SPARC (Secreted Protein Acidic and Rich in Cysteine) deficiency prot

PEIXOTO E; ATORRASAGASTI C; AQUINO JB; 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; 49º Congreso Internacional de Higado de la Sociedad Europea para el; 2014

Abstract 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. 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. 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-􀀀􀀀and IL-6, and the presence of apoptosis were attenuated in ConAtreated 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. 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.