title: Regulation of SREBP-2 intracellular trafficking improves impaired autophagic flux and alleviates endoplasmic reticulum stress in NAFLD.
abstract: 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 S1P 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-EIF2α signaling. Taken together, these findings suggest that regulating the nuclear transport of SREBP-2 reduces lipid deposition and ERS via an autophagy-dependent pathway.
authors.affiliation: Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Road, Wuhan 430022, PR China.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Deng
authors.affiliation: Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Road, Wuhan 430022, PR China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Pan
authors.affiliation: Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Road, Wuhan 430022, PR China.
authors.forename: Chunwei
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Road, Wuhan 430022, PR China.
authors.forename: Beibei
authors.initials: B
authors.lastname: Liu
authors.affiliation: Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Road, Wuhan 430022, PR China.
authors.forename: Huan
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Road, Wuhan 430022, PR China.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, No. 1277 Jiefang Road, Wuhan 430022, PR China. Electronic address: xuzoumedmail@163.com.
authors.forename: Keshu
authors.initials: K
authors.lastname: Xu
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D045744:Cell Line, Tumor; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D056945:Hep G2 Cells; D006801:Humans; D008055:Lipids / Q000502:physiology; D008297:Male; D008666:Metalloendopeptidases / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism* / Q000473:pathology*; D043484:Proprotein Convertases / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D012697:Serine Endopeptidases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000378:metabolism
chemical_list: D008055:Lipids; D008666:Metalloendopeptidases; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D051782:Sterol Regulatory Element Binding Protein 2; D019892:eIF-2 Kinase; C115575:membrane-bound transcription factor peptidase, site 1
keywords: Autophagy; Endoplasmic reticulum stress; Hepatic steatosis; Site-1 protease; Site-2 protease; Sterol regulatory element-binding protein 2