Diethyldithiocarbamate, an anti-abuse drug, alleviates steatohepatitis and fibrosis in rodents through modulating lipid metabolism and oxidative stress
Diethyldithiocarbamate, an anti-abuse drug, alleviates steatohepatitis and fibrosis in rodents through modulating lipid metabolism and oxidative stress
复制标题
二乙基二硫代氨基甲酸酯是一种抗滥用药物，通过调节脂质代谢和氧化应激来减轻啮齿动物的脂肪性肝炎和纤维化。
DOI：
10.1111/bph.14503
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发表时间：
2018-12-01
影响因子：
7.3
通讯作者：
You, Hong
中科院分区：
文献类型：
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作者：
Liu, Tianhui;Wang, Ping;You, Hong
背景和目的实验方法二乙二硫代氨基甲酸酯（DDC）是双硫仑的主要代谢物，双硫仑是一种潜在的酗酒治疗药物。在本研究中，我们试图探讨DDC对体内非酒精性脂肪性肝病（NAFLD）及其相关纤维化的可能影响。C57 BL/6小鼠和Sprague道利（SD）大鼠接受蛋氨酸/胆碱缺乏（MCD）饲料，以建立伴或不伴DDC治疗的NAFLD模型。评估肝脏和血清的组织学变化以及与脂质代谢、肝损伤、炎症和纤维化相关的参数。通过免疫组织化学（IHC）评估细胞凋亡和巨噬细胞相关标志物。关键结果结论和意义DDC可显著降低MCD饮食诱导的NAFLD大鼠的肝脏脂肪变性。DDC降低了由MCD饮食诱导的非酒精性脂肪性肝炎小鼠的氧化应激和内质网应激相关参数。免疫组化法检测Bax和caspase-3的表达，结果显示DDC可抑制肝细胞凋亡。DDC显著减少肝细胞中的气球样变和Mallory-Denk小体（MDB），同时抑制血清丙氨酸氨基转移酶、天冬氨酸氨基转移酶和MDB形成相关基因。DDC可明显减轻肝脏炎症反应，并伴有炎症相关基因的抑制。DDC抑制巨噬细胞的浸润，特别是诱导型NOS阳性促炎巨噬细胞。DDC能明显减轻肝纤维化。微阵列分析表明，DDC强烈影响脂质代谢和氧化应激相关的过程和途径。DDC通过调节脂质代谢和氧化应激改善NAFLD啮齿动物模型中的肝脂肪变性、气球样变、炎症和纤维化。
Background and Purpose Experimental Approach Diethyldithiocarbamate (DDC) is a major metabolite of disulfiram that is a potential drug for alcoholism treatment. In the present study, we attempted to explore the possible effect of DDC on non-alcoholic fatty liver disease (NAFLD) and related fibrosis in vivo. C57BL/6 mice and Sprague Dawley (SD) rats received a methionine/choline-deficient (MCD) diet to establish the model of NAFLD with or without DDC treatment. The livers and serum were assessed for histological changes and parameters related to lipid metabolism, liver injury, inflammation and fibrosis. Apoptosis and macrophage related markers were assessed by immunohistochemistry (IHC). Key Results Conclusion and Implications DDC significantly reduced hepatic steatosis in rats with NAFLD, induced by the MCD diet. DDC reduced the oxidative stress and endoplasmic reticulum stress-related parameters in mice with non-alcoholic steatohepatitis, induced by the MCD diet. IHC for Bax and cleaved caspase-3 showed that DDC inhibited the apoptosis of hepatocytes in the liver. DDC significantly reduced ballooning and Mallory-Denk bodies (MDB) in hepatocytes, accompanied by suppression of serum alanine aminotransferase, aspartate aminotransferase and MDB formation-related genes. DDC significantly alleviated hepatic inflammation, accompanied by suppression of inflammation-related genes. DDC suppressed the infiltration of macrophages, particularly inducible NOS-positive pro-inflammatory macrophages. In addition, DDC significantly alleviated liver fibrosis. Microarray analyses showed that DDC strongly affected lipid metabolism and oxidative stress-related processes and pathways. DDC improves hepatic steatosis, ballooning, inflammation and fibrosis in rodent models of NAFLD through modulating lipid metabolism and oxidative stress.