University of Massachusetts Medical School Faculty Publications

UMMS Affiliation

Program in Molecular Medicine; Davis Lab

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Document Type



Amino Acids, Peptides, and Proteins | Biochemical Phenomena, Metabolism, and Nutrition | Cancer Biology | Cell Biology | Cellular and Molecular Physiology | Enzymes and Coenzymes | Lipids | Molecular Biology | Nutritional and Metabolic Diseases | Physiological Processes


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 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.


JNK, PPARa, bile acid, cholangiocarcinoma

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Copyright © 2020 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

DOI of Published Version



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


Full author list omitted for brevity. For the full list of authors, see article.

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Journal/Book/Conference Title

Proceedings of the National Academy of Sciences of the United States of America

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Creative Commons License

Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.