S100A11 Promotes Liver Steatosis via FOXO1-Mediated Autophagy and Lipogenesis.
S100A11 Promotes Liver Steatosis via FOXO1-Mediated Autophagy and Lipogenesis.
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S100A11 通过 FOXO1 介导的自噬和脂肪生成促进肝脏脂肪变性
DOI：
10.1016/j.jcmgh.2020.10.006
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发表时间：
2021
影响因子：
7.2
通讯作者：
Liang B
中科院分区：
文献类型：
--
作者：
Zhang L;Zhang Z;Li C;Zhu T;Gao J;Zhou H;Zheng Y;Chang Q;Wang M;Wu J;Ran L;Wu Y;Miao H;Zou X;Liang B
非酒精性脂肪性肝病（NAFLD）正在成为世界范围内严重的肝脏疾病。自噬在肝脏脂肪变性中起关键作用。然而，自噬在NAFLD中的作用仍然是排他性的，并且还在争论中。在本研究中，我们探讨了S100钙结合蛋白A11 （S100A11）在肝脂肪变性发病中的作用。我们在一个成熟的树鼩NAFLD模型中进行了肝脏蛋白质组学研究。采用Western blot和/或定量聚合酶链反应检测S100A11在不同NAFLD模型中的表达。通过尾静脉注射重组腺病毒基因转移载体制备肝脏S100A11过表达小鼠，然后用高脂高胆固醇饮食诱导。用重组慢病毒载体建立了S100a11稳定过表达细胞系。脂质含量用Bodipy染色、Oil Red O染色、气相色谱法或甘油三酯试剂盒测定。采用Western blot和定量聚合酶链反应检测小鼠体内、体外自噬和脂肪生成。特异性抑制剂抑制Sirtuin 1、组蛋白去乙酰化酶6 （HDAC6）和fox01的功能。通过免疫共沉淀法和免疫荧光法分析相关蛋白之间的相互作用。在树鼩NAFLD模型中，S100A11的表达呈时间依赖性显著上调。S100A11的表达在油酸处理的肝细胞以及高脂肪饮食小鼠和NAFLD患者的肝脏中一致被诱导。体外和体内过表达S100A11均可诱导肝脏脂质积累。机制上，S100A11过表达通过上调转录因子FOXO1并使其乙酰化，激活自噬和脂肪生成过程，从而促进体内外脂肪生成和脂质积累。抑制FOXO1的去乙酰化酶HDAC6在Hepa 1-6细胞中表现出与S100A11过表达相似的表型。S100A11与HDAC6相互作用抑制其活性，导致FOXO1的释放和激活。在S100A11过表达的情况下，抑制FOXO1和自噬可以减轻自噬的激活和脂质基因的上调。FOXO1、自噬抑制和Dgat2缺失均能显著降低肝细胞脂质积累。高脂饮食促进肝脏S100A11的表达，S100A11可能与HDAC6相互作用，阻断其与FOXO1的结合，释放或增加FOXO1的乙酰化，从而激活自噬和脂肪生成，加速脂质积累和肝脏脂肪变性。这些发现提示了一个全新的S100A11-HDAC6-FOXO1轴调控自噬和肝脏脂肪变性，为NAFLD的治疗提供了潜在的可能性。
Nonalcoholic fatty liver disease (NAFLD) is becoming a severe liver disorder worldwide. Autophagy plays a critical role in liver steatosis. However, the role of autophagy in NAFLD remains exclusive and under debate. In this study, we investigated the role of S100 calcium binding protein A11 (S100A11) in the pathogenesis of hepatic steatosis. We performed liver proteomics in a well-established tree shrew model of NAFLD. The expression of S100A11 in different models of NAFLD was detected by Western blot and/or quantitative polymerase chain reaction. Liver S100A11 overexpression mice were generated by injecting a recombinant adenovirus gene transfer vector through the tail vein and then induced by a high-fat and high-cholesterol diet. Cell lines with S100a11 stable overexpression were established with a recombinant lentiviral vector. The lipid content was measured with either Bodipy staining, Oil Red O staining, gas chromatography, or a triglyceride kit. The autophagy and lipogenesis were detected in vitro and in vivo by Western blot and quantitative polymerase chain reaction. The functions of Sirtuin 1, histone deacetylase 6 (HDAC6), and FOXO1 were inhibited by specific inhibitors. The interactions between related proteins were analyzed by a co-immunoprecipitation assay and immunofluorescence analysis. The expression of S100A11 was up-regulated significantly in a time-dependent manner in the tree shrew model of NAFLD. S100A11 expression was induced consistently in oleic acid–treated liver cells as well as the livers of mice fed a high-fat diet and NAFLD patients. Both in vitro and in vivo overexpression of S100A11 could induce hepatic lipid accumulation. Mechanistically, overexpression of S100A11 activated an autophagy and lipogenesis process through up-regulation and acetylation of the transcriptional factor FOXO1, consequently promoting lipogenesis and lipid accumulation in vitro and in vivo. Inhibition of HDAC6, a deacetylase of FOXO1, showed similar phenotypes to S100A11 overexpression in Hepa 1–6 cells. S100A11 interacted with HDAC6 to inhibit its activity, leading to the release and activation of FOXO1. Under S100A11 overexpression, the inhibition of FOXO1 and autophagy could alleviate the activated autophagy as well as up-regulated lipogenic genes. Both FOXO1 and autophagy inhibition and Dgat2 deletion could reduce liver cell lipid accumulation significantly. A high-fat diet promotes liver S100A11 expression, which may interact with HDAC6 to block its binding to FOXO1, releasing or increasing the acetylation of FOXO1, thus activating autophagy and lipogenesis, and accelerating lipid accumulation and liver steatosis. These findings indicate a completely novel S100A11-HDAC6-FOXO1 axis in the regulation of autophagy and liver steatosis, providing potential possibilities for the treatment of NAFLD.
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影响因子：
9
作者：
Barbato, D. Lettieri;Tatulli, G.;Aquilano, K.;Ciriolo, M. R.
通讯作者：
Ciriolo, M. R.
影响因子：
17.1
作者：
Matsuzaki T;Alvarez-Garcia O;Mokuda S;Nagira K;Olmer M;Gamini R;Miyata K;Akasaki Y;Su AI;Asahara H;Lotz MK
通讯作者：
Lotz MK
影响因子：
13.3
作者：
Li, Yuan;Zong, Wei-Xing;Ding, Wen-Xing
通讯作者：
Ding, Wen-Xing
影响因子：
4.8
作者：
Liu, Hui-Yu;Han, Jianmin;Cao, Wenhong
通讯作者：
Cao, Wenhong
影响因子：
3.7
作者：
Lede V;Meusel A;Garten A;Popkova Y;Penke M;Franke C;Ricken A;Schulz A;Kiess W;Huster D;Schöneberg T;Schiller J
通讯作者：
Schiller J