- and low-density lipoproteins (HDL and LDL). Mutations in LCAT gene causes familial LCAT deficiency, which is characterized by very low plasma HDL-cholesterol levels (Hypoalphalipoproteinemia), corneal opacity and anemia, among other lipid-related traits. Our aim is to evaluate clinical/biochemical features of a Chilean family with a proband showing clinical signs of familial LCAT deficiency, as well as to identify and assess the functional effects of LCAT mutations. METHODS: An adult female proband with hypoalphalipoproteinemia, corneal opacity and mild anemia, as well as her first-degree relatives, were recruited for clinical, biochemical, genetic, in-silico and in-vitro LCAT analysis. Sequencing of exons and intron-exon boundaries was performed to identify mutations. Site-directed mutagenesis was carried out to generate plasmids containing cDNA with wild type or mutant sequences. Such expression vectors were transfected to HEK-239 T cells to asses the effect of LCAT variants in expression, synthesis, secretion and enzyme activity. In-silico prediction analysis and molecular modeling was also used to evaluate the effect of LCAT variants. RESULTS: LCAT sequencing identified rare p.V333 M and p.M404 V missense mutations in compound heterozygous state in the proband, as well the common synonymous p.L363 L variant. LCAT protein was detected in proband's plasma, but with undetectable enzyme activity compared to control relatives. HEK-293 T transfected cells with vector expression plasmids containing either p.M404 V or p.V333 M cDNA showed detectable LCAT protein expression both in supernatants and lysates from cultured cells, but with much lower enzyme activity compared to cells transfected with the wild-type sequence. Bioinformatic analyses also supported a causal role of such rare variations in LCAT lack of function. Additionally, the proband carried the minor allele of the synonymous p.L363 L variant. However, this variant is unlikely to affect the clinical phenotype of the proband given its relatively high frequency in the Chilean population (4%) and its small putative effect on plasma HDL-cholesterol levels. CONCLUSION: Genetic, biochemical, in vitro and in silico analyses indicate that the rare mutations p.M404 V and p.V333 M in LCAT gene lead to suppression of LCAT enzyme activity and cause clinical features of familial LCAT deficiency.
Assuntos
Hipoalfalipoproteinemias/genética , Deficiência da Lecitina Colesterol Aciltransferase/genética , Lipídeos/sangue , Fosfatidilcolina-Esterol O-Aciltransferase/genética , Adulto , Idoso , Chile/epidemiologia , Colesterol/sangue , HDL-Colesterol/sangue , Opacidade da Córnea/genética , Opacidade da Córnea/patologia , Éxons/genética , Feminino , Células HEK293 , Humanos , Hipoalfalipoproteinemias/sangue , Hipoalfalipoproteinemias/epidemiologia , Hipoalfalipoproteinemias/patologia , Deficiência da Lecitina Colesterol Aciltransferase/sangue , Deficiência da Lecitina Colesterol Aciltransferase/epidemiologia , Deficiência da Lecitina Colesterol Aciltransferase/patologia , Lipoproteínas HDL/sangue , Simulação de Dinâmica Molecular , Mutação de Sentido Incorreto/genética , Linhagem , Fosfatidilcolina-Esterol O-Aciltransferase/química , Relação Estrutura-AtividadeRESUMO
BACKGROUND/OBJECTIVES: Abdominal obesity (AO) is associated with elevated risk for cardiovascular diseases; however, this association is less clear for non-obese people. We estimated the association of AO and cardiovascular risk factors (CVRF) and disease in non-obese adult individuals from Chile. SUBJECTS/METHODS: 5248 adults (15 years of age or older) of both sexes from the Chilean National Health Survey (October 2009 -September 2010, response rate 85%.) were included. Information on myocardial infarction and stroke was self-reported. BMI, waist circumference (WC), arterial pressure, plasma glucose, and cholesterol levels were measured. Predictive accuracy of WC was evaluated by area under curve of receiver operating characteristic analysis and cut off points were established by Youden Index. Relationship between AO and CVRF was analyzed by Chi-squared tests. RESULTS: Normal weight/overweight/obesity were present in 34.4%/45.2%/18.1% of men and 33.4%/33.6%/27.5% of women. Predictive accuracy of WC to identify at least one CVRF was 0.70/0.67 and optimal cutoff points for WC in non-obese subjects were 91/83 cm in men/women, respectively. AO was present in 98.2%/99.1% of obese, 70.5%/77.4% of overweight and 12.4%/16.4% of normal weight men/women. AO was associated with increased frequency of CVRF in overweight men (6/8 and stroke) and women (4/8) and higher frequency in normal weight men (8/8 and myocardial infarction/stroke) and women (6/8 and myocardial infarction). CONCLUSIONS: WC cutoff points calculated for non-obese chilean population discriminate more differences in CVRF in normal weight woman. AO significantly increases the frequency of CVRF and diseases in overweight and especially normal weight individuals. WC can be used as a low cost, feasible and reproducible predictor for CVRF in non-obese individuals in most clinical settings.
