JNK-mediated disruption of bile acid homeostasis promotes intrahepatic cholangiocarcinoma
Davis, Roger J.
Document TypeJournal Article
Amino Acids, Peptides, and Proteins
Biochemical Phenomena, Metabolism, and Nutrition
Cellular and Molecular Physiology
Enzymes and Coenzymes
Nutritional and Metabolic Diseases
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AbstractMetabolic 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 PPARalpha. 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 PPARalpha 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.
Manieri E, Folgueira C, Rodríguez ME, Leiva-Vega L, Esteban-Lafuente L, Chen C, Cubero FJ, Barrett T, Cavanagh-Kyros J, Seruggia D, Rosell A, Sanchez-Cabo F, Gómez MJ, Monte MJ, G Marin JJ, Davis RJ, Mora A, Sabio G. JNK-mediated disruption of bile acid homeostasis promotes intrahepatic cholangiocarcinoma. Proc Natl Acad Sci U S A. 2020 Jul 14;117(28):16492-16499. doi: 10.1073/pnas.2002672117. Epub 2020 Jun 29. PMID: 32601222. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/29502
Full author list omitted for brevity. For the full list of authors, see article.