每周一次的4-甲基吡唑治疗可减轻雄性小鼠非肥胖代谢功能障碍相关性脂肪性肝病(MASLD)的发展:JNK的作用

IF 4.4 3区 医学 Q1 MEDICINE, GENERAL & INTERNAL
Katharina Burger, Finn Jung, Raphaela Staltner, Katja Csarmann, Kerstin Schweiger, Annette Brandt, Anja Baumann, Julia Scholda, Florian Kopp, Ina Bergheim
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引用次数: 0

摘要

背景:4-甲基吡唑(4MP,fomepizole)是乙醇脱氢酶(ADH)的竞争性抑制剂,可阻止乙二醇和甲醇分别代谢为有毒的代谢物。4MP 似乎还具有治疗其他物质(如对乙酰氨基酚)中毒的潜力,并能调节依赖于 JNK 的信号传导。在此,我们确定了每周一次使用 4MP 是否会影响 C57BL/6 小鼠饮食诱导的非肥胖代谢功能障碍相关性脂肪性肝病(MASLD)的发展:雄性 C57BL/6 小鼠(6-8 周大,n = 7-8/组)配对饲喂流质对照饮食(C)或富含蔗糖、脂肪和胆固醇的流质饮食(SFC)8 周,同时每周一次接受 4MP (50 毫克/千克体重,i.p. )或药物治疗。对肝损伤、炎症指标和葡萄糖耐量进行了评估。此外,还评估了用 4MP 预处理的内毒素挑战 J774A.1 细胞的促炎标记物:结果:同时用 4MP 处理 SFC 饲养的小鼠可减轻车辆处理的 SFC 饲养小鼠肝组织中 JNK 磷酸化和 IFNγ、IL-6、3-硝基酪氨酸蛋白加合物等促炎标记物的增加,但不会影响葡萄糖耐量的损害或门静脉内毒素水平的增加。此外,用 4MP 对内毒素刺激的 J774A.1 细胞进行预处理,可显著减轻 JNK 磷酸化以及 IL-6 和 Mcp1 等促炎介质的增加:综上所述,我们的研究结果表明,每周使用一次 4MP 可减轻 JNK 的活化,并抑制小鼠非肥胖性 MASLD 的发展。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

A weekly 4-methylpyrazole treatment attenuates the development of non-obese metabolic dysfunction-associated steatotic liver disease (MASLD) in male mice: Role of JNK

A weekly 4-methylpyrazole treatment attenuates the development of non-obese metabolic dysfunction-associated steatotic liver disease (MASLD) in male mice: Role of JNK

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.

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来源期刊
CiteScore
9.50
自引率
3.60%
发文量
192
审稿时长
1 months
期刊介绍: EJCI considers any original contribution from the most sophisticated basic molecular sciences to applied clinical and translational research and evidence-based medicine across a broad range of subspecialties. The EJCI publishes reports of high-quality research that pertain to the genetic, molecular, cellular, or physiological basis of human biology and disease, as well as research that addresses prevalence, diagnosis, course, treatment, and prevention of disease. We are primarily interested in studies directly pertinent to humans, but submission of robust in vitro and animal work is also encouraged. Interdisciplinary work and research using innovative methods and combinations of laboratory, clinical, and epidemiological methodologies and techniques is of great interest to the journal. Several categories of manuscripts (for detailed description see below) are considered: editorials, original articles (also including randomized clinical trials, systematic reviews and meta-analyses), reviews (narrative reviews), opinion articles (including debates, perspectives and commentaries); and letters to the Editor.
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