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High uric acid induces liver fat accumulation via ROS/JNK/AP-1 signaling
American Journal of Physiology-Endocrinology and Metabolism ( IF 5.1 ) Pub Date : 2021-04-26 , DOI: 10.1152/ajpendo.00518.2020
De Xie 1 , Hairong Zhao 1 , Jiaming Lu 1 , Furong He 1 , Weidong Liu 1 , Wei Yu 1 , Qiang Wang 1 , Ichiro Hisatome 2 , Tetsuya Yamamoto 3 , Hidenori Koyama 3 , Jidong Cheng 1, 3
Affiliation  

Uric acid is the end metabolite derived from the oxidation of purine compounds. Overwhelming evidence shows the vital interrelation between hyperuricemia (HUA) and non-alcoholic fatty liver disease (NAFLD). However, the mechanisms for this association remain unclear. In this study, we investigated the effect of HUA on fat accumulation in human HepG2 hepatoma cells and urate oxidase-knockout (Uox-KO) mice. HUA activated c-Jun N-terminal kinase (JNK) in vivo and in vitro. Furthermore, inhibiting JNK activation by a JNK-specific inhibitor, SP600125, decreased fat accumulation and lipogenic gene expression induced by HUA. Overexpression of the lipogenic enzymes fatty acid synthase and acetyl-CoA carboxylase 1 was via activation of JNK, which was blocked by the JNK inhibitor SP600125. HUA activated AP-1 to upregulate lipogenic gene expression via JNK activation. In addition, HUA caused mitochondrial dysfunction and reactive oxygen species production. Pre-treatment with the antioxidant N-acetyl-L-cysteine could ameliorate HUA-activated JNK and hepatic steatosis. These data suggest that ROS/JNK/AP-1 signaling plays an important role in HUA-mediated fat accumulation in liver.

中文翻译:

高尿酸通过 ROS/JNK/AP-1 信号诱导肝脏脂肪积累

尿酸是嘌呤化合物氧化产生的最终代谢物。压倒性的证据表明高尿酸血症 (HUA) 和非酒精性脂肪肝 (NAFLD) 之间存在重要的相互关系。然而,这种关联的机制仍不清楚。在这项研究中,我们研究了 HUA 对人 HepG2 肝癌细胞和尿酸氧化酶敲除 (Uox-KO) 小鼠脂肪积累的影响。HUA 在体内和体外激活 c-Jun N 端激酶 (JNK)。此外,通过 JNK 特异性抑制剂 SP600125 抑制 JNK 活化,减少了 HUA 诱导的脂肪积累和脂肪生成基因表达。脂肪生成酶脂肪酸合酶和乙酰辅酶 A 羧化酶 1 的过度表达是通过 JNK 的激活而实现的,而 JNK 抑制剂 SP600125 会阻止 JNK 的激活。HUA 激活 AP-1 以通过 JNK 激活上调脂肪生成基因表达。此外,HUA 导致线粒体功能障碍和活性氧的产生。用抗氧化剂 N-乙酰-L-半胱氨酸预处理可以改善 HUA 激活的 JNK 和肝脂肪变性。这些数据表明 ROS/JNK/AP-1 信号在 HUA 介导的肝脏脂肪积累中起重要作用。
更新日期:2021-04-28
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