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Diabetologia
Published in: Diabetologia 3/2014

01-03-2014 | Article

Role for sterol regulatory element binding protein-1c activation in mediating skeletal muscle insulin resistance via repression of rat insulin receptor substrate-1 transcription

Authors: Yan Bi, Wenjun Wu, Junfeng Shi, Hua Liang, Wenwen Yin, Yingying Chen, Sunyinyan Tang, Shu Cao, Mengyin Cai, Shanmei Shen, Qian Gao, Jianping Weng, Dalong Zhu

Published in: Diabetologia | Issue 3/2014

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Abstract

Aims/hypothesis

Sterol regulatory element binding protein-1c (SREBP-1c) is a master regulator of fatty acid synthase and controls lipogenesis. IRS-1 is the key insulin signalling mediator in skeletal muscle. In the present study, we investigated the role of SREBP-1c in the regulation of IRS-1 in skeletal muscle cells.

Methods

L6 muscle cells were treated with palmitic acid (PA) or metformin. Adenovirus vectors expressing Srebp-1c (also known as Srebf1) and small interfering RNA (siRNA) against Srebp-1c were transfected into the L6 cells. Protein–DNA interactions were assessed by luciferase reporter analysis, electrophoretic mobility shift assay and chromatin immunoprecipitation assay.

Results

We found that both gene and protein expression of SREBP-1c was increased in contrast to IRS-1 expression in PA-treated L6 cells. SREBP-1c overproduction decreased Irs-1 mRNA and IRS-1 protein expression in a dose-dependent manner, and suppressed the resultant insulin signalling, whereas SERBP-1c knockdown by Serbp-1c siRNA blocked the downregulation of IRS-1 induced by PA. Protein–DNA interaction studies demonstrated that SREBP-1c was able to bind to the rat Irs-1 promoter region, thereby repressing its gene transcription. Of particular importance, we found that metformin treatment downregulated Srebp-1c promoter activity, decreased the specific binding of SREBP-1c to Irs-1 promoter and upregulated Irs-1 promoter activity in PA-cultured L6 cells.

Conclusions/interpretation

Our data indicate for the first time that SREBP-1c activation participates in skeletal muscle insulin resistance through a direct effect of suppressing Irs-1 transcription. These findings imply that SREBP-1c could serve as an attractive therapeutic target for insulin resistance.
Appendix
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Metadata
Title
Role for sterol regulatory element binding protein-1c activation in mediating skeletal muscle insulin resistance via repression of rat insulin receptor substrate-1 transcription
Authors
Yan Bi
Wenjun Wu
Junfeng Shi
Hua Liang
Wenwen Yin
Yingying Chen
Sunyinyan Tang
Shu Cao
Mengyin Cai
Shanmei Shen
Qian Gao
Jianping Weng
Dalong Zhu
Publication date
01-03-2014
Publisher
Springer Berlin Heidelberg
Published in
Diabetologia / Issue 3/2014
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-013-3136-1

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