Impact of osteopontin on the development of non‐alcoholic liver disease and related hepatocellular carcinoma

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 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. Methods Two‐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. 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. 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 therefore a putative therapeutic target only for advanced chronic liver disease.

Identification, Verification and Pathway Enrichment Analysis of Prognosis-Related Immune Genes in Patients With Hepatocellular Carcinoma

“…Studies by AlexanderD.Nardo et al. have indicated that the imbalance of SPP1 expression can promote the malignant development of hepatocellular carcinoma ( 29 ). LiguangYang et al.…”

“…Secreted phosphoprotein 1 (SPP1) also called as Osteopontin (OPN), it has been reported to be involved in tumor progression, metastasis and suggested as a promising prognosis/therapeutic target biomarker (28). Studies by AlexanderD.Nardo et al have indicated that the imbalance of SPP1 expression can promote the malignant development of hepatocellular carcinoma (29). LiguangYang et al found that the overexpression of SPP1 was associated with poor survival and could promote the proliferation of HCC cells (30).…”

Osteopontin Takes Center Stage in Chronic Liver Disease

“…Using a model of HCC with a modified choline–deficient diet, Opn −/− mice show less tumors, ( 60 ) but streptozotocin‐injected Opn −/− mice on an HFD show the reverse. ( 35 ) These discrepancies may be explained by the cellular origin of OPN in these models or by the effect of i‐OPN compared to s‐OPN. Ongoing studies from our laboratory are exploring these possibilities.…”

“…( 34 ) However, streptozotocin‐injected diabetic Opn −/− mice on an HFD show increased liver triglycerides. ( 35 ) Moreover, Opn −/− mice fed the methionine choline–deficient diet or an HFD with 2% cholesterol show no effect on liver steatosis, but protection from fibrosis. ( 36 ) OPN plays a role in the progression of nonalcoholic steatohepatitis (NASH) by inhibiting autophagy ( 37 ) and increasing hepatocyte senescence.…”

SPP1 and CXCL9 Promote Non-alcoholic Steatohepatitis Progression Based on Bioinformatics Analysis and Experimental Studies

“…SPP1 deficiency may reduce liver-related mortality, which may be associated with the promotion of a systemic pro-inflammatory milieu by SPP1 . This suggests that SPP1 plays a dual role in the pathogenesis of fatty liver and that SPP1 may be involved in the internal control of excessive lipid uptake in the liver, thereby protecting the liver from lipotoxicity, apoptosis, and subsequent fibrosis and hepatocyte proliferation ( 26 ).…”