Assuntos
Doenças Cardiovasculares/etiologia , Obesidade Abdominal/complicações , Sobrepeso/complicações , Adulto , Área Sob a Curva , Glicemia/análise , Índice de Massa Corporal , Chile , Colesterol/sangue , Estudos Transversais , Feminino , Inquéritos Epidemiológicos , Humanos , Masculino , Obesidade Abdominal/diagnóstico , Sobrepeso/diagnóstico , Curva ROC , Fatores de Risco , Circunferência da CinturaRESUMO
RESUMEN El huevo es un alimento altamente nutritivo con potenciales beneficios para la salud. Sin embargo, debido a su elevado contenido de colesterol, su consumo ha sido restringido en la población general. El objetivo de esta revisión es difundir en la comunidad científica la evidencia más reciente sobre los efectos del consumo de huevo específicamente en sujetos con diabetes mellitus. Estudios observacionales muestran que el consumo de hasta un huevo al día no se asocia a una mayor prevalencia de enfermedad cardiovascular en la población general, pero podría aumentar el riesgo entre los diabéticos. Asimismo, algunos de estos estudios han mostrado que un elevado consumo de huevo se asocia a un aumento en la incidencia de diabetes en la población general. Por otro lado, estudios de intervención a corto plazo en este subgrupo muestra que el consumo de huevo no afecta negativamente los factores de riesgo cardiovascular ni control glicémico en estos pacientes. Además, su consumo podría aumentar el impacto del uso de dietas hipocalóricas en la disminución de peso corporal, una importante herramienta en el manejo médico de la diabetes.
ABSTRACT Eggs are a highly nutritious food with potential health benefits. However, because of its high cholesterol content, physicians have recommended consumption restrictions in the general population. The aim of this review is to update the scientific community on the latest research about the impact of egg consumption in subjects with diabetes mellitus. Although several observational studies show that an intake of one egg a day does not increase cardiovascular risk in the general population, however risk may increase among diabetics. Additionally, some prospective cohorts have associated associated higher egg intake with an increased diabetes incidence in the general population. On the other hand, short-term intervention studies have not shown any adverse outcome in terms of cardiovascular risk or glycemic control with egg intake. Moreover, there are studies that suggest a beneficial effect of egg consumption in weight reduction, an important therapeutic tool in diabetes management.
