Oriol Morales-Ibanez1, Silvia Affò2, Daniel Rodrigo-Torres2, Delia Blaya2, Cristina Millán2, Mar Coll2, Luis Perea2, Gemma Odena3, Thomas Knorpp4, Markus F Templin4, Montserrat Moreno2, José Altamirano5, Rosa Miquel6, Vicente Arroyo7, Pere Ginès7, Juan Caballería7, Pau Sancho-Bru2, Ramon Bataller8. 1. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Facultat de Medicina, Universitat de Barcelona, Barcelona, Catalonia, Spain Division of Gastroenterology and Hepatology, Departments of Medicine and Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. 2. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Facultat de Medicina, Universitat de Barcelona, Barcelona, Catalonia, Spain. 3. Division of Gastroenterology and Hepatology, Departments of Medicine and Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA. 4. Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Baden-Württemberg, Germany. 5. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Facultat de Medicina, Universitat de Barcelona, Barcelona, Catalonia, Spain Liver Unit, Internal Medicine Department, Vall D'Hebron Institut de Recerca, Barcelona, Catalonia, Spain. 6. Pathology Unit, Hospital Clínic, Barcelona, Catalonia, Spain. 7. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Facultat de Medicina, Universitat de Barcelona, Barcelona, Catalonia, Spain Liver Unit, Hospital Clínic, Barcelona, Catalonia, Spain. 8. Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Facultat de Medicina, Universitat de Barcelona, Barcelona, Catalonia, Spain Division of Gastroenterology and Hepatology, Departments of Medicine and Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
Abstract
OBJECTIVE: Alcoholic hepatitis (AH) is often associated with advanced fibrosis, which negatively impacts survival. We aimed at identifying kinases deregulated in livers from patients with AH and advanced fibrosis in order to discover novel molecular targets. DESIGN: Extensive phosphoprotein analysis by reverse phase protein microarrays was performed in AH (n=12) and normal human livers (n=7). Ribosomal S6 kinase (p90RSK) hepatic expression was assessed by qPCR, Western blot and immunohistochemistry. Kaempferol was used as a selective pharmacological inhibitor of the p90RSK pathway to assess the regulation of experimentally-induced liver fibrosis and injury, using in vivo and in vitro approaches. RESULTS: Proteomic analysis identified p90RSK as one of the most deregulated kinases in AH. Hepatic p90RSK gene and protein expression was also upregulated in livers with chronic liver disease. Immunohistochemistry studies showed increased p90RSK staining in areas of active fibrogenesis in cirrhotic livers. Therapeutic administration of kaempferol to carbon tetrachloride-treated mice resulted in decreased hepatic collagen deposition, and expression of profibrogenic and proinflammatory genes, compared to vehicle administration. In addition, kaempferol reduced the extent of hepatocellular injury and degree of apoptosis. In primary hepatic stellate cells, kaempferol and small interfering RNA decreased activation of p90RSK, which in turn regulated key profibrogenic actions. In primary hepatocytes, kaempferol attenuated proapoptotic signalling. CONCLUSIONS: p90RSK is upregulated in patients with chronic liver disease and mediates liver fibrogenesis in vivo and in vitro. These results suggest that the p90RSK pathway could be a new therapeutic approach for liver diseases characterised by advanced fibrosis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
OBJECTIVE:Alcoholic hepatitis (AH) is often associated with advanced fibrosis, which negatively impacts survival. We aimed at identifying kinases deregulated in livers from patients with AH and advanced fibrosis in order to discover novel molecular targets. DESIGN: Extensive phosphoprotein analysis by reverse phase protein microarrays was performed in AH (n=12) and normal human livers (n=7). Ribosomal S6 kinase (p90RSK) hepatic expression was assessed by qPCR, Western blot and immunohistochemistry. Kaempferol was used as a selective pharmacological inhibitor of the p90RSK pathway to assess the regulation of experimentally-induced liver fibrosis and injury, using in vivo and in vitro approaches. RESULTS: Proteomic analysis identified p90RSK as one of the most deregulated kinases in AH. Hepatic p90RSK gene and protein expression was also upregulated in livers with chronic liver disease. Immunohistochemistry studies showed increased p90RSK staining in areas of active fibrogenesis in cirrhotic livers. Therapeutic administration of kaempferol to carbon tetrachloride-treated mice resulted in decreased hepatic collagen deposition, and expression of profibrogenic and proinflammatory genes, compared to vehicle administration. In addition, kaempferol reduced the extent of hepatocellular injury and degree of apoptosis. In primary hepatic stellate cells, kaempferol and small interfering RNA decreased activation of p90RSK, which in turn regulated key profibrogenic actions. In primary hepatocytes, kaempferol attenuated proapoptotic signalling. CONCLUSIONS:p90RSK is upregulated in patients with chronic liver disease and mediates liver fibrogenesis in vivo and in vitro. These results suggest that the p90RSK pathway could be a new therapeutic approach for liver diseases characterised by advanced fibrosis. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
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