JNK-mediated disruption of bile acid homeostasis promotes intrahepatic cholangiocarcinoma
JNK-mediated disruption of bile acid homeostasis promotes intrahepatic cholangiocarcinoma
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DOI：
10.1073/pnas.2002672117
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发表时间：
2020-07-14
影响因子：
11.1
通讯作者：
Sabio, Guadalupe
中科院分区：
文献类型：
--
作者：
Manieri, Elisa;Folgueira, Cintia;Sabio, Guadalupe
代谢应激导致cJun NH 2-末端激酶（JNK）信号转导途径的激活。已确定JNK激活的一个后果是通过抑制转录因子PPAR α而发展胰岛素抵抗和肝脂肪变性。事实上，肝细胞中JNK 1/2缺陷可防止脂肪变性的发展，这表明JNK抑制剂代表了这种疾病的可能治疗方法。然而，JNK抑制的长期后果尚未评估。在这里，我们证明，肝脏JNK控制胆汁酸的生产。我们发现肝脏JNK缺乏改变胆固醇代谢和胆汁酸合成、结合和转运，导致胆汁淤积、胆管细胞增殖增加和肝内胆管癌。基因消融研究证实，在肝细胞中，PPAR α介导JNK的这些作用。这项分析强调了长期使用JNK抑制剂治疗代谢综合征的潜在后果。
Metabolic stress causes activation of the cJun NH2-terminal kinase (JNK) signal transduction pathway. It is established that one con-sequence of JNK activation is the development of insulin resistance and hepatic steatosis through inhibition of the transcription factor PPAR alpha. Indeed, JNK1/2 deficiency in hepatocytes protects against the development of steatosis, suggesting that JNK inhibition repre-sents a possible treatment for this disease. However, the long-term consequences of JNK inhibition have not been evaluated. Here we demonstrate that hepatic JNK controls bile acid production. We found that hepatic JNK deficiency alters cholesterol metabolism and bile acid synthesis, conjugation, and transport, resulting in cholestasis, increased cholangiocyte proliferation, and intrahepatic cholangiocarcinoma. Gene ablation studies confirmed that PPAR alpha mediated these effects of JNK in hepatocytes. This analysis highlights potential consequences of long-term use of JNK inhibitors for the treatment of metabolic syndrome.