Assuntos
Humanos , Doenças Cardiovasculares , Ingestão de Alimentos , Diabetes Mellitus , OvosRESUMO
BACKGROUND: Diabetes mellitus (DM) is a recognized atherosclerotic cardiovascular disease (ACVD) risk factor. This association has yet to be quantified in the Chilean population. AIM: To compare the frequency of ACVD between diabetic and non-diabetic Chilean subjects. MATERIAL AND METHODS: Data was extracted from the Chile National Health Survey (ENS) performed in 2009-2010. DM diagnosis was made with fasting glucose. ACVD (coronary, cerebral and peripheral vascular disease) was established by self-report. Major cardiovascular risk factors were identified by clinical and laboratory assessment. RESULTS: A total of 5,416 adults (2,200 men and 3,216 women) were surveyed in ENS 2009-2010. Of these, 508 were diabetic and 375 reported ACVD. ACVD frequency was 16.1% and 6.1% in diabetic and non-diabetic subjects, respectively. In diabetic men, the frequency of ACVD steadily increased with age, from 5.1% to 22.1%. In diabetic women, the highest frequency of ACVD (17.4%) was found in ages ranging from 45 to 54 years. In people younger than 54 years, the odds ratio for ACVD in diabetic compared to non-diabetic subjects, was 3.59 in men (χ2 = 4.03 p < 0.03) and 5.26 in women (χ2 = 7.7 p < 0.007). Cardiovascular risk factors and metabolic syndrome were significantly more common in diabetic subjects with reported ACVD. CONCLUSIONS: DM is associated with an increased frequency of ACVD and cardiovascular risk factors in Chilean adults. In line with international reports, our findings suggest that DM is also a cardiovascular risk factor in Chile, particularly relevant for women.
Assuntos
Glicemia/análise , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus/epidemiologia , Adulto , Idoso , Doenças Cardiovasculares/etiologia , Chile/epidemiologia , Estudos Transversais , Jejum , Feminino , Inquéritos Epidemiológicos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , AutorrelatoRESUMO
Atherosclerotic heart disease and stroke are leading causes of disability and death worldwide, affecting not only developed countries, but also low- and middle-income regions. Different strategies for handling dyslipidemia as a critical pathogenic risk factor for atherosclerosis have been proposed. However, these recommendations are not applied at all in many countries or even in whole regions of the world. Recently, new US guidelines on risk assessment, lifestyle changes, and high blood cholesterol level treatment to manage atherosclerotic disease were released. In this article, we analyze these new guidelines and discuss their potential applications in preventive cardiovascular medicine in Latin America.
Assuntos
Aterosclerose/terapia , Estilo de Vida , Guias de Prática Clínica como Assunto , Acidente Vascular Cerebral/terapia , Animais , Aterosclerose/diagnóstico , Humanos , Medição de Risco , América do Sul , Acidente Vascular Cerebral/diagnósticoRESUMO
Background: Diabetes mellitus (DM) is a recognized atherosclerotic cardiovascular disease (ACVD) risk factor. This association has yet to be quantified in the Chilean population. Aim: To compare the frequency of ACVD between diabetic and non-diabetic Chilean subjects. Material and Methods: Data was extracted from the Chile National Health Survey (ENS) performed in 2009-2010. DM diagnosis was made with fasting glucose. ACVD (coronary, cerebral and peripheral vascular disease) was established by self-report. Major cardiovascular risk factors were identified by clinical and laboratory assessment. Results: A total of 5,416 adults (2,200 men and 3,216 women) were surveyed in ENS 2009-2010. Of these, 508 were diabetic and 375 reported ACVD. ACVD frequency was 16.1% and 6.1% in diabetic and non-diabetic subjects, respectively. In diabetic men, the frequency of ACVD steadily increased with age, from 5.1% to 22.1%. In diabetic women, the highest frequency of ACVD (17.4%) was found in ages ranging from 45 to 54 years. In people younger than 54 years, the odds ratio for ACVD in diabetic compared to non-diabetic subjects, was 3.59 in men (χ2 = 4.03 p < 0.03) and 5.26 in women (χ2 = 7.7 p < 0.007). Cardiovascular risk factors and metabolic syndrome were significantly more common in diabetic subjects with reported ACVD. Conclusions: DM is associated with an increased frequency of ACVD and cardiovascular risk factors in Chilean adults. In line with international reports, our findings suggest that DM is also a cardiovascular risk factor in Chile, particularly relevant for women.
