Impact of osteopontin on the development of non‐alcoholic liver disease and related hepatocellular carcinoma
Open Access
- 13 April 2020
- journal article
- research article
- Published by Wiley in Liver International
- Vol. 40 (7), 1620-1633
- https://doi.org/10.1111/liv.14464
Abstract
Background & aims 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 tumor 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 analyzing time points of NASH, fibrosis and HCC compared to wild‐type mice. Methods two‐days‐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 in order to evaluate the NASH, fibrosis and HCC phenotypes, respectively. Results Spp1‐/‐ 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. On the other hand, lack of osteopontin lowered systemic inflammation, prevented HCC progression to less differentiated tumors and improved overall survival. Conclusions 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. (249 words)Funding Information
- Austrian Science Fund (W1205‐B09)
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