SPARC (Secreted Protein Acidic and Rich in Cysteine) deficiency protects from concanavalin A-induced hepatitis in mice

PEIXOTO E; ATORRASAGASTI C; AQUINO J; MILITELLO R; BAYO J; FIORE E; PICCIONI F; SALVATIERRA E; ALANIZ L; GARCIA MG; BATALLER R; CORRALES F; GIDEKEL M; PODHAJCER O; COLOMBO MI; MAZZOLINI G

Londres

Congreso; 49th Annual meeting of the European Association for the Study of the Liver (EASL); 2014

EASL

Background and Aims: Secreted Protein, Acidic and Rich in Cysteine (SPARC) is a matricellular protein involved in liver fibrogenesis but its role in acute liver damage is unknown. Methods: SPARC expression levels were analyzed in liver samples from patients with acute-on-chronic alcoholic hepatitis. SPARC wild-type (SPARC+/+) and knock-out (SPARC−/−) mice were subjected to concanavalin A (ConA) or FAS agonist JO-2 models of acute liver injury. The degree of liver damage, inflammatory infiltrate, cytokines, apoptosis and autophagy were assessed. Microarray analysis was performed to identify the underlying molecular mechanisms. Results: SPARC expression was increased in livers from mice and humans with severe liver damage. SPARC−/− mice showed a marked reduction in ConA and JO-2 induced necroinflammation. Infiltration by CD4+T cells, expression of the pro-inflammatory cytokines TNF-a and IL-6, and the presence of apoptosis were attenuated in ConA-treated SPARC−/− mice. Microscopic analysis revealed that the sinusoidal endothelial cell monolayer was preserved and less activated in ConA-treated SPARC−/− mice compared to wild-type littermates. SPARC knockdown reduced ConA-induced autophagy of cultured endothelial HMEC-1 cells. Consistently, the autophagic flux inhibitor chloroquine reduced ConA-induced liver damage which was almost absent in SPARC−/− mice. Hepatic transcriptome analysis revealed several gene networks that may play a role in the attenuated liver damaged found in ConA-treated SPARC−/− mice. They include genes involved in apoptosis induction, cell adhesion disassembly and cytoskeleton disorganization. Conclusions: SPARC plays a significant role in the development of ConA-induced severe liver injury. These results suggest that SPARC could represent a target for therapy in diseases characterized by severe liver damage.