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Diethyldithiocarbamate, an anti‐abuse drug, alleviates steatohepatitis and fibrosis in rodents through modulating lipid metabolism and oxidative stress
Author(s) -
Liu Tianhui,
Wang Ping,
Cong Min,
Zhao Xinyan,
Zhang Dong,
Xu Hufeng,
Liu Lin,
Jia Jidong,
You Hong
Publication year - 2018
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.14503
Subject(s) - steatohepatitis , steatosis , lipid metabolism , fatty liver , oxidative stress , inflammation , liver injury , fibrosis , medicine , endocrinology , pharmacology , biology , disease
Background and Purpose 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 . Experimental Approach 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 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. Conclusion and Implications DDC improves hepatic steatosis, ballooning, inflammation and fibrosis in rodent models of NAFLD through modulating lipid metabolism and oxidative stress.