高同型半胱氨酸血症（HHcy）及非酒精性脂肪肝（NAFLD）是世界范围内重要的代谢紊乱性疾病，二者的相互关系以及机制尚未阐明。脂肪酸转位酶CD36可通过促进肝脏脂质摄取参与NAFLD的发生。芳香烃受体（AhR）是配体激活的转录因子，它的激活也可引起NAFLD，而CD36是AhR的靶基因。预实验结果发现，HHcy小鼠肝脏中脂质沉积增加，CD36的表达显著上调并且AhR被激活。因此，本项目的科学假说为：HHcy通过增加AhR的内源性配体激活AhR，进而增加CD36的表达促进肝脏的脂质摄取，最终导致NAFLD的发生。本项目拟在动物及细胞水平，运用分子生物学及代谢组学手段研究：HHcy在肝脏中激活AhR，进而增加CD36表达的机制以及其在HHcy所致NAFLD中的作用，同时寻找HHcy增加的AhR内源性配体。以期进一步揭示HHcy引起NAFLD发生的分子机制，并为其治疗提供新的潜在性靶点。

Hyperhomocysteinemia (HHcy) and non-alcoholic fatty liver disease (NAFLD) are metabolic disorders globally. The role of HHcy in NAFLD and the underlying mechanisms are still unknown. CD36 mediates uptake and intracellular transport of long-chain fatty acids and contributes to the pathogenesis of fatty liver disease. As a ligand-activated transcription factor, activation of aryl hydrocarbon receptor（AhR）in mice induced the expression of its target gene CD36 and resulted in increased lipid deposition in liver. In the preliminary study, we found that the HHcy mouse model displayed hepatic steatosis, increased CD36 expression and activation of AhR in liver. Based on those data, the hypothesis of the current project is that HHcy can induce hepatic steatosis by activating AhR/CD36 pathway via increasing AhR ligands. By approaches of molecular biology and metabolomics, we will elucidate the mechanisms of AhR activation and consequent induction of CD36 expression by HHcy, and further search for the ligands of AhR increased by HHcy. This study may extend our knowledge of the mechanisms of NAFLD induced by HHcy and potentially contribute to the development of novel therapeutic approaches to it.