Liver Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBER de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Catalonia, Spain.
Hepatology. 2013 Nov;58(5):1742-56. doi: 10.1002/hep.26521. Epub 2013 Aug 19.
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.
Human and experimental data suggest a role for OPN in the pathogenesis of AH. Further studies should evaluate OPN as a potential therapeutic target.
我们在对酒精性肝炎（AH）患者的转录组分析中发现，骨桥蛋白（OPN）是上调最明显的基因之一。在此，我们采用一种转化方法来研究其致病作用。通过免疫组织化学、蛋白质印迹和酶联免疫吸附试验检测 AH 和其他肝病患者肝组织中 OPN 的基因表达。评估酒精性肝病患者 OPN 基因多态性。在酒精诱导的肝损伤的 OPN（-/-）小鼠中评估 OPN 的作用。在人肝星状细胞（HSCs）和精密切割肝切片中研究 OPN 的生物学作用。与正常肝脏和其他类型的慢性肝病相比，AH 患者肝组织中 OPN 的表达和血清水平明显增加，并与短期生存率相关。OPN 的血清水平也与肝组织表达和疾病严重程度相关。OPN 主要在炎症和纤维化区域表达。两种能处理 OPN 的蛋白酶（凝血酶和基质金属蛋白酶 7）和切割 OPN 的蛋白酶在 AH 肝脏中增加。与无肝病的酒精滥用患者相比，AH 患者 OPN 基因+1239C 单核苷酸多态性的 1239C 单核苷酸多态性的 CC 基因型频率较低。重要的是，OPN（-/-）小鼠对酒精性肝损伤有保护作用，并且炎症细胞因子的表达降低。最后，脂多糖诱导 OPN 的表达并刺激 HSCs 的炎症作用。
人体和实验数据表明 OPN 在 AH 的发病机制中起作用。进一步的研究应该评估 OPN 作为一种潜在的治疗靶点。
