早期营养过剩降低转录因子Srebp1c启动子甲基化──非酒精性脂肪肝病形成的一种新机制？

固醇调节元件结合蛋白1c（Srebp1c）是调节脂质代谢最重要的核转录因子，其表达异常与非酒精性脂肪肝病（NAFLD）的发生密切相关。早期营养过剩能增加成年后胰岛素抵抗和代谢紊乱发生的风险, 但与NAFLD的关系尚不明确。本课题拟在继往的工作基础上利用动物模型研究不同饮食条件下早期营养过剩对肝脏形态、功能、表观遗传特征和基因表达的影响；从DNA甲基化修饰的角度探讨早期营养过剩调节Srebp1c的分子机理, 并在全基因组范围内筛选其他效应分子基因启动子的甲基化修饰图谱；利用RNA干扰和甲基化寡核苷酸特异性地抑制Srebp1c的表达和功能，观察该转录调控蛋白及其甲基化修饰在NAFLD发病过程中的作用，以期揭示NAFLD发病的潜在新机制。以上研究对于阐明NAFLD发生进展的分子机理，寻找有效的预防和干预措施以降低NAFLD的发病率有着十分重要的意义。

Sterol regulatory element binding protein 1c (Srebp1c) is a master regulator of the lipid metabolism and plays a critical role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Although neonatal overfeeding predisposes the development of insulin resistance and metabolic perturbations as adults, whether it is related to the onset of NAFLD remains unclear. This study is designed to investigate the morphological, functional, epigenetic and gene expression features in a well-established neonatal overfeeding model; Specific attention will be paid to Srebp1c promoter methylation under the state of neonatal feeding. In addition, RNA interference and methylated oligonucleotides targeted at Srebp1c will be used to test the role Srebp1 per se and its methylation in the pathogenesis of NAFLD; Finally, DNA methylation microarray will be used to identify those genes with their promoters methylated or demethylated within whole-genome under condition of overfeeding. The current studies will be beneficial to our understanding the molecular mechanism of NAFLD and possibly provide for a novel potential therapeutic target for this disease.