Regulation of SREBP-2 intracellular trafficking improves impaired autophagic flux and alleviates endoplasmic reticulum stress in NAFLD
Regulation of SREBP-2 intracellular trafficking improves impaired autophagic flux and alleviates endoplasmic reticulum stress in NAFLD
复制标题
SREBP-2 细胞内运输的调节可改善 NAFLD 中受损的自噬通量并减轻内质网应激
DOI：
10.1016/j.bbalip.2016.12.007
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发表时间：
2017-03-01
影响因子：
4.8
通讯作者：
Xu, Keshu
中科院分区：
文献类型：
--
作者：
Deng, Xiaoling;Pan, Xiaoli;Xu, Keshu
固醇调节元件结合蛋白2（SREBP-2）是一种已知的胆固醇代谢转录调节因子。SREBP-2被非常规地激活以促进非酒精性脂肪性肝病（NAFLD）中的过度胆固醇积累。此外，最近的研究表明，过量的脂质和胆固醇积累会削弱细胞自噬功能，促进内质网应激（ERS）。然而，SREBP-2加工的调节是否调节自噬和ERS仍然是未知的。在这项研究中，我们证明了通过位点1蛋白酶（S1 P）和位点2蛋白酶（S2 P）特异性抑制剂或靶向SIP和S2 P的shRNA抑制SREBP-2细胞内运输，上调自噬标记物的基因和蛋白表达，并改善NAFLD细胞和小鼠模型中诱导的受损自噬通量。此外，通过自噬增加的脂质降解可以抑制PERK-P-EIF 2 α信号传导。总之，这些发现表明，调节SREBP-2的核转运通过自噬依赖性途径减少脂质沉积和ERS。(C)2016爱思唯尔B. V.保留所有权利。
Sterol regulatory element-binding protein 2 (SREBP-2), is a well-known transcriptional regulator of cholesterol metabolism. SREBP-2 is activated unconventionally to promote excessive cholesterol accumulation in non-alcoholic fatty liver disease (NAFLD). In addition, recent studies suggested that excessive lipid and cholesterol accumulation can weaken cellular autophagy function and promote endoplasmic reticulum stress (ERS). However, it remains unknown whether regulation of SREBP-2 processing modulates autophagy and ERS. In this study, we demonstrated that inhibition of SREBP-2 intracellular trafficking by site-1 protease (S1P) and site-2 protease (S2P) specific inhibitors, or shRNAs targeting SIP and S2P, upregulated gene and protein expression of autophagy markers, and improved the impaired autophagic flux induced in both cell and mouse models of NAFLD. Furthermore, increased lipid degradation by autophagy could repress PERK-P-EIF2 alpha signaling. Taken together, these findings suggest that regulating the nuclear transport of SREBP-2 reduces lipid deposition and ERS via an autophagy-dependent pathway. (C) 2016 Elsevier B.V. All rights reserved.