RESUMO
Sitosterolemia is an autosomal recessive and very rare disease. Its main characteristic is that there is a greater absorption and a decrease in the excretion of sterols, which leads to them being deposited in tissues. It is given by mutations in the ABCG5 or ABCG8 genes found on chromosome 2p21. In this clinical note, we describe the first two patients with familial sitosterolemia described in Colombia, brothers, one of them with xanthomas in extremities as the only symptom, and the other, completely asymptomatic. Genetic studies were performed as a diagnostic test in both patients, where a pathogenic homozygous variant could be identified in the ABCG8 gene in the first case (symptomatic), and a heterozygous variant in the ABCG8 gene in the second case (asymptomatic); the first patient has responded to treatment with ezetimibe. In conclusion, xanthomas should be studied in depth in pediatric age as they may be the only visible sign of such complex and hereditary diseases as familial sitosterolemia, which can be controlled and prevent cardiovascular complications of the disease.
Assuntos
Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Ezetimiba , Hipercolesterolemia , Enteropatias , Erros Inatos do Metabolismo Lipídico , Fitosteróis , Humanos , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/diagnóstico , Masculino , Colômbia , Fitosteróis/efeitos adversos , Fitosteróis/genética , Enteropatias/genética , Enteropatias/diagnóstico , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Hipercolesterolemia/genética , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/diagnóstico , Ezetimiba/uso terapêutico , Xantomatose/genética , Xantomatose/patologia , Xantomatose/diagnóstico , Anticolesterolemiantes/uso terapêutico , Anticolesterolemiantes/administração & dosagem , Mutação , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Homozigoto , Criança , Heterozigoto , Lipoproteínas/genéticaRESUMO
INTRODUCTION: The fat mass and obesity-associated gene (FTO) is largely/primarily expressed in the hypothalamus. It plays a role in energy balance, regulation of food intake, and adipogenesis. According to metabolic phenotypes, studies have associated the FTO rs9939609 variant with body mass index (BMI), body fat mass, and dietary intake but not with serum lipids. This study aimed to analyze the association of the FTO rs9939609 variant with serum lipids in Mexican adults with different metabolic phenotypes. METHODS: We included 306 subjects aged 18-65 years, classified as normal weight or excess weight (EW) according to their BMI. EW included BMI from 25 to 39.9 kg/m2. Participants were classified into two metabolic phenotypes: metabolically healthy/metabolically unhealthy (MH/MUH). We use the homeostatic model assessment of insulin resistance and NCEP-ATP III cutoffs for glucose, triglycerides, high-density lipoprotein, and blood pressure. Subjects with ≥2 altered parameters were classified as MUH. The variant was determined by allelic discrimination with TaqMan® probes. RESULTS: In subjects with the A allele, significantly higher total cholesterol and low-density-lipoprotein cholesterol were found (p < 0.05). Furthermore, subjects with EW-MH and the AA or AT genotype had a significantly higher odds ratio for hypercholesterolemia (odds ratio 4.48, 95% confidence interval: 1.48-13.59, p = 0.008). CONCLUSION: The FTO rs9939609 variant may influence serum lipid concentrations, increasing the risk of hypercholesterolemia.
Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato , Hipercolesterolemia , Humanos , Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Hipercolesterolemia/genética , Voluntários Saudáveis , Índice de Massa Corporal , Aumento de Peso , TriglicerídeosRESUMO
The treatment of hypercholesterolemia is mainly based on statins. However, the response to pharmacological therapy shows high inter-individual variability, resulting in variable effects in both lipid lowering and risk reduction. Thus, a better understanding of the lipid-lowering mechanisms and response variability at the molecular level is required. Previously, we demonstrated a deregulation of the microRNA expression profile in HepG2 cells treated for 24 h with atorvastatin, using a microarray platform. In the present study, we evaluated the expression of hsa-miR-17-5p, hsa-miR-20a-5p and hsa-miR-106a-5p in hypercholesterolemic patients before and after atorvastatin treatment and in HepG2 cells treated for 24 h with atorvastatin The miRNA hsa-mir-20a-5p was repressed after atorvastatin treatment in hypercholesteremic subjects and in HepG2 cells in culture. Repression of hsa-mir-20a-5p increased LDLR gene and protein expression in HepG2 cells, while hsa-mir-20a-5p overexpression reduced LDLR gene and protein expression.
