MiR-145 improves metabolic inflammatory disease through multiple pathways.

Weiwei Zhang,Zi Ye,Rumei Li,Min He,Nan Wu,Naijia Liu,Xiaolong Zhao,Lianxi Li,Xuehong Dong,Zhaoyun Zhang,Qin Li,Renming Hu,Zhihong Yang,Qinghua Wang,Lili Chen,Xuanchun Wang,Man Cheong Leong,Yehong Yang,Xiao Yao,Yintao Li,Wenbai Zhou,Jie Wen,Bin Lü ,Jinjing Huang

doi:10.1093/jmcb/mjz015

Abstract

Chronic inflammation plays a pivotal role in insulin resistance and type 2 diabetes, yet the mechanisms are not completely understood. Here, we demonstrated that serum LPS levels were significantly higher in newly diagnosed diabetic patients than in normal control. miR-145 level in peripheral blood mononuclear cells decreased in type 2 diabetics. LPS repressed the transcription of miR-143/145 cluster and decreased miR-145 levels. Attenuation of miR-145 activity by anti-miR-145 triggered liver inflammation and increased serum chemokines in C57BL/6 J mice. Conversely, lentivirus-mediated miR-145 overexpression inhibited macrophage infiltration, reduced body weight, and improved glucose metabolism in db/db mice. And miR-145 overexpression markedly reduced plaque size in the aorta in ApoE−/− mice. Both OPG and KLF5 were targets of miR-145. miR-145 repressed cell proliferation and induced apoptosis partially by targeting OPG and KLF5. miR-145 also suppressed NF-κB activation by targeting OPG and KLF5. Our findings provide an association of the environment with the progress of metabolic disorders. Increasing miR-145 may be a new potential therapeutic strategy in preventing and treating metabolic diseases such as type 2 diabetes and atherosclerosis.

Highlights

The prevalence of obesity and diabetes is increasing dramatically worldwide, while the underlying mechanism is not fully understood (Mokdad et al, 2001)
We proposed that diseases, including obesity, diabetes, fatty liver disease, atherosclerosis, are different phenotypes of metabolic inflammation induced by activated macrophage, which are collectively referred to as ‘metabolic inflammatory syndrome’ (MIS) (Hu et al, 2018)
A significant downregulation of miR-145 was found in THP-1 cells treated with high glucose, AcLDL and FFA by microRNA microarrays and was proved by quantitative Real-time polymerase chain reaction (Figure 1A and B; Supplementary Table S1). miR-145 levels in peripheral blood mononuclear cells was further compared among newly diagnosed type-2 diabetes mellitus (T2DM) patients, patients with impaired glucose tolerance (IGT), as well as normal subjects, and a significant decrease was found in T2DM patients compared with the other two groups (Figure 1C)

Summary

Introduction

The prevalence of obesity and diabetes is increasing dramatically worldwide, while the underlying mechanism is not fully understood (Mokdad et al, 2001). Growing studies suggested that inflammation plays an important role in the development of obesity and diabetes. Obesity gives rise to a state of chronic, low-grade.

Methods

Results

Conclusion