Methotrexate-induced liver injury is associated with oxidative stress, impaired mitochondrial respiration, and endoplasmic reticulum stress in vitro
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Authors
Author (Corporation)
Publication date
01.12.2022
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Type
01A - Journal article
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Parent work
International Journal of Molecular Sciences
Special issue
Molecular Mechanisms of Hepatotoxicity
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Series number
Volume
23
Issue / Number
23
Pages / Duration
1-17
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Publisher / Publishing institution
MDPI
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Abstract
Low-dose methotrexate (MTX) is a standard therapy for rheumatoid arthritis due to its low cost and efficacy. Despite these benefits, MTX has been reported to cause chronic drug-induced liver injury, namely liver fibrosis. The hallmark of liver fibrosis is excessive scarring of liver tissue, triggered by hepatocellular injury and subsequent activation of hepatic stellate cells (HSCs). However, little is known about the precise mechanisms through which MTX causes hepatocellular damage and activates HSCs. Here, we investigated the mechanisms leading to hepatocyte injury in HepaRG and used immortalized stellate cells (hTERT-HSC) to elucidate the mechanisms leading to HSC activation by exposing mono- and co-cultures of HepaRG and hTERT-HSC to MTX. The results showed that at least two mechanisms are involved in MTX-induced toxicity in HepaRG: (i) oxidative stress through depletion of glutathione (GSH) and (ii) impairment of cellular respiration in a GSH-independent manner. Furthermore, we measured increased levels of endoplasmic reticulum (ER) stress in activated HSC following MTX treatment. In conclusion, we established a human-relevant in vitro model to gain mechanistical insights into MTX-induced hepatotoxicity, linked oxidative stress in HepaRG to a GSH-dependent and -independent pathway, and hypothesize that not only oxidative stress in hepatocytes but also ER stress in HSCs contribute to MTX-induced activation of HSCs.
Keywords
HepaRG, ER stress, Methotrexate, Liver fibrosis, In vitro model, Oxidative stress, Stellate cells, Mitochondria
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ISBN
ISSN
1422-0067
1661-6596
1661-6596
Language
English
Created during FHNW affiliation
Yes
Strategic action fields FHNW
Publication status
Published
Review
Peer review of the complete publication
Open access category
Gold
License
Citation
Schmidt, S., Messner, C., Gaiser, C., Hämmerli, C., & Suter-Dick, L. (2022). Methotrexate-induced liver injury is associated with oxidative stress, impaired mitochondrial respiration, and endoplasmic reticulum stress in vitro. International Journal of Molecular Sciences, 23(23), 1–17. https://doi.org/10.3390/ijms232315116