SPARC gene deletion protects against toxic liver injury and is associated to an enhanced proliferative capacity and reduced oxidative stress response
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Estanislao Peixoto1, Catalina Atorrasagasti1, Mariana Malvicini1, Esteban Fiore1, Marcelo Rodriguez1, Mariana Garcia1, Paola Finocchieto2, Juan J. Poderoso2, Fernando Corrales3, Guillermo Mazzolini1
1Gene Therapy Laboratory, Instituto de Investigaciones Médicas Aplicadas-CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas), Buenos Aires, Argentina
2Instituto INIGEM, UBA-CONCET, Buenos Aires, Argentina
3CIMA, University of Navarra, Pamplona, Spain
Guillermo Mazzolini, email: firstname.lastname@example.org
Keywords: SPARC, hepatocyte proliferation, reactive oxygen species, liver damage, PCNA
Received: January 13, 2016 Accepted: March 31, 2016 Epub: May 18, 2016 Published: June 25, 2019
SPARC, also known as osteonectin and BM-40, is a matricellular protein with a number of biological functions. Hepatic SPARC expression is induced in response to thioacetamide, bile-duct ligation, and acute injuries such as concanavalin A and lipopolysacharide (LPS)/D-galactosamine. We have previously demonstrated that the therapeutic inhibition of SPARC or SPARC gene deletion protected mice against liver injury. We investigated the mechanisms involved in the protective effect of SPARC inhibition in mice. We performed a proteome analysis of livers from SPARC+/+ and SPARC−/− mice chronically treated with thioacetamide. Catalase activity, carbonylation levels, oxidative stress response, and mitochondrial function were studied. Genomic analysis revealed that SPARC−/− mice had an increased expression of cell proliferation genes. Proteins involved in detoxification of reactive oxygen species such as catalase, peroxirredoxine-1, and glutathione-S-transferase P1 and Mu1 were highly expressed as evidenced by proteome analysis; hepatic catalase activity was increased in SPARC−/− mice. Oxidative stress response and carbonylation levels were lower in livers from SPARC−/− mice. Hepatic mitochondria showed lower levels of nitrogen reactive species in the SPARC−/− concanavalin A-treated mice. Mitochondrial morphology was preserved, and its complex activity reduced in SPARC−/− mice. In conclusion, our data suggest that the protection associated with SPARC gene deletion may be partially due to a higher proliferative capacity of hepatocytes and an enhanced oxidative stress defense in SPARC−/− mice after liver injury.
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