Benzbromarone aggravates hepatic steatosis in obese individuals
Benzbromarone aggravates hepatic steatosis in obese individuals
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苯溴马隆加重肥胖者的肝脏脂肪变性
DOI：
10.1016/j.bbadis.2018.03.009
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发表时间：
2018
影响因子：
6.2
通讯作者：
Wang He-Yao
中科院分区：
文献类型：
--
作者：
Sun Peng;Zhu Jing-Jie;Wang Ting;Huang Qi;Zhou Yu-Ren;Yu Bang-Wei;Jiang Hua-Liang;Wang He-Yao
苯溴马龙作为一种广泛应用的抗痛风药物，在临床治疗过程中发现对患者有肝毒性。先前的研究报道苯溴马龙通过细胞色素P450代谢，从而引起肝细胞线粒体毒性。在这项研究中，我们发现苯溴马隆显著加重了肥胖db/db小鼠和高脂饮食（HFD）诱导的肥胖（DIO）小鼠模型的肝脏脂肪变性。而苯溴马龙对瘦小鼠肝脏的影响较小。结果发现，与对照组相比，苯溴马龙处理的DIO小鼠的脂质代谢编码mrna和一些肝脏特异性基因的表达明显受到干扰。苯溴马龙处理的DIO小鼠肝脏炎症和氧化应激因子也被激活。与体内实验结果一致，利用人肝癌HepG2细胞进行的体外实验也证实了苯溴马龙通过调节脂质代谢基因的表达，促进高游离脂肪酸（FFAs）条件下细胞内脂质积累。重要的是，长时间的苯溴马龙治疗显著增加了高游离脂肪酸存在下HepG2细胞的细胞凋亡。此外，在苯溴马龙治疗的高尿酸血症患者中，血清转氨酶水平与患者的肥胖水平呈正相关。结论本研究表明苯溴马隆可加重肥胖者肝脂肪变性，进而导致肝细胞损伤，提示苯溴马隆引起肝毒性的一种新的毒理学机制。
As a widely used anti-gout drug, benzbromarone has been found to induce hepatic toxicity in patients during clinical treatment. Previous studies have reported that benzbromarone is metabolized via cytochrome P450, thus causing mitochondrial toxicity in hepatocytes. In this study, we found that benzbromarone significantly aggravated hepatic steatosis in both obese db/db mice and high fat diet (HFD)-induced obese (DIO) mouse models. However, benzbromarone had less effect on the liver of lean mice. It was found that the expression of mRNAs encoding lipid metabolism and some liver-specific genes were obviously disturbed in benzbromarone-treated DIO mice compared to the control group. The inflammatory and oxidative stress factors were also activated in the liver of benzbromarone-treated DIO mice. In accordance with the in vivo results, an in vitro experiment using human hepatoma HepG2 cells also confirmed that benzbromarone promoted intracellular lipid accumulation under high free fatty acids (FFAs) conditions by regulating the expression of lipid metabolism genes. Importantly, prolonged treatment of benzbromarone significantly increased cell apoptosis in HepG2 cells in the presence of high FFAs. In addition, in benzbromarone-treated hyperuricemic patients, serum transaminase levels were positively correlated with patients' obesity level.ConclusionThis study demonstrated that benzbromarone aggravated hepatic steatosis in obese individuals, which could subsequently contribute to hepatic cell injury, suggesting a novel toxicological mechanism in benzbromarone-induced hepatotoxicity.