Beschreibung:
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background & aims</jats:title><jats:p>Osteopontin, 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<jats:sup>−/−</jats:sup>) mice analysing time points of NASH, fibrosis and HCC compared to wild‐type mice.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Two‐day‐old wild‐type and Spp1<jats:sup>−/−</jats:sup> 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.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Spp1<jats:sup>−/−</jats:sup> 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<jats:sup>−/−</jats:sup> 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.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Lack 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.</jats:p></jats:sec>