INVESTIGADORES
GARCIA Mariana Gabriela
congresos y reuniones científicas
Título:
SPARC (Secreted Protein Acidic and Rich in Cysteine) promotes lipid deposition and hepatocarcinogenesis in non-alcoholic fatty liver disease models in mice.
Autor/es:
ONORATO A ; RODRÍGUEZ M; FIORE E; CASALI C; FERNÁNDEZ-TOMÉ M; DOMÍNGUEZ L; CANTERO M; BAYO J; MALVICINI M; GARCIA M; MAZZOLINI G; ATORRASAGASTI C
Lugar:
Mar del Plata
Reunión:
Congreso; Reunión Anual de Sociedades de Biociencia (SAIC SAFE SAB SAP); 2019
Resumen:
Non-alcoholic fatty liver (NAFLD) is characterized by excessive lipid accumulation in >5% of hepatocytes. It encompasses a set of clinical conditions ranging from steatosis alone (NAFL) to NASH (non-alcoholic steatohepatitis), which is characterized by the presence of hepatocellular ballooning, inflammation and fibrosis. NAFLD can progress to cirrhosis and hepatocellular carcinoma (HCC). SPARC is a matricellular protein associated with inflammatory processes, tissue remodeling, regulation of fibrillar collagen deposits, among other biological functions.The aim of this study was to evaluate the role of SPARC in the development of HCC in NAFLD models in mice.Methods: 2 days born SPARC knockout (SPARC-/-) or wild type (SPARC+/+) mice were subcutaneously injected with 200 µg of streptozotocin and fed with high fat (HF) or chow diet for 8 or 16 weeks. SPARC and proinflammatory cytokines expression were measured by qPCR. Hepatic damage, fibrosis and tumor development were evaluated. Liver differential gene expression in 16 weeks mice HF-fed was analyzed by RNAseq. Primary hepatocyte cultures and SPARC knockdown HepG2 cell were used in free fatty acids presence to study SPARC effect on lipid droplets and expression of lipogenic genes.Results: HF diet induced SPARC overexpression after 8 weeks. Proinflammatory factors and collagen deposits were decreased in SPARC-/- HF despite increased in steatosis. After 16 weeks, all SPARC-/- HF mice (n=10) developed spontaneous HCC while in SPARC+/+ HF mice (n=14) incidence was about 60%. Pathways related to lipid metabolism and cellular detoxification were upregulated in SPARC-/- HF mice. SPARC inhibition in HepG2 showed an increase in triglyceride deposits. In SPARC-/- primary hepatocyte cultures we observed that genes involved in lipid transport and lipogenesis were overexpressed, coupled with an increase triglyceride synthesis.Conclusion: The absence of SPARC is associated with a low degree of inflammation and fibrosis in NASH, but exacerbated hepatocarcinogenesis.