Ultraconserved element uc.333 increases insulin sensitivity by binding to miR-223.

Yang Zhang,Gang Hu,Jingyu Sun,Jun Guo,Jie Wei,He Yao,Yajun Lin,Jian Li

doi:10.18632/aging.103020

Abstract

Insulin resistance (IR) contributes to diabetes and aging. Ultraconserved elements (UCEs) are a class of long noncoding RNAs (lncRNAs) that are 100% conserved in humans, mice, and rats. We identified the lncRNA uc.333 using an lncRNA microarray and then used quantitative real-time polymerase chain reaction to analyze its expression in the livers of nonalcoholic fatty liver disease (NAFLD) patients, db/db mice, high-fat diet–fed mice, IL-6-treated mice, and TNF-α-treated mice. The underlying mechanisms of uc.333 in IR were investigated using fluorescence in situ hybridization, Western blot, and miRNA microarray analyses. The results revealed that uc.333 expression was decreased in liver tissues from NAFLD patients and treated mice. Furthermore, overexpression of uc.333 decreased IR, whereas knocking down uc.333 increased IR. We also confirmed that uc.333 binds to miR-223 and that the levels of miR-223 were increased in the livers of patients and treated mice. These findings showed that uc.333 improves IR by binding to miR-223; thus, uc.333 may be a useful target for the treatment and prevention of IR.

Highlights

Insulin resistance (IR) is a leading cause of more than 90% all diagnosed cases of diabetes and metabolic syndromes [1, 2]
We identified the long noncoding RNAs (lncRNAs) uc.333 using an lncRNA microarray and used quantitative real-time polymerase chain reaction to analyze its expression in the livers of nonalcoholic fatty liver disease (NAFLD) patients, db/db mice, high-fat diet–fed mice, IL-6-treated mice, and tumor necrosis factor-α (TNF-α)-treated mice
To assess transcribed ultraconserved regions (T-UCRs), we profiled lncRNA expression using a microarray with liver tissue from NAFLD patients and controls

Summary

Introduction

Insulin resistance (IR) is a leading cause of more than 90% all diagnosed cases of diabetes and metabolic syndromes [1, 2]. IR is an epidemic condition prevalent worldwide and has been shown to strongly correlate with the inflammatory factors that cause abnormal glucose metabolism in hepatocytes and vessel walls, [4] thereby leading to liver injury and atherosclerosis [5, 6]. Emerging evidence shows that long noncoding RNAs (LncRNAs) regulate IR [7]. Among LncRNAs, the ultraconserved noncoding RNAs (ucRNAs), termed ultraconserved elements (UCEs), include 481 members and transcribe across the human, mouse, and rat genomes with 100% conservation. They are frequently located in gene fragile sites and cancer-associated genomic regions [8, 9]. The function of ucRNAs in IR is still unclear [13]

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Results

Conclusion