Circulating miR-33a and miR-33b are up-regulated in familial hypercholesterolaemia in paediatric age

Abstract

Hypercholesterolaemia is one of the major causes of CVD (cardiovascular disease). It is associated with enhanced oxidative stress, leading to increased lipid peroxidation which in turn determines endothelial dysfunction and susceptibility to coronary vasoconstriction and atherosclerosis. Different miRNAs are involved in the pathogenesis of CVD and play an important role in inflammatory process control, therefore, together with atherogenic factors, they can stimulate atherosclerotic degeneration of the vessel walls of arteries. miR-33a and miR-33b play a pivotal role in a variety of biological processes including cholesterol homoeostasis, HDL (high-density lipoprotein)-cholesterol formation, fatty acid oxidation and insulin signalling. Our study aimed to determine whether circulating miR-33a and miR-33b expression was altered in familial hypercholesterolaemic children. Total RNA was extracted from plasma, and miR-33a and miR-33b were measured by quantitative real-time PCR. We found that miR-33a and miR-33b were significantly up-regulated in the plasma of 28 hypercholesterolaemic children compared with 25 healthy subjects (4.49±0.27-fold increase, P<0.001, and 3.21±0.39-fold increase, P<0.05 respectively), and for both miRNAs, a positive correlation with total cholesterol, LDL (low-density lipoprotein)-cholesterol, LDL-cholesterol/HDL-cholesterol ratio, apolipoprotein B, CRP (C-reactive protein) and glycaemia was found. OLS (ordinary least squares) regression analysis revealed that miR-33a was significantly affected by the presence of FH (familial hypercholesterolaemia), glycaemia and CRP (P<0.001, P<0.05 and P<0.05 respectively). The same analysis showed that miR-33b was significantly related to FH and CRP (P<0.05 and P<0.05 respectively). Although it is only explorative, the present study could be the first to point to the use of miR-33a and miR-33b as early biomarkers for cholesterol levels in childhood, once validated in independent larger cohorts.

miRNAs and High-Density Lipoprotein metabolism

“…Hence, the levels of miR-33a and/or miR-33b were shown to be increased in: i) human atherosclerotic plaques, compared to normal artery walls [45, 52]; ii) plasma from hypercholesterolemic children, compared to healthy controls [53]; and iii) plasma from obese children, compared to lean controls [54]. The caveat of these latter reports, however, is the small number of patients involved, and the very low levels of miR-33 in the circulation.…”

Novel Insights in the Metabolic Syndrome in Childhood and Adolescence

“…A large number of miRNAs were identified as intrinsic in the pathogenesis of insulin resistance by affecting pancreatic β-cell development, insulin biosynthesis, insulin secretion, or by interacting with insulin signaling pathways [81]. In addition, several miRNAs proved to be associated with endothelial dysfunction [83], serum lipid level alterations [78, 84, 85], inflammation [86], and other additional markers of metabolic dysfunction in children [85]. Interestingly, some miRNAs are enriched in the hypothalamus, suggesting a primary role in the hypothalamic regulation of energy intake, expenditure, and body weight control [87].…”

Clinical Significance of Determining Plasma MicroRNA33b in Type 2 Diabetic Patients with Dyslipidemia

“…Recently, plasma miR33a and miR33b had been reported to be significantly upregulated in familial hypercholesterolaemic children and both miRNAs had shown a positive correlation with LDL-C, LDL-C/HDL-C ratio, apolipoprotein B, CRP (C-reactive protein) and glycaemia 45) . Authors quoted the report which illustrated SREBP transcriptional increase in fibroblasts derived from patients with genetic FH 46) .…”

“…Authors quoted the report which illustrated SREBP transcriptional increase in fibroblasts derived from patients with genetic FH 46) . They hypothesized that the cholesterol content of hepatocytes in genetic FH participants is low, which should stimulate SREBP gene expression and, in turn, the expression of miR33a and miR33b 45) .…”

“…In this study, levels of miRNA33b, harbored within the SREBP-1c gene, were demonstrated to be upregulated in response to insulin stimulation 37, 44) . In other words, this has led to the concept that circulating miRNA33b could be useful as a biomarker for the detection of SREBP-1c expression in the liver 45, 47) . Second, selection of an optimal reference gene for the normalization of circulating miRNA levels is problematic; a universal reference gene has not yet been established.…”