MiR-103/107 promote ER stress-mediated apoptosis via targeting the Wnt3a/β-catenin/ATF6 pathway in preadipocytes

Zhenzhen Zhang,Song Wu,Saeed Muhammad,Qian Ren,Chao Sun

doi:10.1194/jlr.m082602

Abstract

Both miR-103 and miR-107 have been demonstrated to restrain cell proliferation and regulate lipid metabolism and inflammation. However, the effects of miR-103/107 on preadipocyte apoptosis remain unknown. In the present research, we have investigated how miR-103/107 regulated preadipocyte apoptosis. We found that miR-103/107 aggravated endoplasmic reticulum (ER) stress-mediated apoptosis in preadipocytes. We confirmed that miR-103/107 targeted WNT family member 3a (Wnt3a) in preadipocytes. It was found that overexpressing Wnt3a resulted in suppression of ER stress-mediated apoptosis, while restoration of miR-103/107 counteracted the effects of Wnt3a in preadipocytes. Moreover, bioinformatics and luciferase assays indicated that activating transcription factor (ATF)6 is a key player linking miR-103/107-induced ER stress to apoptosis. ATF6 is regulated by lymphoid enhancer-binding factor 1, a transcription factor downstream of the Wnt3a/β-catenin signaling pathway, and ATF6 binds to the B-cell lymphoma 2 (Bcl2) promoter to regulate apoptosis further. In conclusion, miR-103/107 promoted ER stress-mediated apoptosis by targeting the Wnt3a/β-catenin/ATF6 signaling pathway in preadipocytes. This study revealed that the miR-103/107-Wnt3a/β-catenin-ATF6 pathway is critical to the progression of apoptosis in preadipocytes, which suggested that approaches to activate miR-103/107 could potentially be useful as new therapies for treating obesity and metabolic syndrome-related disorders.

Highlights

Both miR-103 and miR-107 have been demonstrated to restrain cell proliferation and regulate lipid metabolism and inflammation
For miRNAs known to regulate target mRNAs by binding to their 3′untranslated region (UTR) regions, WNT family member 3a (Wnt3a) was identified as a potential target of miR-103/107 based on sequences in its 3′-UTR region that were complementary to the seed sequences of miR-103/107
We found that mRNA levels of Bcl-2-associated X protein (Bax) were increased by about 78% and 191%, while B-cell lymphoma 2 (Bcl2) mRNA experienced a degradation of 43% and 56% after 24 h incubation with serum-free medium and 250 nM palmitate, respectively, meaning a 24 h incubation period was sufficient to induce apoptosis. (Fig. 2A, F)

Summary

Introduction

Both miR-103 and miR-107 have been demonstrated to restrain cell proliferation and regulate lipid metabolism and inflammation. The effects of miR103/107 on preadipocyte apoptosis remain unknown. It was found that overexpressing Wnt3a resulted in suppression of ER stress-mediated apoptosis, while restoration of miR-103/107 counteracted the effects of Wnt3a in preadipocytes. ATF6 is regulated by lymphoid enhancerbinding factor 1, a transcription factor downstream of the Wnt3a/ -catenin signaling pathway, and ATF6 binds to the B-cell lymphoma 2 (Bcl2) promoter to regulate apoptosis further. MiR-103/107 promoted ER stressmediated apoptosis by targeting the Wnt3a/ -catenin/ATF6 signaling pathway in preadipocytes. This study revealed that the miR-103/107-Wnt3a/ -catenin-ATF6 pathway is critical to the progression of apoptosis in preadipocytes, which suggested that approaches to activate miR-103/107 could potentially be useful as new therapies for treating obesity and metabolic syndrome-related disorders.—Zhang, Z., S. Sun. miR-103/107 promote ER stress-mediated apoptosis via targeting the Wnt3a/ catenin/ATF6 pathway in preadipocytes.

Methods

Results

Conclusion