JNK-mediated disruption of bile acid homeostasis promotes intrahepatic cholangiocarcinoma.

Autor: Manieri E; Centro Nacional de Investigaciones Cardiovasculares, Myocardial Pathophysiology Area, 28029 Madrid, Spain.; Department of Immunology and Oncology, Centro Nacional de Biotecnología, Consejo Superior de Investigaciones Científicas, 28049 Madrid, Spain., Folgueira C; Centro Nacional de Investigaciones Cardiovasculares, Myocardial Pathophysiology Area, 28029 Madrid, Spain., Rodríguez ME; Centro Nacional de Investigaciones Cardiovasculares, Myocardial Pathophysiology Area, 28029 Madrid, Spain., Leiva-Vega L; Centro Nacional de Investigaciones Cardiovasculares, Myocardial Pathophysiology Area, 28029 Madrid, Spain., Esteban-Lafuente L; Centro Nacional de Investigaciones Cardiovasculares, Myocardial Pathophysiology Area, 28029 Madrid, Spain., Chen C; Department of Immunology, Ophthalmology, and ENT, Complutense University School of Medicine, 28040 Madrid, Spain., Cubero FJ; Department of Immunology, Ophthalmology, and ENT, Complutense University School of Medicine, 28040 Madrid, Spain., Barrett T; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605., Cavanagh-Kyros J; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605., Seruggia D; Division of Hematology/Oncology, Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215., Rosell A; Centro Nacional de Investigaciones Cardiovasculares, Myocardial Pathophysiology Area, 28029 Madrid, Spain., Sanchez-Cabo F; Centro Nacional de Investigaciones Cardiovasculares, Myocardial Pathophysiology Area, 28029 Madrid, Spain., Gómez MJ; Centro Nacional de Investigaciones Cardiovasculares, Myocardial Pathophysiology Area, 28029 Madrid, Spain., Monte MJ; Laboratory of Experimental Hepatology and Drug Targeting, National Institute for Study of Liver and Gastrointestinal Diseases (CIBERehd), University of Salamanca, 37007 Salamanca, Spain., G Marin JJ; Laboratory of Experimental Hepatology and Drug Targeting, National Institute for Study of Liver and Gastrointestinal Diseases (CIBERehd), University of Salamanca, 37007 Salamanca, Spain., Davis RJ; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605; roger.davis@umassmed.edu amora@cnic.es guadalupe.sabio@cnic.es., Mora A; Centro Nacional de Investigaciones Cardiovasculares, Myocardial Pathophysiology Area, 28029 Madrid, Spain; roger.davis@umassmed.edu amora@cnic.es guadalupe.sabio@cnic.es., Sabio G; Centro Nacional de Investigaciones Cardiovasculares, Myocardial Pathophysiology Area, 28029 Madrid, Spain; roger.davis@umassmed.edu amora@cnic.es guadalupe.sabio@cnic.es.
Jazyk: angličtina
Zdroj: Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Jul 14; Vol. 117 (28), pp. 16492-16499. Date of Electronic Publication: 2020 Jun 29.
DOI: 10.1073/pnas.2002672117
Abstrakt: Metabolic stress causes activation of the cJun NH 2 -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.
Competing Interests: The authors declare no competing interest.
(Copyright © 2020 the Author(s). Published by PNAS.)
Databáze: MEDLINE
Externí odkaz: