A weekly 4-methylpyrazole treatment attenuates the development of non-obese metabolic dysfunction-associated steatotic liver disease (MASLD) in male mice: Role of JNK
- Autor(en)
- Katharina Burger, Finn Jung, Raphaela Staltner, Katja Csarmann, Kerstin Schweiger, Annette Brandt, Anja Baumann, Julia Scholda, Florian Kopp, Ina Bergheim
- Abstrakt
Background: 4-methylpyrazole (4MP, fomepizole) is a competitive inhibitor of alcohol dehydrogenase (ADH) preventing the metabolism of ethylene glycol and methanol, respectively, into their toxic metabolites. 4MP seems also to possess a potential in the treatment of intoxication from other substance, for example, acetaminophen, and to modulate JNK-dependent signalling. Here, we determined if a treatment with 4MP once weekly affects the development of diet-induced non-obese metabolic dysfunction-associated steatotic liver disease (MASLD) in C57BL/6 mice. Methods: Male C57BL/6 mice (6–8 weeks old, n = 7-8/group) were pair-fed either a liquid control diet (C) or a liquid sucrose-, fat- and cholesterol-rich diet (SFC) for 8 weeks while being concomitantly treated with 4MP (50 mg/kg bw i.p.) or vehicle once a week. Liver damage, inflammatory markers and glucose tolerance were assessed. Moreover, in endotoxin-challenged J774A.1 cells pretreated with 4MP, pro-inflammatory markers were assessed. Results: The concomitant treatment of SFC-fed mice with 4MP attenuated the increase in JNK phosphorylation and pro-inflammatory markers like IFNγ, IL-6 and 3-nitrotyrosine protein adducts in liver tissue found in vehicle-treated SFC-fed mice, while not affecting impairments of glucose tolerance or the increase in portal endotoxin levels. Moreover, a pretreatment of endotoxin-stimulated J774A.1 cells with 4MP significantly attenuated the increases in JNK phosphorylation and pro-inflammatory mediators like IL-6 and Mcp1. Conclusions: Taken together, our results suggest that a treatment with 4MP once weekly attenuates the activation of JNK and dampens the development of non-obese MASLD in mice.
- Organisation(en)
- Department für Ernährungswissenschaften, Department für Pharmazeutische Wissenschaften
- Journal
- European Journal of Clinical Investigation
- Band
- 55
- ISSN
- 0014-2972
- DOI
- https://doi.org/10.1111/eci.14320
- Publikationsdatum
- 09-2024
- Peer-reviewed
- Ja
- ÖFOS 2012
- 303009 Ernährungswissenschaften
- Schlagwörter
- ASJC Scopus Sachgebiete
- Biochemistry, Clinical Biochemistry
- Link zum Portal
- https://ucrisportal.univie.ac.at/de/publications/ae39394e-7d97-4768-aabf-a075c70ee1c0