Cubero Palero, Francisco JavierTrautwein, Christian2024-02-012024-02-012016-08-02Cubero FJ, Zoubek ME, Hu W, Peng J, Zhao G, Nevzorova YA, Al Masaoudi M, Bechmann LP, Boekschoten MV, Muller M, Preisinger C, Gassler N, Canbay AE, Luedde T, Davis RJ, Liedtke C, Trautwein C. Combined Activities of JNK1 and JNK2 in Hepatocytes Protect Against Toxic Liver Injury. Gastroenterology. 2016 Apr;150(4):968-81. doi: 10.1053/j.gastro.2015.12.0190016-508510.1053/j.gastro.2015.12.019https://hdl.handle.net/20.500.14352/97631Instituciones participantes: 1Department of Internal Medicine III, University Hospital, RWTH Aachen; 2Department of Gastroenterology and Hepatology, University Hospital Duisburg-Essen, Essen, Germany; 3Nutrition, Metabolism & Genomics group, Wageningen University, Division of Human Nutrition, Wageningen, The Netherlands; 4Norwich Medical School, University of East Anglia, Norwich, United Kingdom; 5Proteomics Facility, University Hospital, RWTH Aachen; 6Institute of Pathology, University Hospital, RWTH Aachen, Germany; and 7Howard Hughes Medical Institute and University of Massachusetts Medical School, Worcester, MassachusettsBACKGROUND & AIMS: c-Jun N-terminal kinase (JNK) 1 and JNK2 are expressed in hepatocytes and have overlapping and distinct functions. JNK proteins are activated via phosphorylation in response to acetaminophen- or carbon tetrachloride (CCl4)- induced liver damage; the level of activation correlates with the degree of injury. SP600125, a JNK inhibitor, has been reported to block acetaminophen-induced liver injury. We investigated the role of JNK in drug-induced liver injury (DILI) in liver tissue from patients and in mice with genetic deletion of JNK in hepatocytes. METHODS: We studied liver sections from patients with DILI (due to acetaminophen, phenprocoumon, nonsteroidal antiinflammatory drugs, or autoimmune hepatitis) or patients without acute liver failure (controls) collected from a DILI Biobank in Germany. Levels of total and activated (phosphorylated) JNK were measured by immunohistochemistry and Western blotting. Mice with hepatocyte-specific deletion of Jnk1 (Jnk1Dhepa) or combination of Jnk1 and Jnk2 (JnkDhepa), as well as Jnk1-floxed C57BL/6 (control) mice, were given injections of CCl4 (to induce fibrosis) or acetaminophen (to induce toxic liver injury). We performed gene expression microarray and phosphoproteomic analyses to determine mechanisms of JNK activity in hepatocytes. RESULTS: Liver samples from DILI patients contained more activated JNK, predominantly in nuclei of hepatocytes and in immune cells, than healthy tissue. Administration of acetaminophen to JnkDhepa mice produced a greater level of liver injury than that observed in Jnk1Dhepa or control mice, based on levels of serum markers and microscopic and histologic analysis of liver tissues. Administration of CCl4 also induced stronger hepatic injury in JnkDhepa mice, based on increased inflammation, cell proliferation, and fibrosis progression, compared with Jnk1Dhepa or control mice. Hepatocytes from JnkDhepa mice given acetaminophen had an increased oxidative stress response, leading to decreased activation of adenosine monophosphate-activated protein kinase, total protein adenosine monophosphate-activated protein kinase levels, and pJunD and subsequent necrosis. Administration of SP600125 before or with acetaminophen protected JnkDhepa and control mice from liver injury. CONCLUSIONS: In hepatocytes, JNK1 and JNK2 appear to have combined effects in protecting mice from CCl4- and acetaminophen-induced liver injury. It is important to study the tissue-specific functions of both proteins, rather than just JNK1, in the onset of toxic liver injury. JNK inhibition with SP600125 shows off-target effects.engAttribution-NonCommercial-NoDerivatives 4.0 Internationaljournal articlehttps://www.sciencedirect.com/science/article/pii/S0016508515018144?via%3Dihub26708719https://pubmed.ncbi.nlm.nih.gov/26708719/open access577APAPGene RegulationMouse ModelPharmacologic TreatmentCiencias BiomédicasBiologíaBiología celular (Biología)Biología molecular (Biología)MedicinaGastroenterología y hepatologíaInmunología24 Ciencias de la Vida2407 Biología Celular2410 Biología Humana2412 Inmunología2415 Biología Molecular