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  • 标题:JNK-mediated disruption of bile acid homeostasis promotes intrahepatic cholangiocarcinoma
  • 本地全文:下载
  • 作者:Elisa Manieri ; Cintia Folgueira ; María Elena Rodríguez
  • 期刊名称:Proceedings of the National Academy of Sciences
  • 印刷版ISSN:0027-8424
  • 电子版ISSN:1091-6490
  • 出版年度:2020
  • 卷号:117
  • 期号:28
  • 页码:16492-16499
  • DOI:10.1073/pnas.2002672117
  • 出版社:The National Academy of Sciences of the United States of America
  • 摘要:Metabolic stress causes activation of the cJun NH 2 -terminal kinase (JNK) signal transduction pathway. It is established that one consequence of JNK activation is the development of insulin resistance and hepatic steatosis through inhibition of the transcription factor PPARα. Indeed, JNK1/2 deficiency in hepatocytes protects against the development of steatosis, suggesting that JNK inhibition represents 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 PPARα 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.
  • 关键词:JNK ; PPARa ; bile acid ; cholangiocarcinoma
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