Abstract
miR-33 and miR-122 are major regulators of lipid metabolism in the liver, and their deregulation has been linked to the development of metabolic diseases such as obesity and metabolic syndrome. However, the biological importance of these miRNAs has been defined using genetic models. The aim of this study was to evaluate whether the levels of miR-122 and miR-33a in rat liver correlate with lipemia in nutritional models. For this purpose, we analyzed the levels of miRNA-33a and miR-122 in the livers of dyslipidemic cafeteria diet-fed rats and of cafeteria diet-fed rats supplemented with proanthocyanidins and/or ω-3 PUFAs because these two dietary components are well-known to counteract dyslipidemia. The results showed that the dyslipidemia induced in rats that were fed a cafeteria diet resulted in the upregulation of miR-33a and miR-122 in the liver, whereas the presence of proanthocyanidins and/or ω-3 PUFAs counteracted the increase of these two miRNAs. However, srebp2, the host gene of miR-33a, was significantly repressed by ω-3 PUFAs but not by proanthocyanidins. Liver mRNA levels of the miR-122 and miR-33a target genes, fas and pparβ/δ, cpt1a and abca1, respectively, were consistent with the expression of these two miRNAs under each condition. Moreover, the miR-33a and abca1 levels were also analyzed in PBMCs. Interestingly, the miR-33a levels evaluated in PBMCs under each condition were similar to the liver levels but enhanced. This demonstrates that miR-33a is expressed in PBMCs and that these cells can be used as a non-invasive way to reflect the expression of this miRNA in the liver. These findings cast new light on the regulation of miR-33a and miR-122 in a dyslipidemic model of obese rats and the way these miRNAs are modulated by dietary components in the liver and in PBMCs.
Highlights
In the last decade, mi(cro)RNAs have emerged as a novel class of non-coding RNAs that are 20–25 nucleotides long and that regulate the expression of specific target genes at the posttranscriptional level, mainly by binding to the 39 untranslated region (39UTR) of target mRNAs
MiR-33 and miR-122 are known as major regulators of lipid metabolism in the liver, and their deregulation may contribute to the development of metabolic diseases such as obesity and metabolic syndrome [5,6]. miR-122 plays a critical role in liver homeostasis by regulating genes with key roles in the synthesis of triglycerides (TGs) and fatty acids (FAs), such as FA synthase (FAS) and sterol regulatory element-binding protein 1c (SREBP1c), as well as genes that regulate FA b-oxidation [7,8]
We analyzed liver miRNA-33a and miR-122 levels in dyslipidemic cafeteria diet(CD) fed rats and in rats fed a CD supplemented with proanthocyanidins and/or v-3 polyunsaturated fatty acids (PUFAs), two dietary components that are known to counteract dyslipidemia
Summary
Mi(cro)RNAs have emerged as a novel class of non-coding RNAs that are 20–25 nucleotides long and that regulate the expression of specific target genes at the posttranscriptional level, mainly by binding to the 39 untranslated region (39UTR) of target mRNAs. MiR-122 plays a critical role in liver homeostasis by regulating genes with key roles in the synthesis of triglycerides (TGs) and fatty acids (FAs), such as FA synthase (FAS) and sterol regulatory element-binding protein 1c (SREBP1c), as well as genes that regulate FA b-oxidation [7,8]. The silencing of miR33 by knockout or antisense techniques in mice results in an improvement in the plasma lipid profile, increasing plasma high density lipoprotein-cholesterol (HDL-C) levels [15,17,18]. The inhibition of miR-33 in African green monkeys increased hepatic abca expression and the HDL-C plasma levels and decreased plasma very low density lipoprotein (VLDL) levels [19]
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