Drug-induced hepatic steatosis in absence of severe mitochondrial dysfunction in HepaRG cells: proof of multiple mechanism-based toxicity.
Drug-induced hepatic steatosis in absence of severe mitochondrial dysfunction in HepaRG cells: proof of multiple mechanism-based toxicity.
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DOI：
10.1007/s10565-020-09537-1
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发表时间：
2021-04
影响因子：
6.1
通讯作者：
Fromenty B
中科院分区：
文献类型：
--
作者：
Allard J;Bucher S;Massart J;Ferron PJ;Le Guillou D;Loyant R;Daniel Y;Launay Y;Buron N;Begriche K;Borgne-Sanchez A;Fromenty B
脂肪变性是一种用多种药物治疗的肝脏病变。以往的研究表明，线粒体脂肪酸氧化(MtFAO)的严重损伤会持续导致肝脏中的脂质堆积。然而，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(S)知之甚少，尽管先前的研究表明，轻度到中度抑制mtFAO，增加新生脂肪生成，以及极低密度脂蛋白(VLDL)分泌的损害。本研究主要在人肝癌HepaRG细胞中进行，目的是用12种药物：胺碘酮(AMIO，阳性对照)、别嘌醇(Allo)、D-青霉胺(DPEN)、5-氟尿嘧啶(5FU)、吲哚美辛(Indi)、吲哚美辛(Indo)、甲硫咪唑(Meti)、甲氨蝶呤(METO)、硝苯地平(NIF)、利福平(RIF)、舒林达(Sul)和曲格列酮(Tro)，研究这3种诱导人类脂肪变性的药物的作用机制。肝细胞染毒4天，药物浓度不超过100 × Cmax，使三磷酸腺苷水平下降30%以下。在12种药物中，Amio、Allo、5FU、INDI、INDO、METO、RIF、SUL和TRO可诱导HepaRG细胞发生脂肪变性。AMIO、INDO和RIF降低了粮农组织的mtFAO。Amio、Indo和Sul增强了DNL。Allo、5FU、INDi、INDO、Sul、RIF和tro可抑制VLDL的分泌。这七种药物降低了在极低密度脂蛋白组装中起主要作用的基因的mRNA水平，也诱导了内质网(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由不同的机制触发，尽管VLDL分泌的损害似乎更常见，可能是内质网应激的结果。本文的在线版本(10.1007/s10565.020-09537-1)包含补充材料，可供授权用户使用。
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 × Cmax. 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. The online version of this article (10.1007/s10565-020-09537-1) contains supplementary material, which is available to authorized users.
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影响因子：
3.5
作者：
Cuykx, Matthias;Claes, Leen;Covaci, Adrian
通讯作者：
Covaci, Adrian
影响因子：
--
作者：
Bucher S;Le Guillou D;Allard J;Pinon G;Begriche K;Tête A;Sergent O;Lagadic-Gossmann D;Fromenty B
通讯作者：
Fromenty B
DOI：
10.1016/j.comtox.2019.01.007
发表时间：
2019-01-01
期刊：
Computational toxicology (Amsterdam, Netherlands)
影响因子：
--
作者：
Corton, J Christopher
通讯作者：
Corton, J Christopher
影响因子：
3
作者：
Basseri S;Austin RC
通讯作者：
Austin RC
影响因子：
13.5
作者：
Antherieu, Sebastien;Rogue, Alexandra;Robin, Marie-Anne
通讯作者：
Robin, Marie-Anne