We identified in the transcriptome analysis of patients with alcoholic hepatitis (AH) osteopontin (OPN) as one of the most up-regulated genes. Here, we used a translational approach to investigate its pathogenic role. OPN hepatic gene expression was quantified in patients with AH and other liver diseases. OPN protein expression and processing were assessed by immmunohistochemistry, Western blotting and ELISA. OPN gene polymorphisms were evaluated in patients with alcoholic liver disease. The role of OPN was evaluated in OPN−/− mice with alcohol-induced liver injury. OPN biological actions were studied in human hepatic stellate cells and in precision-cut liver slices. Hepatic expression and serum levels of OPN were markedly increased in AH compared to normal livers and other types of chronic liver diseases and correlated with short-term survival. Serum levels of OPN also correlated with hepatic expression and disease severity. OPN was mainly expressed in areas with inflammation and fibrosis. Two proteases that process OPN (thrombin and MMP-7) and cleaved-OPN were increased in livers with AH. Patients with AH had a tendency of a lower frequency of the CC genotype of the +1239C SNP of the OPN gene compared to patients with alcohol abuse without liver disease. Importantly, OPN−/− mice were protected against alcohol-induced liver injury and showed decreased expression of inflammatory cytokines. Finally, OPN was induced by LPS and stimulated inflammatory actions in hepatic stellate cells
