Osteopontin acts as a negative regulator of autophagy accelerating lipid accumulation during the development of nonalcoholic fatty liver disease
Osteopontin acts as a negative regulator of autophagy accelerating lipid accumulation during the development of nonalcoholic fatty liver disease
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骨桥蛋白作为自噬的负调节因子，在非酒精性脂肪肝疾病的发展过程中加速脂质积累
DOI：
10.1080/21691401.2019.1699822
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发表时间：
2020-01
影响因子：
5.8
通讯作者：
Changqing Yang
中科院分区：
文献类型：
--
作者：
Min Tang;Yan Jiang;Haoyu Jia;Bhuvanesh Kinish Patpur;Bo Yang;Jing Li;Changqing Yang
摘要：越来越多的证据表明骨桥蛋白（OPN）（一种促纤维化的细胞外基质蛋白）与非酒精性脂肪性肝病（NAFLD）的发病机制有关。在这项研究中，从非酒精性脂肪性肝炎 (NASH) 患者分离的肝组织中表达的 OPN 高于对照组。然而，这种现象的确切机制尚不清楚。自噬是细胞功能失调成分的自然、受调节的降解和回收，以维持体内平衡。越来越多的证据表明自噬可以构成针对 NAFLD 病症的有效防御机制。在此，我们通过高脂（HF）和蛋氨酸胆碱缺乏（MCD）饮食构建NAFLD小鼠模型，发现NAFLD小鼠肝脏中OPN表达上调。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 可减轻自噬损伤并减少脂质积累，而补充 OPN 则表现出相反的效果。此外，抗 OPN Ab 治疗可显着减轻脂肪变性以及肝脏自噬损伤。我们的研究结果表明，OPN 通过自噬损伤在 NAFLD 的发病机制中发挥着至关重要的作用，这可能成为治疗 NAFLD 的潜在新治疗靶点。
Abstract 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.
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