Gene Therapy Laboratory, Instituto de Investigaciones en Medicina Traslacional, Facultad de Ciencias Biomédicas, CONICET- Universidad Austral, Buenos Aires, Argentina.
Departamento de Ciencias Biológicas, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Cátedra de Biología Celular y Molecular, Buenos Aires, Argentina.
Liver Int. 2021 Jul;41(7):1677-1693. doi: 10.1111/liv.14857. Epub 2021 Mar 11.
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.
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.
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.
The absence of SPARC is associated with an altered hepatic lipid metabolism, and an accelerated NAFLD-related HCC development.
非酒精性脂肪性肝病（NAFLD）及其更严重的形式非酒精性脂肪性肝炎（NASH）会增加肝细胞癌（HCC）的风险。脂质代谢改变及其在 HCC 发展中的作用尚不清楚。富含半胱氨酸的酸性分泌蛋白（SPARC）参与脂质代谢、NAFLD 和糖尿病，但它对肝脂质代谢和 HCC 发展的影响尚不清楚。本研究旨在评估 SPARC 在 NAFLD 背景下对 HCC 发展的作用。
使用从敲除（SPARC ）或野生型（SPARC ）小鼠分离的原代肝细胞培养物和 HepG2 细胞来评估游离脂肪酸对脂质积累、生脂基因表达和从头甘油三酯（TG）合成的影响。在 SPARC 或 SPARC 小鼠上稳定了 NAFLD-HCC 模型。使用 HCC 基因表达数据集研究了 SPARC 与脂质代谢相关基因表达模式之间的相关性及其与临床预后的关系。
SPARC 小鼠的肝脂质沉积随时间增加。来自 SPARC 小鼠的肝细胞或在 HepG2 细胞中通过反义腺病毒抑制 SPARC 导致 TG 沉积增加、脂质相关基因表达增加和 SREBP1c 的核易位。人类 HCC 数据库分析显示，SPARC 与参与脂质代谢的基因呈负相关，与不良预后相关。在 NAFLD-HCC 小鼠模型中，SPARC 的缺失加速了 HCC 的发展。RNA-seq 研究显示，SPARC 荷瘤小鼠的脂质代谢、细胞解毒和增殖相关途径上调。
SPARC 的缺失与肝脂质代谢改变和加速的 NAFLD 相关 HCC 发展有关。
