Steatosis is a liver lesion reported with numerous pharmaceuticals. Prior studies showed that severe impairment of mitochondrial fatty acid oxidation (mtFAO) constantly leads to lipid accretion in liver. However, much less is known about the mechanism(s) of drug-induced steatosis in the absence of severe mitochondrial dysfunction, although previous studies suggested the involvement of mild-to-moderate inhibition of mtFAO, increased de novo lipogenesis (DNL), and impairment of very low-density lipoprotein (VLDL) secretion. The objective of our study, mainly carried out in human hepatoma HepaRG cells, was to investigate these 3 mechanisms with 12 drugs able to induce steatosis in human: amiodarone (AMIO, used as positive control), allopurinol (ALLO), d-penicillamine (DPEN), 5-fluorouracil (5FU), indinavir (INDI), indomethacin (INDO), methimazole (METHI), methotrexate (METHO), nifedipine (NIF), rifampicin (RIF), sulindac (SUL), and troglitazone (TRO). Hepatic cells were exposed to drugs for 4 days with concentrations decreasing ATP level by less than 30% as compared to control and not exceeding 100 × C_max. Among the 12 drugs, AMIO, ALLO, 5FU, INDI, INDO, METHO, RIF, SUL, and TRO induced steatosis in HepaRG cells. AMIO, INDO, and RIF decreased mtFAO. AMIO, INDO, and SUL enhanced DNL. ALLO, 5FU, INDI, INDO, SUL, RIF, and TRO impaired VLDL secretion. These seven drugs reduced the mRNA level of genes playing a major role in VLDL assembly and also induced endoplasmic reticulum (ER) stress. Thus, in the absence of severe mitochondrial dysfunction, drug-induced steatosis can be triggered by different mechanisms, although impairment of VLDL secretion seems more frequently involved, possibly as a consequence of ER stress.

脂肪变性是多种药物报道的一种肝脏病变。先前的研究表明，线粒体脂肪酸氧化（mtFAO）的严重受损会不断导致肝脏中的脂质堆积。然而，对于在没有严重线粒体功能障碍的情况下药物诱导的脂肪变性的机制知之甚少，尽管之前的研究表明与轻度至中度抑制 mtFAO、增加从头脂肪生成 (DNL) 和极低密度脂蛋白（VLDL）分泌受损。我们的研究主要在人肝癌 HepaRG 细胞中进行，目的是研究 12 种能够诱导人脂肪变性的药物的 3 种机制：胺碘酮（AMIO，用作阳性对照）、别嘌呤醇（ALLO）、 d-青霉胺（ DPEN)、5-氟尿嘧啶 (5FU)、茚地那韦 (INDI)、吲哚美辛 (INDO)、甲硫咪唑 (METHI)、甲氨蝶呤 (METHO)、硝苯地平 (NIF)、利福平 (RIF)、舒林酸 (SUL) 和曲格列酮 (TRO) 。肝细胞暴露于药物 4 天，与对照相比，药物浓度使 ATP 水平降低不到 30%，且不超过 100 × C _max 。 12种药物中，AMIO、ALLO、5FU、INDI、INDO、METHO、RIF、SUL和TRO诱导HepaRG细胞脂肪变性。 AMIO、INDO 和 RIF 降低了 mtFAO。 AMIO、INDO 和 SUL 增强了 DNL。 ALLO、5FU、INDI、INDO、SUL、RIF 和 TRO 损害 VLDL 分泌。这七种药物降低了在 VLDL 组装中起主要作用的基因的 mRNA 水平，并诱导内质网 (ER) 应激。因此，在没有严重线粒体功能障碍的情况下，药物诱导的脂肪变性可以通过不同的机制触发，尽管 VLDL 分泌受损似乎更常见，可能是 ER 应激的结果。