SPARC (SECRETED PROTEIN ACIDIC AND RICH IN CYSTEINE) REGULATES HEPATOCYTE LIPID CONTENTBY MODULATING SREBP1C EXPRESSION AND LOCALIZATION: IMPLICATIONS IN NON-ALCOHOLIC FATTY LIVER DISEASE

AGOSTINA MARIANA ONORATO; ESTEBAN FIORE; CASALI, CECILIA IRENE; FERNÁNDEZ TOME, MARIA DEL CARMEN; GARCÍA, MARIANA; BAYO, JUAN; MAZZOLINI, GUILLERMO D.; ATORRASAGASTI, CATALINA

Virtual

Congreso; Reunión Anual de Sociedades de Biociencias; 2020

Soc de Biociencias

Nonalcoholic fatty liver disease (NAFLD) is a pathology with epidemicproportions. It characterizes by the accumulation of triglycerides inhepatocytes (steatosis), which could generate hepatic inflammation.Fatty acid accumulation is triggered by an excessive arrival of thesefrom adipose tissue, or a dysregulation between de novo lipogenesisand lipid catabolism. SPARC is a widely expressed protein withpleiotropic role. We previously demonstrated that SPARC absenceincreased hepatic steatosis in a murine diet-induced obesity model.The aim this study was to evaluate the role of SPARC in hepatic lipiddeposition and lipogenesis.Primary hepatocyte cultures from SPARC+/+ and SPARC-/- mice orSPARC knockdown HepG2 cells were used to study SPARC effecton lipid droplets and expression of lipogenic genes in free fatty acids(FFA) presence. Hepatocyte survival was assessed by AO/EB stainingand MTT. De novo triglyceride synthesis was evaluated in hepatocytes.Immunofluorescence for SREBP1 in hepatocyte was performed.In hepatic sections of SPARC+/+ and SPARC-/- mice SREBP1protein localization was evaluated by immunohistochemistry.SPARC-/- hepatocytes and SPARC knockdown HepG2 cells accumulatedhigher amounts of lipids in FFA presence. It was demonstratedthat the absence of SPARC stimulates de novo triglyceridesynthesis in hepatocytes. In turn, there is an increase in the expressionof genes related to lipid metabolism. In primary hepatocytecultures it was observed that genes involved in lipid metabolism,transport and lipogenesis were overexpressed in SPARC absence.Srebp1c expression, a key transcription factor in lipogenesis, wasincreased. Immunofluorescence for SREBP1c showed that, inSPARC absence, this transcription factor is located at the nucleus,while in SPARC+/+ hepatocytes it has a cytoplasmic and perinuclearlocalization.Our results suggest a key role of SPARC in hepatic lipid depositionand metabolism that could modulate hepatic steatosis development.