2026-04-29T15:04:01Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/112392024-09-27T09:50:42Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Manieri, Elisa author Folgueira, Cintia author Rodríguez, María Elena author Leiva-Vega, Luis author Esteban-Lafuente, Laura author Chen, Chaobo author Cubero, Francisco Javier author Barrett, Tamera author Cavanagh-Kyros, Julie author Seruggia, Davide author Rosell, Alejandro author Sanchez-Cabo, Fatima author Gomez, Manuel J author Monte, Maria J author G Marin, Jose J author Davis, Roger J author Mora, Alfonso author Sabio, Guadalupe author 2020-07 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. Proc Natl Acad Sci U S A. 2020; 117(28):16492-16499 10.1073/pnas.2002672117 0027-8424 Proceedings of the National Academy of Sciences of the United States of America 32601222 http://hdl.handle.net/20.500.12105/11239 JNK-mediated disruption of bile acid homeostasis promotes intrahepatic cholangiocarcinoma.