Hepatic SPARC Expression Is Associated with Inflammasome Activation during the Progression of Non-Alcoholic Fatty Liver Disease in Both Mice and Morbidly Obese Patients

ONORATO, AGOSTINA; LAMEROLI, LUCÍA; BAYO, JUAN; FIORE, ESTEBAN; CANTERO, MARIA JOSE; BUELONI, BARBARA; GARCIA, MARIANA; LAGUES, CECILIA; MARTINEZ DUARTEZ, PEDRO; MENALDI, GABRIEL; PALEARI, NICOLAS; ATORRASAGASTI, CATALINA; MAZZOLINI, GUILLERMO D.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES

MOLECULAR DIVERSITY PRESERVATION INTERNATIONAL-MDPI

Año: 2023 vol. 24

1422-0067

The severity of non-alcoholic fatty liver disease (NAFLD) ranges from simple steatosis to steato-hepatitis, and it is not yet clearly understood which patients will progress to liver fibrosis or cir-rhosis. SPARC (Secreted Protein, Acidic and Rich in Cysteine) has been involved in NAFLD patho-genesis in mice and humans. The aim of this study was to investigate the role of SPARC in in-flammasome activation, and to evaluate the relationship between hepatic expression of inflam-masome genes and the biochemical and histological characteristics of NAFLD in obese patients. In vitro studies were conducted in a macrophage cell line and primary hepatocyte cultures to assess the effect of SPARC on inflammasome. A NAFLD model was established in SPARC knockout (SPARC-/-) and SPARC+/+ mice to explore inflammasome activation. A hepatic RNAseq database from NAFLD patients was analyzed to identify genes associated with SPARC expression. The results were validated in a prospective cohort of 59 morbidly obese patients with NAFLD un-dergoing bariatric surgery. Our results reveal that SPARC alone or in combination with saturated fatty acids promoted IL-1 expression in cell cultures. SPARC-/- mice had reduced hepatic in-flammasome activation during the progression of NAFLD. NAFLD patients showed increased expression of SPARC, NLRP3, CASP1, and IL-1. Gene ontology analysis revealed that genes positively correlated with SPARC are linked to inflammasome-related pathways during the pro-gression of the disease, enabling the differentiation of patients between steatosis and steatohepa-titis. In conclusion, SPARC may play a role in hepatic inflammasome activation in NAFLD