Regulation of SREBP-2 intracellular trafficking improves impaired autophagic flux and alleviates endoplasmic reticulum stress in NAFLD

被引：39

作者：

Deng, Xiaoling ^{[1
]}

Pan, Xiaoli ^{[1
]}

Cheng, Chunwei ^{[1
]}

Liu, Beibei ^{[1
]}

Zhang, Huan ^{[1
]}

Zhang, Yuping ^{[1
]}

Xu, Keshu ^{[1
]}

机构：

[1] Huazhong Univ Sci & Technol, Union Hosp, Div Gastroenterol, Tongji Med Coll, 1277 Jiefang Rd, Wuhan 430022, Peoples R China

来源：

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS | 2017年 / 1862卷 / 03期

基金：

中国国家自然科学基金;

关键词：

Autophagy; Hepatic steatosis; Sterol regulatory element-binding protein 2; Site-1; protease; Site-2; Endoplasmic reticulum stress; ELEMENT-BINDING PROTEIN-1; FATTY LIVER-DISEASE; INSULIN-RESISTANCE; METABOLISM; NELFINAVIR; MICE; EXPRESSION; PROTEASE; CELLS; MECHANISMS;

D O I：

10.1016/j.bbalip.2016.12.007

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：337 / 350

页数：14

共 38 条

[1] Secreted site-1 protease cleaves peptides corresponding to luminal loop of sterol regulatory element-binding proteins [J].