Abstract
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.
Highlights
Acute and chronic liver damage is a growing worldwide health problem due to the increasing incidence of toxic insults such as alcohol abuse, drugs or metabolic syndrome
We studied the expression of proliferating cell nuclear antigen (PCNA) at the onset of liver injury, and observed that 24 h after TAA injection the levels of hepatic PCNA were increased in SPARC−/− mice in comparison with SPARC+/+ mice
SPARC−/− mice were protected from acute liver failure induced by concanavalin A (ConA) and the agonistic anti-CD95 antibody Jo2 [5]
Summary
Acute and chronic liver damage is a growing worldwide health problem due to the increasing incidence of toxic insults such as alcohol abuse, drugs or metabolic syndrome. We have previously demonstrated that downregulation of SPARC has the capacity to reduce acute liver damage after concanavalin A (ConA) administration [5], and the degree of fibrosis in tioacetamide (TAA) and bile duct ligation models [5, 4]. The mechanistic role of SPARC in liver pathologies has not been addressed, our previous works demonstrated that SPARC−/− mice treated with ConA showed reduction in T CD4+ lymphocytes infiltration, www.oncotarget.com tumor necrosis factor alpha (TNFα) production, and apoptosis. In two fibrogenic models generated by TAA administration and by bile duct ligation, SPARC−/− mice showed a reduction in the degree of inflammation, deposits and expression levels of collagen, and in the number of activated myofibroblasts [4, 7]
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