Downregulation of glucose‐6‐phosphatase expression contributes to fluoxetine‐induced hepatic steatosis
Downregulation of glucose‐6‐phosphatase expression contributes to fluoxetine‐induced hepatic steatosis
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DOI：
10.1002/jat.4109
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发表时间：
2020-11
影响因子：
3.3
通讯作者：
Shuanghui Lu;Zhiyuan Ma;Yong Gu;Ping Li;Yingchun Chen;Mengru Bai;Hui Zhou;Xi Yang;Huidi Jiang
中科院分区：
文献类型：
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作者：
Shuanghui Lu;Zhiyuan Ma;Yong Gu;Ping Li;Yingchun Chen;Mengru Bai;Hui Zhou;Xi Yang;Huidi Jiang
氟西汀是广泛用于治疗抑郁症的一线选择性5-羟色胺再摄取抑制剂;然而，它可诱导肝脏脂质代谢异常。考虑到葡萄糖-6-磷酸酶（G6 β）（肝脏生成中的关键酶）的表达或功能降低，或脂肪酸摄取的上调，会导致肝脏脂质蓄积。本研究的目的是阐明G6 β调节和脂肪酸摄取改变是否有助于氟西汀诱导的肝脏脂质代谢异常。我们的研究显示，氟西汀8周口服给药剂量依赖性增加肝脏甘油三酯，导致肝脏脂肪变性。同时，小鼠肝脏和原代小鼠肝细胞（PMH）中G6 β的表达以浓度依赖性方式下调。此外，氟西汀增加了小鼠肝脏中葡萄糖-6-磷酸（G6 β底物）和乙酰辅酶A（从头脂肪生成的底物）的浓度。此外，氟西汀还诱导HepG 2细胞中的脂质蓄积并下调G6 β表达。然而，氟西汀治疗后PMH中绿色荧光脂肪酸（BODIPY™ FL C16）的摄取未发生变化，表明氟西汀诱导的肝脏脂肪变性与脂肪酸摄取改变无关。总之，氟西汀下调肝脏G6 β表达，随后增强葡萄糖向脂质的转化，最终导致肝脏脂肪变性，但对脂肪酸摄取无影响。
Fluoxetine is a first‐line selective serotonin reuptake inhibitor widely applied for the treatment of depression; however, it induces abnormal hepatic lipid metabolism. Considering decreased expression or function of glucose‐6‐phosphatase (G6Pase), a key enzyme in gluconeogenesis, or the upregulation of fatty acid uptake, causes hepatic lipid accumulation. The aim of this study was to elucidate whether G6Pase regulation and fatty acid uptake alteration contribute to fluoxetine‐induced abnormal hepatic lipid metabolism. Our study revealed that 8‐week oral administration of fluoxetine dose‐dependently increased hepatic triglyceride, causing hepatic steatosis. Concomitantly, the expression of G6Pase in mouse livers and primary mouse hepatocytes (PMHs) was downregulated in a concentration‐dependent manner. Furthermore, fluoxetine increased the concentrations of glucose‐6‐phosphate (G6Pase substrate) and acetyl CoA (the substrate for de novo lipogenesis) in mouse livers. Additionally, fluoxetine also induced lipid accumulation and downregulated G6Pase expression in HepG2 cells. However, the uptake of green fluorescent fatty acid (BODIPY™ FL C16) in PMHs was not changed after fluoxetine treatment, indicating that fluoxetine‐induced hepatic steatosis was not associated with fatty acid uptake alteration. In conclusion, fluoxetine downregulated hepatic G6Pase expression, subsequently enhanced the transformation of glucose to lipid, and ultimately resulted in hepatic steatosis, but with no impact on fatty acid uptake.