Assuntos
Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Glicemia/análise , Doenças Cardiovasculares/epidemiologia , Diabetes Mellitus/epidemiologia , Doenças Cardiovasculares/etiologia , Chile/epidemiologia , Estudos Transversais , Jejum , Inquéritos Epidemiológicos , Fatores de Risco , AutorrelatoRESUMO
Cholesterol has evolved to fulfill sophisticated biophysical, cell signaling and endocrine requirements of animal systems. At a cellular level, cholesterol is found in membranes, where it increases both bilayer stiffness and impermeability to water and ions. Furthermore, cholesterol is integrated into specialized lipid-protein membrane microdomains with critical topographical and signaling functions. At an organismal level, cholesterol is the precursor for all steroid hormones, including gluco- and mineralo-corticoids, sex hormones and vitamin D, all of which regulate carbohydrate, sodium, reproductive and bone homeostasis, respectively. This sterol is also the precursor for bile acids, which are important for intestinal absorption of dietary lipids as well as energy and glucose metabolic regulation. Importantly, complex mechanisms maintain cholesterol within physiological ranges and the disregulation of these mechanisms results in embryonic or adult diseases, caused by either excessive or reduced tissue cholesterol levels. The causative role of cholesterol in these diseases has been demonstrated by diverse genetic and pharmacologic animal models that are commented in this review.
Assuntos
Colesterol/fisiologia , Aterosclerose/fisiopatologia , Transporte Biológico , Colesterol/biossíntese , Colesterol/metabolismo , Desenvolvimento Fetal/fisiologia , HumanosRESUMO
Cholesterol has evolved to fulfill sophisticated biophysical, cell signalling, and endocrine functions in animal systems. At the cellular level, cholesterol is found in membranes where it increases both bilayer stiffness and impermeability to water and ions. Furthermore, cholesterol is integrated into specialized lipid-protein membrane microdomains with critical topographical and signalling functions. At the organismal level, cholesterol is the precursor of all steroid hormones, including gluco- and mineralo-corticoids, sex hormones, and vitamin D, which regulate carbohydrate, sodium, reproductive, and bone homeostasis, respectively. This sterol is also the immediate precursor of bile acids, which are important for intestinal absorption of dietary lipids as well as energy homeostasis and glucose regulation. Complex mechanisms maintain cholesterol within physiological ranges and the dysregulation of these mechanisms results in embryonic or adult diseases, caused by either excessive or reduced tissue cholesterol levels. The causative role of cholesterol in these conditions has been demonstrated by genetic and pharmacological manipulations in animal models of human disease that are discussed herein. Importantly, the understanding of basic aspects of cholesterol biology has led to the development of high-impact pharmaceutical therapies during the past century. The continuing effort to offer successful treatments for prevalent cholesterol-related diseases, such as atherosclerosis and neurodegenerative disorders, warrants further interdisciplinary research in the coming decades.
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Background: In December 1985, the Nobel Prize of Medicine was awarded to Drs. Joseph L. Goldstein and Michael S. Brown for their fundamental scientific work on the regulation of cholesterol metabolism mediated by the low density lipoprotein receptor pathway. This article briefly reviews the academic and research accomplishments of Drs. Brown and Goldstein as a tribute to these physician-scientists for their well-deserved award and enormous contribution to biomedical science worldwide.
Assuntos
História do Século XX , Colesterol/metabolismo , Colesterol/história , Prêmio NobelRESUMO
In December 1985, the Nobel Prize of Medicine was awarded to Drs. Joseph L. Goldstein and Michael S. Brown for their fundamental scientific work on the regulation of cholesterol metabolism mediated by the low density lipoprotein receptor pathway. This article briefly reviews the academic and research accomplishments of Drs. Brown and Goldstein as a tribute to these physician-scientists for their well-deserved award and enormous contribution to biomedical science worldwide.