SNX10 mediates alcohol-induced liver injury and steatosis by regulating the activation of chaperone-mediated autophagy
SNX10 mediates alcohol-induced liver injury and steatosis by regulating the activation of chaperone-mediated autophagy
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SNX10 通过调节伴侣介导的自噬的激活来介导酒精引起的肝损伤和脂肪变性。
DOI：
10.1016/j.jhep.2018.01.038
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发表时间：
2018-07-01
影响因子：
25.7
通讯作者：
Shen, Xiaoyan
中科院分区：
文献类型：
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作者：
You, Yan;Li, Wan-Zhen;Shen, Xiaoyan
背景与目的：酒精性肝病（ALD）是世界范围内发病和死亡的主要原因。然而，ALD背后的细胞防御机制还不清楚。最近的研究强调了分子伴侣介导的自噬（CMA）参与调节肝脏脂质代谢。分选连接蛋白（SNX）-10在内溶酶体运输和稳定中具有调节功能。在这里，我们调查的角色SNX 10在CMA激活和酒精诱导的肝损伤和脂肪atoes.Methods的发病机制：Snx 10基因敲除（Snx 10 KO）小鼠和野生型（WT）同窝喂养的Lieber-DeCarli液体酒精饮食或控制液体饮食，原代培养的WT和Snx 10 KO肝细胞刺激乙醇，分别作为在体内和体外ALD模型。CMA的激活，肝损伤参数，炎症细胞因子，氧化应激和脂质代谢measured.Results：与WT同窝仔相比，Snx 10 KO小鼠表现出显着改善乙醇诱导的肝损伤和肝脂肪变性。体内和体外研究表明，SNX 10缺陷上调溶酶体相关膜蛋白2A（LAMP-2A）的表达和CMA激活，这可以逆转SNX 10在体外过表达。LAMP-2A干扰证实SNX 10缺陷诱导的Nrf 2和AMPK信号通路的上调依赖于CMA激活。下拉分析揭示了SNX 10和组织蛋白酶A（CTSA），一个关键酶参与LAMP-2A降解之间的相互作用。SNX 10缺陷抑制CTSA成熟，并增加了LAMP-2A的稳定性，导致CMA activity.Conclusions的增加：SNX 10控制CMA活性通过介导CTSA成熟，因此，在酒精诱导的肝损伤和脂肪变性中起着重要作用。我们的研究结果提供了证据SNX 10作为一个潜在的有前途的治疗靶点，用于预防或改善肝损伤ALD.Lay摘要：酒精性肝病是世界范围内发病率和死亡率的主要原因。最近的研究强调了分子伴侣介导的自噬（CMA）参与调节肝脏脂质代谢。我们的研究表明，缺乏分选连接蛋白（SNX）10通过抑制组织蛋白酶A成熟增加LAMP-2A的稳定性，导致CMA活性增加，从而加重酒精诱导的肝损伤和脂肪变性。(C)2018年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: Alcoholic liver disease (ALD) is a major cause of morbidity and mortality worldwide. However, the cellular defense mechanisms underlying ALD are not well understood. Recent studies highlighted the involvement of chaperone-mediated autophagy (CMA) in regulating hepatic lipid metabolism. Sorting nexin (SNX)-10 has a regulatory function in endolysosomal trafficking and stabilisation. Here, we investigated the roles of SNX10 in CMA activation and in the pathogenesis of alcohol-induced liver injury and steatosis.Methods: Snx10 knockout (Snx10 KO) mice and their wild-type (WT) littermates fed either the Lieber-DeCarli liquid alcohol diet or a control liquid diet, and primary cultured WT and Snx10 KO hepatocytes stimulated with ethanol, were used as in vivo and in vitro ALD models, respectively. Activation of CMA, liver injury parameters, inflammatory cytokines, oxidative stress and lipid metabolism were measured.Results: Compared with WT littermates, Snx10 KO mice exhibited a significant amelioration in ethanol-induced liver injury and hepatic steatosis. Both in vivo and in vitro studies showed that SNX10 deficiency upregulated lysosome-associated membrane protein type 2A (LAMP-2A) expression and CMA activation, which could be reversed by SNX10 overexpression in vitro. LAMP-2A interference confirmed that the upregulation of Nrf2 and AMPK signalling pathways induced by SNX10 deficiency relied on CMA activation. Pull-down assays revealed an interaction between SNX10 and cathepsin A (CTSA), a key enzyme involved in LAMP-2A degradation. Deficiency in SNX10 inhibited CTSA maturation and increased the stability of LAMP-2A, resulting in an increase in CMA activity.Conclusions: SNX10 controls CMA activity by mediating CTSA maturation, and, thus, has an essential role in alcohol-induced liver injury and steatosis. Our results provide evidence for SNX10 as a potential promising therapeutic target for preventing or ameliorating liver injury in ALD.Lay summary: Alcoholic liver disease is a major cause of morbidity and mortality worldwide. Recent studies highlight the involvement of chaperone-mediated autophagy (CMA) in regulating hepatic lipid metabolism. Our study reveals that deficiency of sorting nexin (SNX) 10 increases the stability of LAMP-2A by inhibiting cathepsin A maturation, resulting in the increase of CMA activity and, thus, alleviates alcohol-induced liver injury and steatosis. (C) 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.