at the CNIC

Tag: PPARα

JNK-mediated disruption of bile acid homeostasis promotes intrahepatic cholangiocarcinoma

Elisa Manieri, Cintia Folgueira, María Elena Rodríguez, Luis Leiva-Vega, Laura Esteban-Lafuente, Chaobo Chen, Francisco Javier Cubero, Tamera Barrett, Julie Cavanagh-Kyros, Davide Seruggia, Alejandro Rosell, Fátima Sanchez-Cabo, Manuel Jose Gómez, Maria J. Monte, Jose J. G. Marin, Roger J. Davis, Alfonso Mora & Guadalupe Sabio.

Obesity is associated with hepatic steatosis and activation of the cJun NH2-terminal kinase (JNK) stress-signaling pathway. Studies in mice demonstrate that JNK deficiency in the liver prevents the development of hepatic steatosis. This observation suggests that inhibition of JNK signaling may represent a possible treatment for hepatic steatosis. However, the long-term consequences of JNK inhibition are poorly understood.

Liver cholangiocarcinoma (Photo: Chaobo Chen).

Here we demonstrate that loss of JNK causes changes in cholesterol and bile acid metabolism that promote cholestasis, bile duct proliferation, and intrahepatic cholangiocarcinoma. We identify PPARα activation as the molecular mechanism that accounts for this phenotype .

Our analysis has important implications for the long-term use of JNK inhibitors for the treatment of obesity.

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