A20 Attenuates FFAs-induced Lipid Accumulation in Nonalcoholic Steatohepatitis.
A20 Attenuates FFAs-induced Lipid Accumulation in Nonalcoholic Steatohepatitis.
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DOI：
10.7150/ijbs.13371
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发表时间：
2015
影响因子：
9.2
通讯作者：
Fan Z
中科院分区：
文献类型：
--
作者：
Ai L;Xu Q;Wu C;Wang X;Chen Z;Su D;Jiang X;Xu A;Lin Q;Fan Z
A20是一种泛素编辑酶，可减弱促炎受体的近端信号复合物的活性。研究表明，A20蛋白在肝损伤和肝细胞凋亡中起重要作用。然而，腺病毒介导的A20蛋白过表达在mRNA水平上上调了两个脂肪酸代谢调控基因（PPARa和CPT 1a）的表达，除此之外，几乎没有证据表明A20蛋白参与了脂肪酸的稳态。本研究发现：1）A20蛋白在脂肪肝中的表达水平显著高于对照组：2）A20蛋白过表达抑制脂肪酸刺激的HepG 2细胞甘油三酯沉积，而A20蛋白低表达增加脂肪酸刺激的HepG 2细胞甘油三酯沉积; 3）A20蛋白在HepG 2细胞中的过表达上调了促进β-氧化的基因，并降低了脂肪酸合成酶（FAS）等关键脂肪生成基因的mRNA水平，表明A20通过激活线粒体β-氧化和减弱从头脂肪生成而起抗脂肪变性因子的作用; 4）非酒精性脂肪性肝炎（NASH）患者肝脏A20表达水平显著高于对照组。我们的研究结果表明，A20蛋白在人类和动物的脂肪酸稳态中起着重要作用。此外，我们的数据表明，肝细胞中A20蛋白从脂毒性到NASH的病理功能是通过减轻肝细胞中甘油三酯的积累。A20蛋白的高表达可能是预防非酒精性脂肪性肝炎进展的潜在治疗策略。
A20 is a ubiquitin-editing enzyme that attenuates the activity of proximal signaling complexes at pro-inflammatory receptors. It has been well documented that A20 protein plays an important role in response to liver injury and hepatocytes apoptosis in pro-inflammatory pathways. However, there was little evidence showing that A20 protein was involving in fatty-acid homeostasis except the up-regulation of two fatty acid metabolism regulatory genes at mRNA level (PPARa and CPT1a) by adenovirus-mediated A20 protein overexpression. In this study we found that: 1) the expression level of A20 protein was significantly higher in the steatotic liver from MCD-fed mice than the controls; 2) Overexpression of A20 protein suppressed FFAs-stimulated triglyceride deposition in HepG2 cells while under expression of A20 protein increased FFAs-stimulated triglyceride deposition; 3) Overexpression of A20 protein in HepG2 cells upregulated genes that promote β-oxidation and decreased the mRNA levels of key lipogenic genes such as fatty acid synthase (FAS), indicating A20 function as anti-steatotic factor by the activation of mitochondrial β-oxidation and attenuation of de novo lipogenesis; 4) Nonalcoholic steatohepatitis (NASH) patients showed significantly higher A20 expression level in liver compared with control individuals. Our results demonstrated that A20 protein plays an important role in fatty-acid homeostasis in human as well as animals. In addition, our data suggested that the pathological function of A20 protein in hepatocyte from lipotoxicity to NASH is by the alleviation of triglyceride accumulation in hepatocytes. Elevated expression of A20 protein could be a potential therapeutic strategy for preventing the progression of nonalcoholic steatohepatitis.