RT Journal Article
SR Electronic
T1 Hepatic JNK-mediated bile acid homeostasis regulates liver cancer through PPARα
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 783761
DO 10.1101/783761
A1 Elisa Manieri
A1 Laura Esteban-Lafuente
A1 María Elena Rodríguez
A1 Luis Leiva-Vega
A1 Chaobo Chen
A1 Francisco Javier Cubero
A1 Tamera Barrett
A1 Julie Cavanagh-Kyros
A1 Davide Seruggia
A1 Maria J. Monte
A1 Jose J.G. Marin
A1 Roger J. Davis
A1 Alfonso Mora
A1 Guadalupe Sabio
YR 2019
UL http://biorxiv.org/content/early/2019/09/29/783761.abstract
AB cJun NH2-terminal kinase (JNK) inhibition has been suggested as a potential treatment for insulin resistance and steatosis through activation of the transcription factor PPARα. 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 PPARα identifies PPARα hyperactivation as the molecular mechanism for these deleterious effects. Our analysis indicates that hepatic PPARα activation is oncogenic: PPARα 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.