Division of Gastroenterology and Hepatology, Institution of Digestive Diseases, Tongji Hospital, Tongji University School of Medicine, Shanghai, P. R. China.
Artif Cells Nanomed Biotechnol. 2020 Dec;48(1):159-168. doi: 10.1080/21691401.2019.1699822.
Accumulating evidence links osteopontin (OPN), a pro-fibrogenic extracellular matrix protein, to the pathogenesis of non-alcoholic fatty liver disease (NAFLD). In this study, liver tissues isolated from non-alcoholic steatohepatitis (NASH) patients expressed higher OPN than those of controls. However, the exact mechanism(s) for this phenomenon is yet to be clarified. Autophagy is the natural, regulated degradation and recycling of a cell's dysfunctional components, in order to maintain homeostasis. Increasing evidence supports that autophagy can constitute an effective Defence mechanism against NAFLD conditions. Herein, we constructed NAFLD mice model by high-fat (HF) and methionine-choline-deficient (MCD) diet and found that OPN is upregulated in livers of NAFLD mice. Besides, secreted OPN inhibited autophagosome-lysosome fusion via binding with its receptors integrin αVβ3 and αVβ5 in HepG2 cells supplemented with free fatty acids (FFA) and the livers of NAFLD mice. Silencing of OPN attenuated autophagy impairment and reduced lipid accumulation, while supplementation of OPN exhibited the opposite effect. Furthermore, treatment with anti-OPN Ab significantly attenuated steatosis as well as autophagy impairment in the liver. Our findings indicated that OPN plays a vital role in the pathogenesis of the development of NAFLD via autophagy impairment, which might represent a potential new therapeutic target for the treatment of NAFLD.
越来越多的证据表明，骨桥蛋白（OPN）是一种促纤维化细胞外基质蛋白，与非酒精性脂肪性肝病（NAFLD）的发病机制有关。在这项研究中，非酒精性脂肪性肝炎（NASH）患者的肝组织表达的 OPN 高于对照组。然而，这种现象的确切机制尚不清楚。自噬是细胞内功能失调成分的自然、调节性降解和再循环，以维持细胞内环境稳定。越来越多的证据支持自噬可以构成对抗 NAFLD 条件的有效防御机制。在此，我们通过高脂肪（HF）和蛋氨酸-胆碱缺乏（MCD）饮食构建了 NAFLD 小鼠模型，发现 OPN 在 NAFLD 小鼠的肝脏中上调。此外，在补充游离脂肪酸（FFA）的 HepG2 细胞和 NAFLD 小鼠的肝脏中，分泌的 OPN 通过与其受体整合素αVβ3 和αVβ5 结合，抑制自噬体-溶酶体融合。沉默 OPN 可减轻自噬损伤和减少脂质积累，而补充 OPN 则表现出相反的效果。此外，抗 OPN Ab 的治疗可显著减轻肝脏的脂肪变性和自噬损伤。我们的研究结果表明，OPN 通过自噬损伤在 NAFLD 的发病机制中起着重要作用，这可能代表了治疗 NAFLD 的一个潜在新的治疗靶点。
