高糖环境下肝细胞SREBP-1转录调控网络研究

Sterol regulatory element binding proteins (SREBPs) are major nuclear transcription factor which maintain cellular lipid homeostasis. The overexpression of SREBPs can lead to significantly enhanced gene expression related to lipid synthesis, which results in the accumulation of excess fat in non-adipose tissue and thereby causing metabolic diseases related to lipids. The mechanism of action of SREBPs in type two diabetes is not fully clarified. Recently, the rapid development of high-throughput genomic technologies provides new opportunities for study transcription factor regulatory networks. Studies have shown that there may be some new SREBPs binding sites in the genome, and SREBPs target genes could be expanded. In our previous studies, the expression of SREBP-1 was changed and a novel splicing isoform was found in liver of rats fed a high glucose diet. So, this project will be focused on investigation of SREBP-1 binding sites, target genes and splicing isoform in hunamn hepatic cell cultured in a high glucose environment with high-throughput genomic technologies. A comprehensive picture of gene regulatory networks will illuminate the mechanism of action of SREBPs in hepatic cell cultured in a high glucose environment. The completion of this project will further clarify the pathogenesis of diabetes, which will contribute to the understanding of the lipid metabolism disorders and guiding clinical practice.

固醇调节元件结合蛋白(SREBPs)是重要的核转录因子之一，体内脂质代谢的稳定依赖于SREBPs的调节。SREBPs过表达可使脂质合成相关基因表达明显增强，导致脂肪在非脂肪组织中过度积聚，从而引起多种与脂类有关的代谢类疾病。目前SREBPs在2型糖尿病中具体的分子机制还有待系统的研究。近期组学技术的完善为转录因子调控网络研究提供了新的机遇。研究表明，基因组中可能存在一些新的SREBPs结合位点，且其调控的靶基因仍有待于补充。本课题组前期研究发现，高糖时大鼠肝组织SREBP-1的表达强度及剪切模式均发生明显改变。据此本项目拟采用高通量测序系统探讨高糖状态时人肝细胞SREBP-1的结合位点、靶基因及其剪切模式的变化；通过基因网络的构建全面描绘SREBP-1在高糖环境下对肝细胞的转录调控机制。本项目的完成将进一步明确糖尿病的发病机制，有助于提高对上述脂质代谢性疾病的认识以及指导临床。

固醇调节元件结合蛋白(SREBPs)是细胞调控脂类代谢的重要转录因子之一，其过表达可导致脂质在非脂肪组织中过度积聚，从而引起多种代谢类疾病。本项目采用高通量组学技术系统描绘高糖状态时人肝细胞SREBP-1 的结合位点及靶基因表达的变化，构建人肝SREBP-1基因调控网络；进一步通过分子生物学手段验证SREBP-1对重要靶基因的直接调控作用。在此基础上以SREBP-1表达调控紊乱为切入点，证实SREBP-1抑制剂（Betulin）具有治疗非酒精性脂肪肝以及肝癌的潜在作用。本项目的完成有助于深入理解SREBP-1对代谢及非代谢基因（如凋亡相关基因）的调控，进一步提高对上述脂质代谢相关疾病的认识以及指导临床。