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Title: Kinase analysis in alcoholic hepatitis identifies p90RSK as a potential mediator of liver fibrogenesis
Author: Morales-Ibanez, Oriol
Affò, Silvia
Rodrigo Torres, Daniel
Blaya, Delia
Millán, Cristina
Coll, Mar
Perea, Luis
Odena, Gemma
Knorpp, Thomas
Templin, Markus F
Moreno Sánchez, Montserrat
Altamirano, José
Miquel Morera, Rosa
Arroyo, Vicente
Ginès i Gibert, Pere
Caballería Rovira, Joan
Sancho Bru, Pau
Bataller Alberola, Ramón
Keywords: Hepatitis
Consum d'alcohol
Drinking of alcoholic beverages
Issue Date: 1-May-2016
Publisher: BMJ Publishing Group
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.
Note: Versió postprint del document publicat a:
It is part of: Gut, 2016, vol. 65, num. 5, p. 1-12
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ISSN: 0017-5749
Appears in Collections:Articles publicats en revistes (Medicina)
Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer)

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