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

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.

• 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
• Journal: Diabetologia (Diabetologia) Vol. 57 Issue 3 Pg. 592-602 (Mar 2014) ISSN: 1432-0428 [Electronic] Germany
• PMID: 24362725 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Hypoglycemic Agents
• Insulin Receptor Substrate Proteins
• Intracellular Signaling Peptides and Proteins
• Irs1 protein, rat
• Sterol Regulatory Element Binding Protein 1
• Metformin

Topics

• Adenoviridae
• Animals
• Blotting, Western
• Cells, Cultured
• Diet, High-Fat
• Hypoglycemic Agents (pharmacokinetics)
• Insulin Receptor Substrate Proteins (metabolism)
• Insulin Resistance
• Intracellular Signaling Peptides and Proteins (metabolism)
• Metformin (pharmacology)
• Muscle, Skeletal (metabolism)
• Promoter Regions, Genetic
• Rats
• Rats, Sprague-Dawley
• Sterol Regulatory Element Binding Protein 1 (drug effects, metabolism)
• Transcriptional Activation