Human and experimental evidence supporting a role for osteopontin in alcoholic hepatitis

Abstract

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. Conclusion Human and experimental data suggest a role for OPN in the pathogenesis of AH. Further studies should evaluate OPN as a potential therapeutic target.

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

“…OPN is a multifunctional protein, involved in different pathological conditions and it is associated with inflammation, autoimmunity, angiogenesis, fibrosis and cancer progression in various tissues. The OPN levels in the liver are correlated with fibrosis in patients with ALD [135] . OPN is profibrogenic by promoting HSC activation and ECM deposition in vitro and in vivo.…”

Animals Models of Gastrointestinal and Liver Diseases. Animal models of alcohol-induced liver disease: pathophysiology, translational relevance, and challenges

“…Their results showed increased expression of OPN in ethanol-fed rats that correlated with neutrophilia, and these effects were enhanced by LPS (2). A recent study analyzed liver biopsies from patients with different forms of liver disease and revealed a significant increase in OPN mRNA and protein in cases of compensated cirrhosis and alcoholic hepatitis compared with normal livers (20). Importantly, patients with alcoholic hepatitis had the greatest increase in OPN, and the level of expression correlated with disease severity and mortality (20).…”

Invariant natural killer T cells contribute to chronic-plus-binge ethanol-mediated liver injury by promoting hepatic neutrophil infiltration

“…This suggests that other chemokines rather than IL-4 may play a more important role in promoting hepatic neutrophil infiltration and injury induced by chronic-plusbinge ethanol feeding. Indeed, in addition to IL-4, several other important inflammatory mediators that are associated with neutrophil recruitment, such as OPN and MIP-2, 27,37 were markedly elevated in hepatic iNKT cells after chronicplus-binge ethanol feeding ( Figure 6). Deletion of the OPN gene markedly diminished hepatic neutrophil infiltration and injury in the chronic-plus-binge ethanol feeding model, 37 although this was not observed in a more severe injury model of Tsukamoto-hybrid ethanol feeding 38 or in a mouse model with long-term (7-week) ethanol feeding.…”

“…Indeed, in addition to IL-4, several other important inflammatory mediators that are associated with neutrophil recruitment, such as OPN and MIP-2, 27,37 were markedly elevated in hepatic iNKT cells after chronicplus-binge ethanol feeding ( Figure 6). Deletion of the OPN gene markedly diminished hepatic neutrophil infiltration and injury in the chronic-plus-binge ethanol feeding model, 37 although this was not observed in a more severe injury model of Tsukamoto-hybrid ethanol feeding 38 or in a mouse model with long-term (7-week) ethanol feeding. 39 Furthermore, the concanavalin-A-induced T-cell hepatitis model was used to demonstrate that release of OPN from iNKT cells led to the subsequent release of MIP-2, both of which aid in the recruitment of neutrophils into the liver and contribute to hepatic injury.…”