Abstract
Background & aimsOsteopontin, a multifunctional protein and inflammatory cytokine, is overexpressed in adipose tissue and liver in obesity and contributes to the induction of adipose tissue inflammation and non‐alcoholic fatty liver (NAFL). Studies performed in both mice and humans also point to a potential role for OPN in malignant transformation and tumour growth. To fully understand the role of OPN on the development of NAFL‐derived hepatocellular carcinoma (HCC), we applied a non‐alcoholic steatohepatitis (NASH)‐HCC mouse model on osteopontin‐deficient (Spp1−/−) mice analysing time points of NASH, fibrosis and HCC compared to wild‐type mice.MethodsTwo‐day‐old wild‐type and Spp1−/− mice received a low‐dose streptozotocin injection in order to induce diabetes, and were fed a high‐fat diet starting from week 4. Different cohorts of mice of both genotypes were sacrificed at 8, 12 and 19 weeks of age to evaluate the NASH, fibrosis and HCC phenotypes respectively.ResultsSpp1−/− animals showed enhanced hepatic lipid accumulation and aggravated NASH, as also increased hepatocellular apoptosis and accelerated fibrosis. The worse steatotic and fibrotic phenotypes observed in Spp1−/− mice might be driven by enhanced hepatic fatty acid influx through CD36 overexpression and by a pathological accumulation of specific diacylglycerol species during NAFL. Lack of osteopontin lowered systemic inflammation, prevented HCC progression to less differentiated tumours and improved overall survival.ConclusionsLack of osteopontin dissociates NASH‐fibrosis severity from overall survival and HCC malignant transformation in NAFLD, and is therefore a putative therapeutic target only for advanced chronic liver disease.
Highlights
Hepatocellular carcinoma (HCC) is the most common form of liver cancer and the cause of approximately one million deaths yearly, with an alarming mortality rate of 94%.1 Even though hepatitis B(HBV) and C (HCV) virus infections are major risk factors for hepatocellular carcinoma (HCC), nutrition-related diseases strongly promote the increase in HCC prevalence worldwide
The worse steatotic and fibrotic phenotypes observed in Spp1−/− mice might be driven by enhanced hepatic fatty acid influx through CD36 overexpression and by a pathological accumulation of specific diacylglycerol species during non-alcoholic fatty liver (NAFL)
This may be due to a chain of events starting with obesity, metabolic syndrome, type-2 diabetes mellitus (T2DM) and fatty liver and potentially leading to non-alcoholic liver steatohepatitis (NASH), liver fibrosis and HCC
Summary
Spp1−/− animals showed enhanced hepatic lipid accumulation and aggravated NASH, as increased hepatocellular apoptosis and accelerated fibrosis. The worse steatotic and fibrotic phenotypes observed in Spp1−/− mice might be driven by enhanced hepatic fatty acid influx through CD36 overexpression and by a pathological accumulation of specific diacylglycerol species during NAFL. Lack of osteopontin lowered systemic inflammation, prevented HCC progression to less differentiated tumours and improved overall survival. Conclusions: Lack of osteopontin dissociates NASH-fibrosis severity from overall survival and HCC malignant transformation in NAFLD, and is a putative therapeutic target only for advanced chronic liver disease. KEYWORDS acute-on-chronic liver failure, fibrosis, lipoapoptosis, metabolic syndrome, non-alcoholic fatty liver
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