Induction of Vesicular Steatosis by Amiodarone and Tetracycline Is Associated with Up-regulation of Lipogenic Genes in HepaRG Cells
Induction of Vesicular Steatosis by Amiodarone and Tetracycline Is Associated with Up-regulation of Lipogenic Genes in HepaRG Cells
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DOI：
10.1002/hep.24290
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发表时间：
2011-06-01
期刊：
影响因子：
13.5
通讯作者：
Robin, Marie-Anne
中科院分区：
文献类型：
--
作者：
Antherieu, Sebastien;Rogue, Alexandra;Robin, Marie-Anne
药物性肝损伤通常发生在几周后，并且通常是不可预测的。其特征在于包括脂肪变性和磷脂质病的大范围病变。已报告许多药物（如胺碘酮和四环素）可引起磷脂质病和/或脂肪变性。在这项研究中，使用分化良好的人肝癌HepaRG细胞研究了这两种药物的急性和慢性肝脏作用。重复暴露于任一药物后，在肝细胞样HepaRG细胞中观察到油红O标记的典型脂滴蓄积。胺碘酮导致形成额外的胞浆内囊泡，在所有HepaRG细胞中均未染色。在电子显微镜水平上，这些囊泡表现为典型的板层体，并与磷脂酰乙醇胺和磷脂酰胆碱的增加有关。重复暴露于胺碘酮或四环素后，观察到甘油三酯（TG）的剂量依赖性诱导。这两种药物处理后，几个已知与脂肪生成相关的基因被诱导。相比之下，在由油酸过载诱导的脂肪HepaRG细胞中观察到这些基因中的一些（FXR、SCD 1和THSRP）的相反的失调，支持药物和油酸诱导脂肪变性涉及不同机制的结论。此外，几个与脂滴形成相关的基因（ADFP，PLIN 4）在暴露于药物和油酸后上调。结论：我们的研究结果表明，胺碘酮在短期治疗后引起磷脂质病，并且与四环素一样，在HepaRG细胞中重复暴露后诱导囊泡性脂肪变性。这些数据代表了药物可以在体外诱导囊泡性脂肪变性的第一个证明，并显示了TG积累和脂肪生成基因表达增强之间的直接关系。（肝脏学2011;53：1895-1905）
Drug-induced liver injury occurs in general after several weeks and is often unpredictable. It is characterized by a large spectrum of lesions that includes steatosis and phospholipidosis. Many drugs such as amiodarone and tetracycline have been reported to cause phospholipidosis and/or steatosis. In this study, acute and chronic hepatic effects of these two drugs were investigated using well-differentiated human hepatoma HepaRG cells. Accumulation of typical lipid droplets, labeled with Oil Red O, was observed in hepatocyte-like HepaRG cells after repeat exposure to either drug. Amiodarone caused the formation of additional intracytoplasmic vesicles that did not stain in all HepaRG cells. At the electron microscopic level, these vesicles appeared as typical lamellar bodies and were associated with an increase of phosphatidylethanolamine and phosphatidylcholine. A dose-dependent induction of triglycerides (TG) was observed after repeat exposure to either amiodarone or tetracycline. Several genes known to be related to lipogenesis were induced after treatment by these two drugs. By contrast, opposite deregulation of some of these genes (FASN, SCD1, and THSRP) was observed in fat HepaRG cells induced by oleic acid overload, supporting the conclusion that different mechanisms were involved in the induction of steatosis by drugs and oleic acid. Moreover, several genes related to lipid droplet formation (ADFP, PLIN4) were up-regulated after exposure to both drugs and oleic acid. Conclusion: Our results show that amiodarone causes phospholipidosis after short-term treatment and, like tetracycline, induces vesicular steatosis after repeat exposure in HepaRG cells. These data represent the first demonstration that drugs can induce vesicular steatosis in vitro and show a direct relationship between TG accumulation and enhanced expression of lipogenic genes. (HEPATOLOGY 2011;53:1895-1905)