Drug-induced hepatic steatosis in absence of severe mitochondrial dysfunction in HepaRG cells: proof of multiple mechanism-based toxicity

Autor: Allard, Julien, Bucher, Simon, Massart, Julie, Ferron, Pierre-Jean, Le Guillou, Dounia, Loyant, Roxane, Daniel, Yoann, Launay, Youenn, Buron, Nelly, Begriche, Karima, Borgne-Sanchez, Annie, Fromenty, Bernard
Přispěvatelé: Nutrition, Métabolismes et Cancer (NuMeCan), Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Mitologics S.A.S., Hôpital Robert Debré Paris, INSERM (Institut National de la Santé et de la Recherche Médicale), ANR-16-CE18-0010,MITOXDRUGS,Toxicité mitochondriale des médicaments et stéatose hépatique. Généralisation de la relation causale pour le développement de nouveaux tests prédictifs.(2016), European Project: 825489,H2020,GOLIATH(2019), Jonchère, Laurent, Toxicité mitochondriale des médicaments et stéatose hépatique. Généralisation de la relation causale pour le développement de nouveaux tests prédictifs. - - MITOXDRUGS2016 - ANR-16-CE18-0010 - AAPG2016 - VALID, Beating Goliath: Generation Of NoveL, Integrated and Internationally Harmonised Approaches for Testing Metabolism Disrupting Compounds - GOLIATH - - H20202019-01-19 - 2023-12-31 - 825489 - VALID, Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Agence Nationale de la RechercheFrench National Research Agency (ANR) [ANR-16-CE18-0010], ANR programFrench National Research Agency (ANR), European Union's Horizon 2020 research and innovation program [825489], INSERM (Institut National de la SanteSante et de la Recherche Medicale)
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Cell Biology and Toxicology
Cell Biology and Toxicology, 2021, 37 (2), pp.151-175. ⟨10.1007/s10565-020-09537-1⟩
Cell Biology and Toxicology, Springer Verlag, 2021, 37 (2), pp.151-175. ⟨10.1007/s10565-020-09537-1⟩
ISSN: 0742-2091
1573-6822
Popis: 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. Electronic supplementary material The online version of this article (10.1007/s10565-020-09537-1) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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