Article

MicroRNA 144 Impairs Insulin Signaling by Inhibiting the Expression of Insulin Receptor Substrate 1 in Type 2 Diabetes Mellitus

University of Barcelona, Spain
PLoS ONE (Impact Factor: 3.53). 08/2011; 6(8):e22839. DOI: 10.1371/journal.pone.0022839
Source: PubMed

ABSTRACT Dysregulation of microRNA (miRNA) expression in various tissues and body fluids has been demonstrated to be associated with several diseases, including Type 2 Diabetes mellitus (T2D). Here, we compare miRNA expression profiles in different tissues (pancreas, liver, adipose and skeletal muscle) as well as in blood samples from T2D rat model and highlight the potential of circulating miRNAs as biomarkers of T2D. In parallel, we have examined the expression profiles of miRNAs in blood samples from Impaired Fasting Glucose (IFG) and T2D male patients.
Employing miRNA microarray and stem-loop real-time RT-PCR, we identify four novel miRNAs, miR-144, miR-146a, miR-150 and miR-182 in addition to four previously reported diabetes-related miRNAs, miR-192, miR-29a, miR-30d and miR-320a, as potential signature miRNAs that distinguished IFG and T2D. Of these microRNAs, miR-144 that promotes erythropoiesis has been found to be highly up-regulated. Increased circulating level of miR-144 has been found to correlate with down-regulation of its predicted target, insulin receptor substrate 1 (IRS1) at both mRNA and protein levels. We could also experimentally demonstrate that IRS1 is indeed the target of miR-144.
We demonstrate that peripheral blood microRNAs can be developed as unique biomarkers that are reflective and predictive of metabolic health and disorder. We have also identified signature miRNAs which could possibly explain the pathogenesis of T2D and the significance of miR-144 in insulin signaling.

0 Followers
 · 
103 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: To analyse regulatory microRNA(s) leading to increased TLR2 expression in livers of high-fat-diet induced metabolic syndrome (HFD-MetS) in rats with non-alcoholic steatohepatitis (NASH). TLRs, inflammatory cytokines, candidate miRNAs targeting key TLR and its cellular localization were determined in liver. The miR-144 targeting TLR2 and regulating TLR2 signaling were further determined by Dual Luciferase Reporter Assay and miR-144 mimics or inhibitor. Expression of miR-144 was negatively correlated with TLR2 expression in Kupffer cells. The miR-144 bound to 3'UTR of rat TLR2 mRNA. In addition, compared to control group, TLR2, TNF-α, IFN-γ and activation of NF-κB decreased after miR-144 mimic challenge in NR8383 cells and BMM from E3 rats,which could be compensated by Pam3CSK4; while opposite effects on their expressions were observed after miR-144 inhibitor administration, augmented by Pam3CSK4. Decreased miR-144 could enhance TNF-α and IFN-γ production by targeting TLR2 in vitro, and might contribute to TLR2 up-regulation and the progression of NASH in HFD-MetS E3 rats. This might offer a novel and potential target for NASH therapy. Copyright © 2014. Published by Elsevier Ireland Ltd.
    Molecular and Cellular Endocrinology 12/2014; 402. DOI:10.1016/j.mce.2014.12.007 · 4.24 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: MicroRNAs (miRNAs) are a class of endogenous small non-coding RNAs that have been found highly conserved among species. MiRNAs are able to negatively regulate gene expression through base pairing of 3¿ UTRs of their target genes. Therefore, miRNAs have been shown to play an important role in regulating various cellular activities. Over the past decade, substantial evidences have been obtained to show that miRNAs are aberrantly expressed in human malignancies and could act as ¿OncomiRs¿ or ¿Tumor suppressor miRs¿. In recent years, increasing number of studies have demonstrated the involvement of miRNAs in cancer metastasis. Many studies have shown that microRNAs could directly target genes playing a central role in epithelia-mesenchymal-transition (EMT), a cellular transformation process that allows cancer cells to acquire motility and invasiveness. EMT is considered an essential step driving the early phase of cancer metastasis. This review will summarize the recent findings and characterization of miRNAs that are involved in the regulation of EMT, migration, invasion and metastasis of cancer cells. Lastly, we will discuss potential use of miRNAs as diagnostic and prognostic biomarkers as well as therapeutic targets for cancer.
    Journal of Biomedical Science 01/2015; 22(1):9. DOI:10.1186/s12929-015-0113-7 · 2.74 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To assess the regulatory effect of microRNA-185 (miR-185) on lipid metabolism and the insulin signalling pathway in human HepG2 hepatocytes and a high-fat diet mouse model. Quantitative reverse transcription-polymerase chain reaction was used to assess the mRNA levels of lipogenic genes after loss or gain of miR-185. In addition, the amounts of insulin signalling intermediates were determined after transfection of HepG2 cells with pre-miR-185. MiR-185 levels decreased in a time- and dose-dependent manner in response to palmitic acid in human HepG2 hepatocytes. Transfection of HepG2 cells with miR-185 significantly decreased the mRNA levels of fatty acid synthase, 3-hydroxy-3-methylglutaryl-CoA reductase, sterol-regulatory element binding protein-2, and sterol-regulatory element binding protein-1c, whereas inhibition of miR-185 using an anti-miR-185 oligonucleotide produced the opposite effect in HepG2 cells. In a high-fat diet mouse model, the accumulation of lipids was significantly improved after treatment with miR-185, compared with control animals. Induction of miR-185 enhanced the insulin signalling pathway by up-regulating the insulin-receptor substrate-2. These findings suggest that miR-185 plays an important role in regulating fatty-acid metabolism and cholesterol homeostasis in hepatocytes, as well as in improving insulin sensitivity, both in vitro and in vivo.

Full-text (3 Sources)

Download
26 Downloads
Available from
May 29, 2014