胆固醇调节元件结合蛋白-1 c（sterol regulatory element-binding protein 1c，SREBP-1c）是脂肪酸合成的关键转录因子。我们的最新研究发现:SREBP-1c高表达也可抑制骨骼肌胰岛素受体底物-1转录，促进细胞胰岛素抵抗，表明SREBP-1c可能是脂毒性形成的重要环节。肝脏X受体（liver X receptor, LXR）可诱导SREBP-1c转录，我们通过CHIP-qPCR分析发现：高脂使SREBP-1c转录调控区特别是LXR结合原件位点的组蛋白乙酰化水平增加，而去乙酰化酶（Sirtuin1）激动剂使其水平降低，表明高脂可能通过乙酰化组蛋白调控LXR诱导的SREBP-1c转录。本课题拟在前期工作基础上研究高脂对组蛋白乙酰化修饰的作用及其对SREBP-1c转录、骨骼肌胰岛素抵抗形成的病理作用机制，为胰岛素抵抗特异性治疗提供新的思路。

Although lipotoxicity has been associated with type 2 diabetes mellitus, the precise occurrence mechanism of lipotoxicity is not yet known. We found that sterol regulatory element binding protein 1c (SREBP1c), as a master transcription factor that control lipogenesis, has directly inhibitory effect on transcription of insulin receptor substrate 1(IRS-1) in L6 myotube cells and suppress skeletal muscle insulin signaling. These studies suggest that SREBP-1c could be central to the pathogenesis of fatty acids-induced insulin resistance in skeletal muscle, however, much less is known about transcriptional control mechanism of SREBP-1c expression in that setting. Liver X receptor (LXR), which form heterodimers with retinoid X receptor (RXR), is known to be inducer of the SREBP-1c gene. We demonstrated by chromatin immunoprecipition (CHIP-qPCR) assay that the acetylation of histone H3 and H4 at the promoter of SREBP-1c especially in LXR response element (LXRE) was increased in palmitic acid (PA)-treated L6 cells, which was decreased by histone deacetylase sirtuin 1(SirT1) agonist resveratrol treatment.Our results suggest that fatty acids promote SREBP-1c transcription involved in insulin resistance potentially through the mechanism of histone acetylation to allow increased binding of key transcription factors to the promoter of SREBP-1c. Thus, further studies will be performed to investigate the chromatin events and molecular mechanism in lipotoxicity conditions in vivo and in vitro, and to examine the dysregulation of histone acetylation to the development of SREBP-1c transcription and insulin resistance, which will provide clues into the specific therapeutic target for improving insulin resistance in type 2 diabetes mellitus.