RESUMO
Aim: Functional analysis of PCSK9 3'UTR variants and mRNA-miRNA interactions were explored in patients with familial hypercholesterolemia (FH). Materials & methods:PCSK9 3'UTR variants were identified by exon-targeted gene sequencing. Functional effects of 3'UTR variants and mRNA-miRNA interactions were analyzed using in silico and in vitro studies in HEK293FT and HepG2 cells. Results: Twelve PCSK9 3'UTR variants were detected in 88 FH patients. c.*75C >T and c.*345C >T disrupted interactions with miR-6875, miR-4721 and miR-564. Transient transfection of the c.*345C >T decreased luciferase activity in HEK293FT cells. miR-4721 and miR-564 mimics reduced PCSK9 expression in HepG2 cells. Conclusion:PCSK9 c.*345C >T has a possible role as loss-of-function variant. miR-4721 and miR-564 downregulate PCSK9 and may be useful to improve lipid profile in FH patients.
Assuntos
Hiperlipoproteinemia Tipo II/genética , MicroRNAs , Pró-Proteína Convertase 9/genética , RNA Mensageiro , Regiões 3' não Traduzidas , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Variação Genética , Células HEK293 , Células Hep G2 , Humanos , Hiperlipoproteinemia Tipo II/metabolismo , Masculino , Pessoa de Meia-Idade , Pró-Proteína Convertase 9/metabolismo , Adulto JovemRESUMO
Aim: To explore the association of circulating miRNAs with adiposity, metabolic status and inflammatory biomarkers in patients with metabolic syndrome (MetS). Methods: Serum levels of 372 miRNAs were measured in patients with (n = 6) and without MetS (n = 6) by quantitative PCR array, and dysregulated miRNAs were validated in a larger cohort (MetS, n = 89; non-MetS, n = 144). Results: In the screening study, seven miRNAs were dysregulated in patients with MetS, and miR-421 remained increased in the validation study. miR-421 was associated with a high risk of MetS and insulin resistance and hypertension and correlated with glycated hemoglobin, triacylglycerols, high-sensitivity CRP, IL-6, resistin and adiponectin (p < 0.05). Conclusion: Circulating miR-421 is a potential biomarker for insulin resistance, metabolic dysregulation and inflammatory status in patients with MetS.
Assuntos
Biomarcadores/sangue , Regulação da Expressão Gênica , Inflamação/patologia , Resistência à Insulina , Síndrome Metabólica/complicações , MicroRNAs/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína C-Reativa/análise , Feminino , Seguimentos , Humanos , Inflamação/sangue , Inflamação/etiologia , Masculino , MicroRNAs/sangue , Pessoa de Meia-Idade , Prognóstico , Resistina/sangue , Triglicerídeos/sangueRESUMO
ABSTRACT: To explore the association of circulating miRNAs with adiposity, metabolic status and inflammatory biomarkers in patients with metabolic syndrome (MetS). METHODS: Serum levels of 372 miRNAs were measured in patients with (n = 6) and without MetS (n = 6) by quantitative PCR array, and dysregulated miRNAs were validated in a larger cohort (MetS, n = 89; non-MetS, n = 144). RESULTS: In the screening study, seven miRNAs were dysregulated in patients with MetS, and miR-421 remained increased in the validation study. miR-421 was associated with a high risk of MetS and insulin resistance and hypertension and correlated with glycated hemoglobin, triacylglycerols, high-sensitivity CRP, IL-6, resistin and adiponectin (p < 0.05). CONCLUSION: Circulating miR-421 is a potential biomarker for insulin resistance, metabolic dysregulation and inflammatory status in patients with MetS.