miR-467 regulates inflammation and blood insulin and glucose
inflammation; insulin resistance; macrophages; microRNA/miR-467a-5p
Obesity is associated with inflammation and insulin resistance (IR), but the regulation of insulin sensitivity (IS) and connections between IS and inflammation remain unclear. We investigated the role of miR-467a-5p, a miRNA induced by hyperglycaemia, in regulating inflammation and blood glucose handling. We previously demonstrated that miR-467a-5p is induced by hyperglycaemia and inhibits the production of thrombospondin-1 (TSP-1), a protein implicated in regulating inflammation. To investigate the role of miR-467 in blood glucose handling and tissue inflammation, WT C57BL/6 mice were fed chow or Western diet from 5 to 32 weeks of age and injected weekly with miR-467a-5p antagonist. Inhibiting miR-467a-5p resulted in 47% increase in macrophage infiltration and increased Il6 levels in adipose tissue, higher plasma insulin levels (98 ng/mL vs 63 ng/mL), and 17% decrease in glucose clearance without increase in weight or HDL/LDL. The antagonist effect was lost in mice on Western diet. Mice lacking TSP-1 lost some but not all of the miR-467 effects, suggesting Thbs1 (and other unknown transcripts) are targeted by miR-467 to regulate inflammation. miR-467a-5p provides a physiological feedback when blood glucose is elevated to avoid inflammation and increased blood glucose and insulin levels, which may prevent IR.
Gajeton J; Krukovets I; Yendamuri R; Verbovetskiy D; Vasanji A; Sul L; Stenina-Adognravi O
Journal Of Cellular And Molecular Medicine
journalArticle
<a href="http://doi.org/10.1111/jcmm.16224" target="_blank" rel="noreferrer noopener">10.1111/jcmm.16224</a>
miR-145 is differentially regulated by TGF-ss 1 and ischaemia and targets Disabled-2 expression and wnt/ss-catenin activity
gene-expression; Myocardial infarction; Cell Biology; Myocardial infarction; Research & Experimental Medicine; stem-cells; binding; pathway; cytokines; growth factors; c-myc; cell-differentiation; dab2; epithelial ovarian-cancer; myosin-vi; nasopharyngeal carcinoma
The effect of wnt/beta-catenin signalling in the response to acute myocardial infarction (AMI) remains controversial. The membrane receptor adaptor protein Disabled-2 (Dab2) is a tumour suppressor protein and has a critical role in stem cell specification. We recently demonstrated that down-regulation of Dab2 regulates cardiac protein expression and wnt/beta-catenin activity in mesenchymal stem cells (MSC) in response to transforming growth factor-beta 1 (TGF-beta 1). Although Dab2 expression has been shown to have effects in stem cells and tumour suppression, the molecular mechanisms regulating this expression are still undefined. We identified putative binding sites for miR-145 in the 3'-UTR of Dab2. In MSC in culture, we observed that TGF-beta 1 treatment led to rapid and sustained up-regulation of primiR-145. Through gain and loss of function studies we demonstrate that miR-145 up-regulation was required for the down-regulation of Dab2 and increased beta-catenin activity in response to TGF-beta 1. To begin to define how Dab2 might regulate wnt/beta-catenin in the heart following AMI, we quantified myocardial Dab2 as a function of time after left anterior descending ligation. There was no significant Dab2 expression in sham-operated myocardium. Following AMI, Dab2 levels were rapidly up-regulated in cardiac myocytes in the infarct border zone. The increase in cardiac myocyte Dab2 expression correlated with the rapid and sustained down-regulation of myocardial primiR-145 expression following AMI. Our data demonstrate a novel and critical role for miR-145 expression as a regulator of Dab2 expression and beta-catenin activity in response to TGF-beta 1 and hypoxia.
Mayorga M E; Penn M S
Journal of Cellular and Molecular Medicine
2012
2012-05
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1111/j.1582-4934.2011.01385.x" target="_blank" rel="noreferrer noopener">10.1111/j.1582-4934.2011.01385.x</a>