抑郁症是一种高患病率、高复发率的慢性疾病。药物治疗是抗抑郁的主要手段，但药物引起的脂代谢异常易导致治疗中断，因此迫切需要阐明其发生机制。氟西汀(FLX)是主要抗抑郁药物之一，我们前期体内外研究发现，FLX诱发肝细胞脂质蓄积，下调G6PC表达，但对肝脏脂肪酸转运蛋白2/5无影响。进一步研究显示，FLX下调小鼠原代肝细胞中G6PC上游转录因子PPARα的表达，且抑制PPARα激动剂对PPARα及G6PC的上调，但对其他转录因子及其靶基因无明显影响。鉴于G6PC为糖异生过程的关键酶，其功能或表达的下降可加剧脂肪酸从头合成，诱发肝脏脂质蓄积。本研究将结合临床样本，从细胞和整体水平证实FLX通过抑制G6PC的表达，引起肝脏脂代谢异常，阐明FLX经PPARα下调肝脏G6PC机制，寻找改善FLX引起肝脏脂代谢异常的有效策略，为提高临床FLX的依从性提供理论依据和可行的治疗方案。

Depression is a chronic disease with high prevalence and high recurrence rate. Drug therapy is the main treatment for anti-depression, however, the hepatic lipid metabolism abnormalities induced by drug leads to the treatment interruption, so the mechanism is urgent to investigate. Fluoxetine (FLX) is one of the most widely used antidepressant. Our previous study showed that FLX could induce hepatic lipid accumulation and inhibit the expression of G6PC significantly both in vitro and in vivo, but there’s no effect on fatty acid transporters 2, 5. Further studies showed that FLX down-regulated the expression of PPARα, an upstream transcription factor of G6PC, in mouse primary hepatocytes without any significantly effect on other upstream transcription factors or their target genes. Meanwhile, FLX can prevent the upregulation of PPARα and G6PC against PPARα agonists. In view of the fact that G6PC is a key enzyme in gluconeogenesis, and the decline of its function or expression can enhances the production of de novo synthesis of fatty acids raw materials, then induce the liver lipid accumulation. In our study, combined with clinical samples, the role of G6PC in the abnormality of liver lipid metabolism caused by FLX both in vitro and in vivo will be evaluated, and the mechanism of FLX down-regulate G6PC through PPARα will be clarified. Meanwhile, the effective strategy to improve the abnormality of liver lipid metabolism caused by FLX will be explored, which provides a theoretical basis and a viable treatment plan.