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Inducing and Characterizing Vesicular Steatosis in Differentiated HepaRG Cells
Published on: July 18, 2019
SPARC inhibition accelerates NAFLD-associated hepatocellular carcinoma development by dysregulating hepatic lipid
Agostina M Onorato1, Esteban Fiore1, Juan Bayo1
1Gene Therapy Laboratory, Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, CONICET- Universidad Austral, Buenos Aires, Argentina.
Background And Aims:
Non-alcoholic fatty liver (NAFLD) and its more serious form non-alcoholic steatohepatitis increase risk of hepatocellular carcinoma (HCC). Lipid metabolic alterations and its role in HCC development remain unclear. SPARC (Secreted Protein, Acidic and Rich in Cysteine) is involved in lipid metabolism, NAFLD and diabetes, but the effects on hepatic lipid metabolism and HCC development is unknown. The aim of this study was to evaluate the role of SPARC in HCC development in the context of NAFLD.
Methods:
Primary hepatocyte cultures from knockout (SPARC-/- ) or wild-type (SPARC+/+ ) mice, and HepG2 cells were used to assess the effects of free fatty acids on lipid accumulation, expression of lipogenic genes and de novo triglyceride (TG) synthesis. A NAFLD-HCC model was stabilized on SPARC-/- or SPARC+/+ mice. Correlations among SPARC, lipid metabolism-related gene expression patterns and clinical prognosis were studied using HCC gene expression dataset.
Results:
SPARC-/- mice increases hepatic lipid deposits over time. Hepatocytes from SPARC-/- mice or inhibition of SPARC by an antisense adenovirus in HepG2 cells resulted in increased TG deposit, expression of lipid-related genes and nuclear translocation of SREBP1c. Human HCC database analysis revealed that SPARC negatively correlated with genes involved in lipid metabolism, and with poor survival. In NAFLD-HCC murine model, the absence of SPARC accelerates HCC development. RNA-seq study revealed that pathways related to lipid metabolism, cellular detoxification and proliferation were upregulated in SPARC-/- tumour-bearing mice.
Conclusions:
The absence of SPARC is associated with an altered hepatic lipid metabolism, and an accelerated NAFLD-related HCC development.
Insights
The absence of SPARC protein accelerates non-alcoholic fatty liver disease (NAFLD)-related liver cancer (HCC) by altering hepatic lipid metabolism. SPARC deficiency promotes lipid accumulation and tumor development in NAFLD models.
Area of Science:
- Hepatology and Cancer Biology
- Molecular Metabolism
Background:
- Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis are significant risk factors for hepatocellular carcinoma (HCC).
- The precise role of lipid metabolic alterations in HCC development remains incompletely understood.
- SPARC (Secreted Protein, Acidic and Rich in Cysteine) is implicated in lipid metabolism and diabetes, but its specific function in NAFLD-associated HCC is unknown.
Purpose of the Study:
- To investigate the role of SPARC in the development of HCC within the context of NAFLD.
- To elucidate the impact of SPARC on hepatic lipid metabolism and its correlation with HCC progression.
Main Methods:
- Primary hepatocyte cultures (SPARC knockout vs. wild-type mice) and HepG2 cells were used to assess lipid accumulation and lipogenic gene expression.
- A murine model of NAFLD-associated HCC was established using SPARC knockout and wild-type mice.
- Human HCC gene expression datasets were analyzed to correlate SPARC expression with lipid metabolism genes and patient survival.
Main Results:
- SPARC deficiency led to increased hepatic lipid deposits, triglyceride synthesis, and expression of lipogenic genes in hepatocytes.
- Absence of SPARC accelerated HCC development in the NAFLD murine model.
- SPARC negatively correlated with lipid metabolism genes and poor survival in human HCC datasets, with upregulated lipid metabolism, detoxification, and proliferation pathways observed in SPARC-deficient tumors.
Conclusions:
- SPARC deficiency is linked to dysregulated hepatic lipid metabolism.
- The absence of SPARC accelerates the development of NAFLD-related HCC, highlighting SPARC as a potential therapeutic target.