Assuntos
Atorvastatina , Inibidores de Hidroximetilglutaril-CoA Redutases , Hipercolesterolemia , MicroRNAs , Atorvastatina/farmacologia , Atorvastatina/uso terapêutico , Regulação para Baixo/genética , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/genética , MicroRNAs/efeitos dos fármacos , MicroRNAs/genética , MicroRNAs/metabolismoRESUMO
Background: Hyperuricemia is a pathological condition associated with risk factors of cardiovascular disease. In this study, three genetic polymorphisms were genotyped as predisposing factors of hyperuricemia. Methods: A total of 860 Mexicans between 18 and 25 years of age were genotyped for the ABCG2 (rs2231142), SLC22A12 (rs476037), and XDH (rs1042039) polymorphisms, as predisposing factors of hyperuricemia. Biochemical parameters were measured by spectrophotometry, while genetic polymorphisms were analyzed by real-time PCR. An analysis of the risk of hyperuricemia in relation to the variables studied was carried out using a logistic regression. Results: Male sex, being overweight or obese, having hypercholesterolemia or having hypertriglyceridemia were factors associated with hyperuricemia ( p ≤ 0.05). The ABCG2 polymorphism was associated with hyperuricemia (OR = 2.43, 95% CI: 1.41-4.17, p = 0.001) and hypercholesterolemia (OR = 4.89, 95% CI: 1.54-15.48, p = 0.003), employing a dominant model, but only in male participants. Conclusions: The ABCG2 (rs2231142) polymorphism increases the risk of hyperuricemia and hypercholesterolemia in young Mexican males.
Assuntos
Hipercolesterolemia , Hiperuricemia , Transportadores de Ânions Orgânicos , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Predisposição Genética para Doença , Humanos , Hipercolesterolemia/genética , Hiperuricemia/genética , Masculino , Proteínas de Neoplasias/genética , Transportadores de Ânions Orgânicos/genética , Proteínas de Transporte de Cátions Orgânicos/genética , Polimorfismo de Nucleotídeo Único , Ácido Úrico , Adulto JovemRESUMO
BACKGROUND: Statins are potent cholesterol-lowering drugs that prevent cardiovascular events. microRNAs (miRNAs) modulate the expression of genes involved in metabolic pathways and cardiovascular functions post-transcriptionally. This study explored the effects of statins on the expression of miRNAs and their target genes involved in lipid metabolism in HepG2 cells. METHODS: HepG2 cells were treated with atorvastatin or simvastatin (0.1-10 µM) for 24 h. The expression of 84 miRNAs and nine target genes, selected by in silico studies, was measured by qPCR Array and TaqMan-qPCR, respectively. RESULTS: Five miRNAs were upregulated (miR-129, miR-143, miR-205, miR-381 and miR-495) and two downregulated (miR-29b and miR-33a) in atorvastatin-treated HepG2 cells. Simvastatin also downregulated miR-33a expression. Both statins upregulated LDLR, HMGCR, LRP1, and ABCG1, and downregulated FDFT1 and ABCB1, whereas only atorvastatin increased SCAP mRNA levels. In silico analysis of miRNA-mRNA interactions revealed a single network with six miRNAs modulating genes involved in lipogenesis and lipid metabolism. The statin-dysregulated miRNAs were predicted to target genes involved in cellular development and differentiation, regulation of metabolic process and expression of genes involved in inflammation, and lipid metabolism disorders contributing to metabolic and liver diseases. CONCLUSIONS: Atorvastatin-mediated miR-129, miR-143, miR-205, miR-381, and miR-495 upregulation, and miR-29b, and miR-33a downregulation, modulate the expression of target genes involved in lipogenesis and lipid metabolism. Thus, statins may prevent hepatic lipid accumulation and ameliorate dyslipidemia.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , MicroRNAs/genética , Anticolesterolemiantes/farmacologia , Atorvastatina/farmacologia , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Células Hep G2 , Humanos , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/genética , Fígado/efeitos dos fármacos , RNA Mensageiro/genética , Sinvastatina/farmacologia , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genéticaRESUMO
