title: Kinase analysis in alcoholic hepatitis identifies p90RSK as a potential mediator of liver fibrogenesis.
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.
  
  
  METHODS
  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.
authors: 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.
authors: Oriol
authors: O
authors: Morales-Ibanez
authors: 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.
authors: Silvia
authors: S
authors: Affò
authors: 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.
authors: Daniel
authors: D
authors: Rodrigo-Torres
authors: 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.
authors: Delia
authors: D
authors: Blaya
authors: 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.
authors: Cristina
authors: C
authors: Millán
authors: 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.
authors: Mar
authors: M
authors: Coll
authors: 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.
authors: Luis
authors: L
authors: Perea
authors: 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.
authors: Gemma
authors: G
authors: Odena
authors: Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Baden-Württemberg, Germany.
authors: Thomas
authors: T
authors: Knorpp
authors: Natural and Medical Sciences Institute at the University of Tübingen, Reutlingen, Baden-Württemberg, Germany.
authors: Markus F
authors: MF
authors: Templin
authors: 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.
authors: Montserrat
authors: M
authors: Moreno
authors: 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.
authors: José
authors: J
authors: Altamirano
authors: Pathology Unit, Hospital Clínic, Barcelona, Catalonia, Spain.
authors: Rosa
authors: R
authors: Miquel
authors: 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.
authors: Vicente
authors: V
authors: Arroyo
authors: 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.
authors: Pere
authors: P
authors: Ginès
authors: 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.
authors: Juan
authors: J
authors: Caballería
authors: 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.
authors: Pau
authors: P
authors: Sancho-Bru
authors: 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.
authors: Ramon
authors: R
authors: Bataller
mesh_terms: D000818:Animals; D005260:Female; D006519:Hepatitis, Alcoholic / Q000150:complications* / Q000201:enzymology*; D006801:Humans; D008103:Liver Cirrhosis / Q000209:etiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000502:physiology*
chemical_list: D038744:Ribosomal Protein S6 Kinases, 90-kDa
keywords: CHRONIC LIVER DISEASE; HEPATIC STELLATE CELL
references: J Vasc Interv Radiol. 2001 May;12(5):583-7
references: 11340136
references: Gastroenterology. 2004 Feb;126(2):529-40
references: 14762790
references: J Med Genet. 1988 May;25(5):344-8
references: 3290491
references: Nature. 1996 Dec 12;384(6609):567-70
references: 8955270
references: Mol Cell Endocrinol. 1999 May 25;151(1-2):65-77
references: 10411321
references: Hepatology. 2005 Jun;41(6):1313-21
references: 15915461
references: J Hepatol. 2005 Aug;43(2):272-82
references: 15964095
references: Gastroenterology. 2007 Feb;132(2):687-97
references: 17258719
references: Cancer Res. 2007 Sep 1;67(17):8104-12
references: 17804722
references: PLoS One. 2007;2(12):e1372
references: 18159255
references: Nat Rev Mol Cell Biol. 2008 Oct;9(10):747-58
references: 18813292
references: Clin Liver Dis. 2008 Nov;12(4):825-52, ix
references: 18984469
references: Am J Gastroenterol. 2008 Nov;103(11):2747-56
references: 18721242
references: Gastroenterology. 2009 May;136(5):1639-50
references: 19208360
references: World J Gastroenterol. 2009 May 7;15(17):2109-15
references: 19418583
references: J Hepatol. 2009 Jun;50(6):1258-66
references: 19398236
references: Proteomics. 2009 Jul;9(13):3535-48
references: 19609961
references: Hepatology. 2010 Mar;51(3):974-85
references: 20077562
references: FASEB J. 2010 Jun;24(6):1971-80
references: 20065107
references: FASEB J. 2010 Sep;24(9):3490-9
references: 20385620
references: Hepatology. 2010 Oct;52(4):1291-300
references: 20842630
references: Nat Rev Gastroenterol Hepatol. 2011 Sep;8(9):491-501
references: 21826088
references: Br J Pharmacol. 2011 Oct;164(3):1008-25
references: 21449918
references: Gastroenterology. 2011 Nov;141(5):1572-85
references: 21920463
references: Toxicology. 2012 Feb 6;292(1):53-62
references: 22155320
references: Circ Res. 2012 Feb 17;110(4):536-50
references: 22267842
references: Cell. 2012 Apr 13;149(2):307-21
references: 22500798
references: Hepatology. 2012 Jun;55(6):1931-41
references: 22278680
references: Biochemistry. 2012 Aug 21;51(33):6499-510
references: 22846040
references: J Clin Invest. 2012 Oct;122(10):3476-89
references: 22945633
references: Circulation. 2013 Jan 29;127(4):486-99
references: 23243209
references: Gut. 2013 Mar;62(3):452-60
references: 22637703
references: Hepatology. 2013 May;57(5):1980-91
references: 23174952
references: Biochim Biophys Acta. 2013 Jul;1834(7):1285-91
references: 23541530
references: Oncol Rep. 2013 Aug;30(2):925-32
references: 23708932
references: J Hepatol. 2013 Nov;59(5):1045-53
references: 23831119
references: Hepatology. 2013 Nov;58(5):1742-56
references: 23729174
references: Alcohol Clin Exp Res. 2014 Mar;38(3):787-800
references: 24164383
references: Gastroenterology. 2014 May;146(5):1231-9.e1-6
references: 24440674
references: Gut. 2014 Nov;63(11):1782-92
references: 24415562