Hepatic JNK-mediated bile acid homeostasis regulates liver cancer through PPARα

Manieri, E.; Esteban-Lafuente, L.; Rodriguez, E.; Leiva-Vega, L.; Chen, C.; Cubero, F. J.; Barrett, T.; Cavanagh-Kyros, J.; Seruggia, D.; Monte, M. J.; Marin, J. J.; Davis, R. R. J.; Mora, A.; Sabio, G.

doi:10.1101/783761

bioRxiv · 10.1101/783761

Hepatic JNK-mediated bile acid homeostasis regulates liver cancer through PPARα

Manieri, E.·Esteban-Lafuente, L.·Rodriguez, E.·Leiva-Vega, L.·Chen, C.·Cubero, F. J.·Barrett, T.·Cavanagh-Kyros, J.·Seruggia, D.·Monte, M. J.·Marin, J. J.·Davis, R. R. J.·Mora, A.·Sabio, G.

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Abstract

cJun NH2-terminal kinase (JNK) inhibition has been suggested as a potential treatment for insulin resistance and steatosis through activation of the transcription factor PPAR. However, the long-term consequences have not been evaluated. We found that hepatic JNK deficiency alters bile acid and cholesterol metabolism, resulting in hepatic expression of FGF15 and activation of ERK in cholangiocytes, which ultimately promotes their proliferation. Genetic inactivation of PPAR identifies PPAR hyperactivation as the molecular mechanism for these deleterious effects. Our analysis indicates that hepatic PPAR activation is oncogenic: PPAR deficiency protects mice against carcinogen-induced hepatocellular carcinoma under high fat diet (HFD) condition. These surprising results urge the re-consideration of using JNK inhibitors or PPAR agonists for the treatment of metabolic syndrome.

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Manieri, E., Esteban-Lafuente, L., Rodriguez, E., Leiva-Vega, L., Chen, C., Cubero, F. J., Barrett, T., Cavanagh-Kyros, J., Seruggia, D., Monte, M. J., Marin, J. J., Davis, R. R. J., Mora, A., Sabio, G.. 2019-09-29. Hepatic JNK-mediated bile acid homeostasis regulates liver cancer through PPARα. https://doi.org/10.1101/783761

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