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

• Published in: Diabetologia 2014-03, Vol.57 (3), p.592-602
• Main Authors: Bi, Yan, Wu, Wenjun, Shi, Junfeng, Liang, Hua, Yin, Wenwen, Chen, Yingying, Tang, Sunyinyan, Cao, Shu, Cai, Mengyin, Shen, Shanmei, Gao, Qian, Weng, Jianping, Zhu, Dalong
• Format: Article
• Language: English
• Subjects: Adenoviridae; Animals; Antibodies; Biological and medical sciences; Blotting, Western; Body fat; Cells, Cultured; Dehydrogenases; Diabetes. Impaired glucose tolerance; Diet, High-Fat; Endocrine pancreas. Apud cells (diseases); Endocrinology; Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fatty acids; Fundamental and applied biological sciences. Psychology; Human Physiology; Hypoglycemic Agents - pharmacokinetics; Insulin Receptor Substrate Proteins - metabolism; Insulin Resistance; Internal Medicine; Intracellular Signaling Peptides and Proteins - metabolism; Kinases; Lipids; Liver; Medical sciences; Medicine; Medicine & Public Health; Metabolic Diseases; Metformin - pharmacology; Muscle, Skeletal - metabolism; Musculoskeletal system; Pallets; Promoter Regions, Genetic; Protein expression; Proteins; Rats; Rats, Sprague-Dawley; Sterol Regulatory Element Binding Protein 1 - drug effects; Sterol Regulatory Element Binding Protein 1 - metabolism; Sterols; Striated muscle. Tendons; Transcriptional Activation; Vertebrates: osteoarticular system, musculoskeletal system
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-013-3136-1

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.