LncRNA AK142643通过调控CD36促进非酒精性脂肪性肝病发生发展的作用及机制研究

Hepatic lipid accumulation is a hallmark of non-alcoholic fatty live disease (NAFLD), however, the underlying mechanisms are largely unknown. Long non-coding RNAs (LncRNAs) are important regulators of lipid metabolism. Our preliminary study showed that AK142643, an uncharacterized LncRNA, was upregulated in animal models of NAFLD and promoted hepatic lipid accumulation. Further study showed that AK142643 could promote the expression of CD36, a well known fatty acid translocase, via a PPARγ/PGC-1α dependent pathway. Besides, bioinformatics analysis showed that AK142643 could bind with PPARγ and PGC-1α. There is no report about the function of AK142643 at present. Thus, we speculated that the upregulated AK142643 could promote NAFLD occurrence and progression by regulating CD36 expression. Mechanistically, AK142643 might bind with and recruit PPARγ/PGC-1α to the promoter of CD36 gene, promoting CD36 transcription. This project is to elucidate the biological function and underlying molecular mechanisms of AK142643 in the onset and progression of NAFLD, and reveal the mechanism of AK142643 regulating CD36 expression by recruiting PPARγ/PGC-1α and promoting hepatic lipid accumulation. This project will provide a new insight into the pathogenesis and treatment of NAFLD.

肝内脂质沉积是非酒精性脂肪性肝病（NAFLD）的重要病理过程，其具体机制尚不清楚。长链非编码RNA（LncRNA）是脂质代谢的重要调控因子，我们前期研究发现LncRNA AK142643在NAFLD中表达水平明显升高，可促进肝细胞内脂质沉积，并依赖转录因子PPARγ和PGC-1α上调CD36的表达。生物信息学分析提示AK142643可能与PPARγ/PGC-1α结合。目前未见关于AK142643功能研究的报道。据此我们提出假说：AK142643可能通过结合并募集PPARγ/PGC-1α至CD36启动子区，转录激活CD36的表达，促进肝内脂质沉积和NAFLD发生发展。本课题拟从分子、细胞和动物等多个水平明确AK142643在NAFLD发生发展过程中的作用，并阐明其通过募集PPARγ/PGC-1α调控CD36表达，促进肝内脂质沉积的作用机制，为NAFLD的发病机制研究和靶向治疗提供实验依据。

非酒精性脂肪性肝病（NAFLD）是目前最常见的慢性肝病，其疾病谱包含单纯脂肪变、脂肪性肝炎、肝纤维化、肝硬化，甚至可进展为肝癌等终末期肝病，其致病机制尚不完全清楚。长链非编码RNA（LncRNA）是脂质代谢的重要调控因子，因此本课题拟研究在NAFLD发生发展过程中起关键作用的LncRNA。我们前期提出LncRNA AK142643通过调控CD36促进肝细胞内脂质沉积，本项目通过RNA pull-down、质谱等分子生物学技术，发现AK142643可与IGF2BP2结合，进而调控CD36的表达。在完成预期研究目标的基础上，为了筛选并鉴定更多的NAFLD关键致病基因，我们构建了高脂饮食（HFD）诱导的NAFLD小鼠模型，采用RNA-seq和TMT标记定量蛋白质组学技术，分析模型小鼠肝组织的转录组和蛋白质组，筛选出了701个差异表达的mRNA，366个差异表达的LncRNA，以及473个差异表达的蛋白质。生物信息学分析发现，这些差异基因大多富集在脂质代谢相关通路，可能参与了NAFLD的发生发展，为后续研究打下坚实的基础。这些研究成果可为NAFLD发病机制研究提供实验依据，为NAFLD的诊断和治疗提供潜在靶点。