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Kinase analysis in alcoholic hepatitis identifies p90RSK as a potential mediator of liver fibrogenesis
  1. Oriol Morales-Ibanez1,2,
  2. Silvia Affò1,
  3. Daniel Rodrigo-Torres1,
  4. Delia Blaya1,
  5. Cristina Millán1,
  6. Mar Coll1,
  7. Luis Perea1,
  8. Gemma Odena2,3,
  9. Thomas Knorpp4,
  10. Markus F Templin4,
  11. Montserrat Moreno1,
  12. José Altamirano1,5,
  13. Rosa Miquel6,
  14. Vicente Arroyo1,7,
  15. Pere Ginès1,7,
  16. Juan Caballería1,7,
  17. Pau Sancho-Bru1,
  18. Ramon Bataller1,2,3
  1. 1Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Facultat de Medicina, Universitat de Barcelona, Barcelona, Catalonia, Spain
  2. 2Division of Gastroenterology and Hepatology, Departments of Medicine and Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  3. 3Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
  4. 4Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Baden-Württemberg, Germany
  5. 5Liver Unit, Internal Medicine Department, Vall D'Hebron Institut de Recerca, Barcelona, Catalonia, Spain
  6. 6Pathology Unit, Hospital Clínic, Barcelona, Catalonia, Spain
  7. 7Liver Unit, Hospital Clínic, Barcelona, Catalonia, Spain
  1. Correspondence to Dr Ramon Bataller, Departments of Medicine and Nutrition, 7340A Medical Biomolecular Research Building, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7032, USA; ramon_bataller{at}med.unc.edu and Dr P Sancho-Bru, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), C/Roselló, 149-153, third floor, Barcelona 08036, Spain; psancho@clinic.ub.es

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.

  • CHRONIC LIVER DISEASE
  • HEPATIC STELLATE CELL

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