SPARC (Secreted protein acidic and rich in cysteine) regulates hepatocyte lipid content by modulating SREBP1C expression and localization: implications in non-alcoholic fatty liver disease.

ONORATO AM; FIORE E; CASALI C; FERNÁNDEZ-TOMÉ M; GARCIA M; BAYO J; MAZZOLINI G; ATORRASAGASTI C

Mar del Plata

Congreso; Reunión Anual de Sociedades de Biociencia (SAIC SAI SAFIS); 2020

Nonalcoholic fatty liver disease (NAFLD) is a pathology with epidemic proportions. It characterizes by the accumulation of triglycerides in hepatocytes (steatosis), which could generate hepatic inflammation. Fatty acid accumulation is triggered by an excessive arrival of these from adipose tissue, or a dysregulation between de novo lipogenesis and lipid catabolism. SPARC is a widely expressed protein with pleiotropic role. We previously demonstrated that SPARC absence increased hepatic steatosis in a murine diet-induced obesity model. The aim this study was to evaluate the role of SPARC in hepatic lipid deposition and lipogenesis. Primary hepatocyte cultures from SPARC+/+ and SPARC-/- mice or SPARC 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 staining and MTT. De novo triglyceride synthesis was evaluated in hepatocytes. Immunofluorescence for SREBP1 in hepatocyte was performed. In hepatic sections of SPARC+/+ and SPARC-/- mice SREBP1 protein localization was evaluated by immunohistochemistry. SPARC-/- hepatocytes and SPARC knockdown HepG2 cells accumulatedhigher amounts of lipids in FFA presence. It was demonstrated that the absence of SPARC stimulates de novo triglyceride synthesis in hepatocytes. In turn, there is an increase in the expression of genes related to lipid metabolism. In primary hepatocyte cultures 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, was increased. Immunofluorescence for SREBP1c showed that, in SPARC 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 deposition and metabolism that could modulate hepatic steatosis development.