超级保守元件uc.372在肝脏甘油三酯代谢紊乱中的作用及其调控机制

It has been indicated that long non coding RNAs (lncRNAs) play a key role in metabolism. However, the function of ultra-conserved elements (UCEs), a kind of lncRNAs, is poorly understood. In our preliminary study, we found that increased uc.372 level was accompanied by accumulation of hepatic triglyceride and up-regulation of lipid metabolism-related genes. Bioinformatic analysis predicted that uc.372 could directly regulate the expression of DNMT1 and lipid metabolism-related genes. These results suggest that uc.372 may have an essential function for hepatic lipid metabolism. At present, no study has been conducted on the functional role of uc.372. Therefore, we hypothesize that uc.372 may function as a scaffold for DNMT1 to regulate triglyceride metabolism-related gene expression, in turn lead to accumulation of triglyceride in livers. In this study, we aim to evaluate the potential role of uc.372 in hepatic triglyceride metabolism disorder. We try to explore the regulation mechanism of uc.372 expression, identify the uc.372 target genes involved in hepatic triglyceride accumulation. Moreover, we will investigate the molecular mechanism by which uc.372 regulates triglyceride metabolism in livers. We will provide insight into pathogenesis of hepatic triglyceride metabolism disorder and novel ideas for prevention of nonalcoholic fatty liver disease (NAFLD).

长链非编码RNA（lncRNA）在机体代谢调控中具有重要作用，作为一种lncRNA，超级保守元件（UCE）的功能尚不清楚。我们前期研究发现，肝脏uc.372升高伴随甘油三酯蓄积与代谢相关基因及DNA甲基转移酶DNMT1的上调。生物信息学预测uc.372能结合DNMT1。提示uc.372在肝脏脂代谢中起重要作用。目前未见关于uc.372功能研究的报道。据此我们提出假说：uc.372以支架的形式绑定DNMT1，通过甲基化修饰调控甘油三酯代谢相关基因的表达，影响肝脏甘油三酯的异常蓄积。本课题拟从分子、细胞、组织以及动物水平等多层次明确uc.372在肝脏脂代谢紊乱中的作用；探讨uc.372表达的调控机制；确定uc.372对甘油三酯代谢相关基因的调控；揭示uc.372影响肝脏甘油三酯异常蓄积的机制。本研究将从超级保守元件这个新视点探讨肝脏甘油三酯异常蓄积的发生机制，为非酒精性脂肪肝的防治提供新思路。

长链非编码RNA在集体代谢调控中具有重要作用，作为一种lncRNA，超级保守元件（UCE）的功能尚不清楚。本项目从分子、细胞、组织以及动物等水平多层次明确uc.372在肝脏脂代谢紊乱中的作用；探讨uc.372表达的调控机制；确定uc.372对甘油三酯代谢相关基因的调控；揭示uc.372影响肝脏甘油三酯异常蓄积的机制。本项目组圆满完成原定研究计划，实现了预期目标，并取得了突出进展，在国外主流杂志上发表SCI论著 1 2篇；其中IF≥10论著1 篇； 培养博士研究生4名，硕士研究生1名。.uc.372在db/db小鼠和高脂喂养小鼠模型肝脏中表达升高；在人脂肪肝标本中uc.372表达升高；提示uc.372同甘油三酯代谢紊乱相关；.1.uc.372诱导肝脏甘油三酯蓄积。在小鼠肝脏中过表达uc.372促进甘油三酯蓄积；在高脂喂养小鼠肝脏中抑制uc.372表达改善甘油三酯蓄积；.2.uc.372通过促进miR-195和miR-4668成熟引起肝脏脂质蓄积。miR-195能够靶向ACC和FAS；miR-4668能够靶向SCD1和CD36。过表达miR-195或miR-4668能够逆转沉默uc.372引起的ACC/FAS或SCD1/CD36的表达下调。.3.uc.372上游调控因子是USF1。在临床样本中证明uc.372、pri-miR-195、pri-miR-4688、USF1和INSM2表达升高；pre-miR-195、pre-miR-4688、miR-195和miR-4688表达升高。