非酒精性脂肪肝病（NAFLD）是国内外最常见的慢性肝病，研究显示大气细颗粒物（PM2.5）可诱发和加剧NAFLD，但具体机制及对肝代谢酶功能的影响尚不清楚。CYP3A4是人体最重要的药物代谢酶。我们前期发现PM2.5暴露可显著下调脂肪肝细胞模型的CYP3A4表达，与miR-200a/miR-150的调控有关。由此提出假说：PM2.5通过miRNA直接或间接影响PXR/CYP3A4信号通路，从而导致NAFLD肝代谢酶功能和活性损伤。我们拟开展NAFLD人群PM2.5暴露与PXR/CYP3A4前瞻性研究；利用PXR-/-小鼠和人源PXR小鼠建立PM2.5诱导的NAFLD模型，探索miRNA对PXR/CYP3A4通路关键环节的调节效应，以期揭示PM2.5调控NAFLD肝代谢酶CYP3A4功能的表观遗传学机制，为NAFLD人群的合理用药提供理论依据。

Nonalcoholic fatty liver disease (NAFLD) is now the most common cause of chronic liver disease. Studies have shown that fine particulate matter (PM2.5) exposure could induce and aggravate NAFLD. However, the mechanism of how PM2.5 affects the pathogenesis of NAFLD and CYP3A4 function remains largely unknown. CYP3A4 is the most abundant CYP450 enzyme in the human liver and intestine. Our previous study showed that CYP3A4 expression decreased dramatically after PM2.5 exposure in NAFLD cell model, which was possibly regulated through miR-200a and miR-150. Therefore, we hypothesize here that PM2.5 inhibits the expression and function of PXR/CYP3A4 in nonalcoholic fatty liver disease through direct and indirect modulations of miRNAs. We intend to carry out a prospective study on PM2.5 exposure, PXR and CYP3A4 expression and function in NAFLD patients. Additionally, PM2.5 exposure-induced NAFLD model will be established in PXR-/- mice and humanized PXR mice to determine the impact of PM2.5 on the key components of PXR/CYP3A4 pathway, and to further demonstrate how PM2.5 regulates PXR/CYP3A4 expression and function through miRNAs or histone modifications. Together, we expect to clarify the molecular mechanisms of liver injury in PM2.5 exposure-induced NAFLD, which will provide theoretical basis for optimized therapeutic strategies for NAFLD patients.