SPARC inhibition accelerates NAFLD‐associated hepatocellular carcinoma development by dysregulating hepatic lipid metabolism

Abstract

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.

Non-Alcoholic Steatohepatitis (NASH) and Organokines: What Is Now and What Will Be in the Future

“…Mazzolini et al [ 93 ] associated low levels of this organokine as a protective factor against NASH and reduced liver damage in morbidly obese patients. In turn, its absence has been related to alterations in the hepatic lipid metabolism and the risk of developing hepatocellular carcinoma, which is closely related to NAFLD [ 94 ].…”

SPARC Overexpression Promotes Liver Cancer Cell Proliferation and Tumor Growth

“…And moreover, the previous study showed that microRNA-211 could suppress liver cancer cell proliferation and invasion by targeting SPARC, which indicated that SPARC overexpression might drive progression of LIHC ( Deng et al, 2016 ). However, by using a non-alcoholic fatty liver (NAFLD)-related HCC murine model, Onorato et al (2021) found that the absence of SPARC accelerated HCC development, which is associated with an altered hepatic lipid metabolism. And moreover, the study by Atorrasagasti et al also showed that SPARC overexpression in hepatocellular carcinoma cells results in a reduced tumorigenicity partially ( Atorrasagasti et al, 2010 ).…”

Targeting T Cell Subtypes for NAFLD and NAFLD-Related HCC Treatment: An Opinion

“…The causing factors such as genetic factor (e.g., the genetic variant I148M of rs738409 in patatin-like phospholipase domain containing 3, PNPLA3) and epigenetic factors (e.g., histone deacetylase) for NAFLD and NASH may result in liver fibrosis and cirrhosis, and finally leading to the development of HCC (14)(15)(16)(17). In addition, several other factors including environmental factors have been identified to be associated with NAFLD-related HCC progression (18), such as lipid metabolism (19), and dysregulation of gut microbiota (20). For example, dysregulation of lipid metabolism in NAFLD induced hepatic accumulation of linoleic acid and subsequent loss of CD4 + T cells due to an increase of reactive oxygen species (ROS) (21), resulting in an increased incidence of HCC.…”