SPARC (Secreted Protein Acidic and Rich in Cysteine) can acts as a ?damage-associated molecular patterns? triggering inflammasome activation in non-alcoholic fatty liver disease (NAFLD).

LAMEROLI, LUCÍA; FIORE, ESTEBAN; BAYO, JUAN; ONORATO, AGOSTINA; GARCIA, MARIANA; CANTERO, MARIA JOSE; DOMINGUEZ, LUCIANA M.; MAZZOLINI, GUILLERMO; ATORRASAGASTI, CATALINA

Buenos Aires

Congreso; LXVI Reunión Anual de la Sociedad Argentina de Investigaciones Clínicas; 2021

Nonalcoholic steatohepatitis (NASH) is a progressive and inflammatory form of NAFLD. Inflammation and hepatocyte damage distinguish NASH from simple fatty liver (steatosis). NLRP3 inflammasome, which sense damage signals and acts as a driver of innate sterile inflammation via activation of caspase1 (casp1) and release of proinflammatory cytokines including IL1, have a central role in NAFLD. SPARC is an extracellular protein expressed in response to injury. We previously demonstrated that SPARC absence reduce NASH in a murine diet-induced obesity model. The present study aimed to assess the role of SPARC in the initiation of inflammasome-mediated immune response that can lead to NAFLD progression. We performed a bioinformatic analysis of available RNAseq data from NAFLD patients. Patients were classified according histopathological NAFLD activity score. NAFLD patients increased SPARC expression, while NLRP3 inflammasome-related gene were increased mainly in NASH patients. Positively correlation between SPARC, IL1, NLRP3 and casp1 were shown. Ontology analysis revealed that genes that positively correlate with SPARC in NASH were involved in innate immune pathways. In a murine diet-induced NAFLD model SPARC+/+ and SPARC-/- mice were fed with high fat diet for 12 (steatosis) or 20 weeks (NASH), we observed that the absence of SPARC attenuated NLRP3 inflammasome-related gene expression. In vitro studies on primary hepatocyte cultures from SPARC-/-mice, showed decrease expression of IL1 and casp1 in response to free fatty acid. Macrophage cell line, primary Kupffer and hepatocyte cultures were incubated with free fatty acids and SPARC to assess effect on inflammasome-related gene expression, IL1 secretion and casp1 activity. SPARC increased IL1 and casp1 expression and secretion. SPARC alone or in combination with fatty acid trigger NLRP3 inflammasome activation. Our results suggest a key role of SPARC as a damage-associated molecular patterns in NAFLD progression.