title: 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 enzyme-linked immunosorbent assay. 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 (HSCs) 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 matrix metalloproteinase 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 single-nucleotide polymorphism 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 lipopolysaccharide and stimulated inflammatory actions in HSCs.
  
  
  CONCLUSIONS
  Human and experimental data suggest a role for OPN in the pathogenesis of AH. Further studies should evaluate OPN as a potential therapeutic target.
authors.affiliation: Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain.
authors.forename: Oriol
authors.initials: O
authors.lastname: Morales-Ibanez
authors.forename: Marlene
authors.initials: M
authors.lastname: Domínguez
authors.forename: Sung H
authors.initials: SH
authors.lastname: Ki
authors.forename: Miguel
authors.initials: M
authors.lastname: Marcos
authors.forename: Javier F
authors.initials: JF
authors.lastname: Chaves
authors.forename: Eric
authors.initials: E
authors.lastname: Nguyen-Khac
authors.forename: Hakim
authors.initials: H
authors.lastname: Houchi
authors.forename: Silvia
authors.initials: S
authors.lastname: Affò
authors.forename: Pau
authors.initials: P
authors.lastname: Sancho-Bru
authors.forename: José
authors.initials: J
authors.lastname: Altamirano
authors.forename: Javier
authors.initials: J
authors.lastname: Michelena
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: García-Pagán
authors.forename: Juan G
authors.initials: JG
authors.lastname: Abraldes
authors.forename: Vicente
authors.initials: V
authors.lastname: Arroyo
authors.forename: Juan
authors.initials: J
authors.lastname: Caballería
authors.forename: Francisco-Javier
authors.initials: FJ
authors.lastname: Laso
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
authors.forename: Ramón
authors.initials: R
authors.lastname: Bataller
mesh_terms: D000818:Animals; D005260:Female; D006519:Hepatitis, Alcoholic / Q000209:etiology*; D006801:Humans; D008108:Liver Diseases, Alcoholic / Q000209:etiology; D008297:Male; D051379:Mice; D008875:Middle Aged; D053495:Osteopontin / Q000097:blood / Q000235:genetics / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide; D012720:Severity of Illness Index
chemical_list: D053495:Osteopontin