Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/11239
JNK-mediated disruption of bile acid homeostasis promotes intrahepatic cholangiocarcinoma.
Manieri, Elisa CNIC | Folgueira, Cintia | Rodríguez, María Elena | Leiva-Vega, Luis CNIC | Esteban-Lafuente, Laura | Chen, Chaobo | Cubero, Francisco Javier | Barrett, Tamera | Cavanagh-Kyros, Julie | Seruggia, Davide | Rosell, Alejandro | Sanchez-Cabo, Fatima CNIC | Gomez, Manuel J CNIC | Monte, Maria J | G Marin, Jose J | Davis, Roger J | Mora, Alfonso CNIC | Sabio, Guadalupe CNIC
Proc Natl Acad Sci U S A. 2020; 117(28):16492-16499
Metabolic stress causes activation of the cJun NH2-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.
Animals | Bile Acids and Salts | Cholangiocarcinoma | Homeostasis | Humans | Male | Mice | Mice, Inbred C57BL | Mice, Knockout | Mitogen-Activated Protein Kinase 8 | Mitogen-Activated Protein Kinase 9 | PPAR alpha
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