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 L; FIORE E; BAYO J; ONORATTO A; GARCIA M; CANTERO MJ; DOMÍNGUEZ L; MAZZOLINI G; ATORRASAGASTI C

Congreso; Reunión de Sociedades de Biociencias 2021; 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 IL1b, 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, IL1b, 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 IL1b 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, IL1b secretion and casp1 activity. SPARC increased IL1b 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.