一种新的长链非编码RNA调控CHCHD3基因对白色脂肪棕色化的机制研究

Energy imbalance is the main cause of obesity. The paramorphia and dysfunction of mitochondria are the central part of obesity. With microarrays analysis, we previously found that lncRNA p19461 was down-regulated in obese patients while low-fat diet can promote its expression. Bioinformatics analysis showed that lncRNA p19461 was co-expressed with CHCHD3 gene, which helped to stabalize protein complex in mitochondria. Therefore, we proposed that lncRNA p19461 might play an important role in obesity through regulating the structure and function of mitochondria as well as the process of white fat brown through mtNOS/NO/cGMP/MAPK signaling pathway. 3T3-L1 preadipocytes will be used in our study. With technique including plasmid/siRNA transfection and other molecular biology techniques, we plan to verify that lncRNA P19461/CHCHD3 contribute to the pathogenesis and development of obesity by regulating the mitochondria dysfunction as well as the process of white fat brown, which may provide a new strategy and treatment for obesity.

能量失衡是肥胖发生的主要原因，线粒体形态及功能异常影响能量代谢是肥胖发生的中心环节。课题组前期通过基因芯片筛选发现：lncRNA P19461在肥胖人群中表达下调，低脂饮食促进其表达上调；生物信息学分析显示lncRNA P19461和线粒体稳定蛋白复合体的核心基因CHCHD3共表达,CHCHD3是其潜在的作用靶点。由此我们提出，lncRNA P19461可能通过参与调控线粒体的结构、功能及白色脂肪棕色化过程参与肥胖进程,其中mtNOS/NO/cGMP/MAPK信号通路可能发挥重要作用。本课题拟应用3T3-L1前脂肪细胞模型，通过质粒/siRNA转染、分子生物学等技术，探讨lncRNA P19461/CHCHD3对高脂诱导线粒体损伤的调控及影响白色脂肪棕色化参与肥胖的发生发展的可能机制，以期为肥胖防治提供新策略。

白色脂肪棕色样变通过产热耗能成为抵抗肥胖新热点，线粒体结构及功能异常影响白色脂肪棕色样变。我们前期通过基因芯片筛选发现:肥胖人群lncRNA-P19461表达下调，脂肪细胞棕色化过程中lncRNA-p19461表达下调，由此我们提出lncRNA-p19461参与脂肪细胞棕色样变调控。. 研究首先通过过表达脂肪细胞lncRNA-P19461验证lncRNA-P19461在脂肪细胞棕色化过程中的作用。研究结果表明，过表达lncRNA-P19461后脂肪细胞产热相关基因及蛋白如UCP1、PRDM16等表达升高，证实lncRNA-P19461可促进脂肪细胞棕色化。我们对转染lncRNA-P19461的脂肪细胞进行透射电镜检查，发现转染lncRNA-P19461的脂肪细胞线粒体增多，提示lncRNA-P19461促进脂肪细胞棕色化可能与线粒体增多有关。相反，抑制lncRNA-P19461后脂肪细胞产热相关基因及蛋白表达下降，线粒体数量较正常组少。结果表明lncRNA-P19461参与调控脂肪细胞棕色化进程。. 为了进一步探讨lncRNA p19461 参与脂肪细胞分化调控的具体机制，我们对过表达lnc19461 组与正常组脂肪细进行PCR芯片测序，结果表明，过表达lncRNA-P19461后胰岛素通路和棕色化通路发生显著改变。. 综上所述，lncRNA-p19461 与脂肪细胞分化密切相关，参与调控脂肪细胞胰岛素信号通路及脂肪细胞棕色样变过程，具体机制可能与lncRNA-p19461 调控脂肪细胞线粒体数量及功能的改变相关。.