Although the benefits of moderate intake of red wine in decreasing incidence of cardiovascular diseases associated to hypercholesterolemia are well recognized, there are still widespread misconceptions about its effects on the hypercholesterolemia-related cognitive impairments. Herein we investigated the putative benefits of regular red wine consumption on cognitive performance of low-density lipoprotein receptor knockout (LDLr-/-) mice, an animal model of familial hypercholesterolemia, which display cognitive impairments since early ages. The red wine was diluted into the drinking water to a final concentration of 6% ethanol and was available for 60 days for LDLr-/- mice fed a normal or high-cholesterol diet. The results indicated that moderate red wine consumption did not alter locomotor parameters and liver toxicity. Across multiple cognitive tasks evaluating spatial learning/reference memory and recognition/identification memory, hypercholesterolemic mice drinking red wine performed significantly better than water group, regardless of diet. Additionally, immunofluorescence assays indicated a reduction of astrocyte activation and lectin stain in the hippocampus of LDLr-/- mice under consumption of red wine. These findings demonstrate that the moderate consumption of red wine attenuates short- and long-term memory decline associated with hypercholesterolemia in mice and suggest that it could be through a neurovascular action.
Assuntos
Disfunção Cognitiva/etiologia , Disfunção Cognitiva/prevenção & controle , Hipercolesterolemia/complicações , Receptores de LDL/fisiologia , Vinho , Animais , Comportamento Animal , Encéfalo/irrigação sanguínea , Colesterol na Dieta/administração & dosagem , Modelos Animais de Doenças , Hipocampo/fisiopatologia , Hipercolesterolemia/genética , Hipercolesterolemia/fisiopatologia , Hepatopatias Alcoólicas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora , Receptores de LDL/deficiência , Receptores de LDL/genéticaRESUMO
Interleukin 37 (IL-37) is an anti-inflammatory cytokine involved in the regulation of cholesterol homeostasis, reducing the levels of plasma cholesterol, fatty acids, and triglycerides. The aim of the present study was to evaluate the association of the IL-37 polymorphisms with the presence of hypercholesterolemia (HC), and with cardiovascular risk factors. Nine IL-37 polymorphisms (rs2708965, rs2708962, rs6717710, rs2708961, rs2708960, rs2708958, rs2723187, rs2708947, and rs2723192) were determined by TaqMan assays in a group of 1292 individuals (514 with and 778 without hypercholesterolemia) belonging to the cohort of the GEA Mexican Study. The associations were evaluated by logistic regression, using inheritance models adjusted by confounding variables. Under codominant 1 model, the rs2708961 (OR = 0.51, p = 0.02), rs2723187 (OR = 0.35, p = 0.005), and rs2708947 (OR = 0.49, p = 0.02) polymorphisms were associated with low risk of HC. The association of the polymorphisms with cardiovascular risk factors was evaluated independently in HC and non-HC individuals. In non-HC individuals, some polymorphisms were associated with the risk of having high levels of LDL-C, glucose, and high risk of T2DM, and low risk of having high visceral abdominal fat. On the other hand, in individuals with HC five, polymorphisms were associated with high levels of C-reactive protein. The IL-37 rs2708961, rs2723187, rs2708947 polymorphisms were associated with low risk of HC, and some IL-37 polymorphisms were associated with cardiometabolic factors in both individuals with and without HC.
