Drug-induced liver injury: Oltipraz and C2-ceramide intervene HNF-1 alpha/GSTA1 expression via JNK signaling pathway

文献类型： 外文期刊

第一作者： Zhang, Yuanyuan

作者： Zhang, Yuanyuan;Ma, Bingke;Hao, Shuangshuang;Wang, Jiaqi;Zhang, Ruichen;Ishfaq, Muhammad;Shi, Chenxi;Yuan, Liang;Li, Rui;Liu, Fangping;Li, Rui;Liu, Fangping;Li, Changwen

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关键词： C2‐ ceramide; drug‐ induced liver injury; GSTA1; HNF‐ 1α JNK signaling pathway; Oltipraz

期刊名称：JOURNAL OF APPLIED TOXICOLOGY （ 影响因子：2.997； 五年影响因子：3.131 ）

ISSN： 0260-437X

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收录情况： SCI

摘要： Drug-induced liver injury (DILI) is a serious and frequently occurring issue in drug development. The c-Jun N-terminal kinase (JNK) signaling pathway plays an important role in many diseases; hepatocyte nuclear factor-1 alpha (HNF-1 alpha) and glutathione S-transferase A1 (GSTA1) are important in regulating liver-specific genes expressions and affecting drug metabolism. Oltipraz is used to treat liver cirrhosis by improving liver function, and C2-ceramide is a pro-apoptotic lipid that regulates multiple signaling pathways. In this study, we investigated the function of the JNK signaling pathway with HNF-1 alpha and GSTA1 in a cellular model of DILI and whether oltipraz and C2-ceramide exert effects via the JNK pathway. The results showed that inhibiting JNK could ameliorate APAP-induced hepatocyte injury, reduced oxidative stress, suppressed JNK and c-Jun activation, and hepatocyte apoptosis. Meanwhile, the mRNA and protein expressions of HNF-1 alpha and GSTA1 were increased significantly compared to control conditions. The effect of oltipraz (8 mu mol/L) was similar to a JNK inhibitor and significantly increased HNF-1 alpha/GSTA1 expression, but oltipraz combined with JNK inhibitor did not show a synergistic effect. Although C2-ceramide (8 mu mol/L) aggravated hepatocyte injury and apoptosis, exacerbated oxidative stress, increased phosphorylation of JNK and c-Jun, and markedly decreased HNF-1 alpha/GSTA1 expression, C2-ceramide combined with JNK inhibitor could partially alleviate these alterations. These results demonstrated that the JNK signaling pathway with HNF-1 alpha/GSTA1 are involved in the process of DILI. Inhibiting JNK up-regulated HNF-1 alpha and GSTA1 expressions which could attenuate hepatocyte injury. Oltipraz and C2-ceramide might affect the expression of HNF-1 alpha/GSTA1 though JNK signaling.

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