Assuntos
Doenças Cardiovasculares/genética , Hipercolesterolemia/genética , Interleucina-1/genética , Modelos Genéticos , Polimorfismo Genético , Adulto , Feminino , Humanos , Masculino , México , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
Effects of statins over clinical changes in Alzheimer's disease (AD) are usually non-significant, but epistatic interactions between genetic variants involved in cholesterol metabolism could be important for such effects. We aimed to investigate whether LDLR single-nucleotide polymorphisms rs11669576 (LDLR8), rs5930 (LDLR10), and rs5925 (LDLR13) are associated with cognitive and functional changes in AD, while also considering APOE haplotypes and lipid-lowering treatment with lipophilic statins for stratification. Consecutive outpatients with late-onset AD were screened with cognitive tests, while caregivers scored functionality and caregiver burden, with prospective neurotranslational correlations documented for 1 year. For 179 patients, minor allele frequencies were 0.078 for rs11669576-A (14.5% heterozygotes), 0.346 for rs5930-A (42.5% heterozygotes), and 0.444 for rs5925-C (56.4% heterozygotes), all in Hardy-Weinberg equilibrium; 134 patients had hypercholesterolemia, and 133 used lipophilic statins. Carriers of rs11669576-G had faster cognitive decline, while functional decline was slower for carriers of rs11669576-A who used lipophilic statins. APOE-ε4 carriers who also carried rs5930-AA had improved caregiver burden, while carriers of haplotypes that included rs5930-AG had worse cognitive and functional outcomes, though carriers of the A allele of rs5930 had better cognitive and functional response to lipophilic statins. APOE-ε4 non-carriers who carried rs5925-TT had slower cognitive decline, while lipophilic statins protected carriers of the other genotypes. We preliminarily conclude that reportedly protective variants of LDLR and APOE against risk of AD also slowed cognitive decline, regardless of cholesterol variations, while therapy with lipophilic statins might benefit carriers of specific genetic variants.
Assuntos
Doença de Alzheimer/genética , Apolipoproteínas E/genética , Cognição , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/genética , Polimorfismo de Nucleotídeo Único , Receptores de LDL/genética , Idoso , Idoso de 80 Anos ou mais , Epistasia Genética , Feminino , Haplótipos , Heterozigoto , Humanos , Hipercolesterolemia/tratamento farmacológico , Masculino , Resultado do TratamentoRESUMO
BACKGROUND: Cholesterol is related to improvements in the rate of sustained virological response and a robust immune response against the hepatitis C virus (HCV). APOE gene polymorphisms regulate cholesterol levels modifying the course of the HCV infection. The relationship between cholesterol, APOE alleles, and the outcome of HCV infection has not been evaluated in the admixed population of Mexico. AIM: To investigate the role of APOE -ε2, -ε3, and -ε4 alleles and the metabolic profile in the outcome of HCV infection. METHODS: A total of 299 treatment-naïve HCV patients were included in this retrospective study. Patients were stratified in chronic hepatitis C (CHC) (n = 206) and spontaneous clearance (SC) (n = 93). A clinical record was registered. Biochemical tests were assessed by dry chemistry assay. APOE genotypes were determined using a Real-Time polymerase chain reaction assay. RESULTS: Total cholesterol, low-density lipoprotein cholesterol (LDL-c), triglycerides, and hypercholesterolemia were higher in SC than CHC patients as well as the frequency of the APOE ε4 allele (12.4% vs 7.3%). SC patients were overweight (54.8%). The ε4 allele was associated with SC (OR = 0.55, 95%CI: 0.31-0.98, P = 0.042) and mild fibrosis (F1-F2) in CHC patients (OR 0.091, 95%CI 0.01-0.75, P = 0.020). LDL-c ≥ 101.5 mg/dL (OR = 0.20, 95%CI: 0.10-0.41, P < 0.001) and BMI ≥ 26.6 kg/m2 (OR= 0.37, 95%CI: 0.18-0.76, P < 0.001) were associated with SC status; while ALT ≥ 50.5 IU/L was negatively associated (OR = 5.67, 95%CI: 2.69-11.97, P < 0.001). CONCLUSION: In SC patients, the APOE ε4 allele and LDL-c conferred a protective effect in the course of the HCV infection in the context of excess body weight.