GRP78 expression inhibits insulin and ER stress-induced SREBP-1c activation and reduces hepatic steatosis in mice

被引:647
作者
Kammoun, Helene L. [1 ,2 ]
Chabanon, Herve [1 ,2 ]
Hainault, Isabelle [1 ,2 ]
Luquet, Serge [3 ]
Magnan, Christophe [3 ]
Koike, Tatsuro [4 ]
Ferre, Pascal [1 ,2 ]
Foufelle, Fabienne [1 ,2 ]
机构
[1] Ctr Rech Cordeliers, UMR S 872, INSERM, F-75006 Paris, France
[2] Univ Paris 06, Paris, France
[3] Univ Paris Diderot, CNRS, Paris, France
[4] Hokkaido Univ, Grad Sch Life Sci, Mol Neurobiol Lab, Sapporo, Hokkaido, Japan
关键词
ELEMENT-BINDING PROTEIN-1C; ENDOPLASMIC-RETICULUM STRESS; FATTY-ACID SYNTHESIS; LIVER-X-RECEPTOR; LIPOGENIC GENE-EXPRESSION; TRANSCRIPTION FACTOR; DIFFERENTIAL REGULATION; GLUCOSE-HOMEOSTASIS; COPII PROTEINS; ENZYME GENES;
D O I
10.1172/JCI37007
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Hepatic steatosis is present in insulin-resistant obese rodents and is concomitant with active lipogenesis. Hepatic lipogenesis depends on the insulin-induced activation of the transcription factor SREBP-1c. Despite prevailing insulin resistance, SREBP-1c is activated in the livers of genetically and diet-induced obese rodents. Recent studies have reported the presence of an ER stress response in the livers of obese ob/ob mice. To assess whether ER stress promotes SREBP-1c activation and thus contributes to lipogenesis, we overexpressed the chaperone glucose-regulated protein 78 (GRP78) in the livers of ob/ob mice using an adenoviral vector. GRP78 overexpression reduced ER stress markers and inhibited SREBP-1c cleavage and the expression of SREBP-lc and SREBP-2 target genes. Furthermore, hepatic triglyceride and cholesterol contents were reduced, and insulin sensitivity improved, in GRP78-injected mice. These metabolic improvements were likely mediated by restoration of IRS-2 expression and tyrosine phosphorylation. Interestingly, GRP78 overexpression also inhibited insulin-induced SREBP-1c cleavage in cultured primary hepatocytes. These findings demonstrate that GRP78 inhibits both insulin-dependent and ER stress-dependent SREBP-1c proteolytic cleavage and explain the role of ER stress in hepatic steatosis in obese rodents.
引用
收藏
页码:1201 / 1215
页数:15
相关论文
共 58 条
[1]   Adenovirus-mediated overexpression of sterol regulatory element binding protein-1c mimics insulin effects on hepatic gene expression and glucose homeostasis in diabetic mice [J].
Bécard, D ;
Hainault, I ;
Azzout-Marniche, D ;
Bertry-Coussot, L ;
Ferré, P ;
Foufelle, F .
DIABETES, 2001, 50 (11) :2425-2430
[2]   Differential regulation of sterol regulatory element-binding protein 1c transcriptional activity by insulin and liver X receptor during liver development [J].
Bobard, A ;
Hainault, I ;
Ferré, P ;
Foufelle, F ;
Bossard, P .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (01) :199-206
[3]   PERK-dependent regulation of lipogenesis during mouse mammary gland development and adipocyte differentiation [J].
Bobrovnikova-Marjon, Ekaterina ;
Hatzivassiliou, Georgia ;
Grigoriadou, Christina ;
Romero, Margarita ;
Cavener, Douglas R. ;
Thompson, Craig B. ;
Diehl, J. Alan .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2008, 105 (42) :16314-16319
[4]   A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood [J].
Brown, MS ;
Goldstein, JL .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (20) :11041-11048
[5]   Insulin activates the rat sterol-regulatory-element-binding protein 1c (SREBP-1c) promoter through the combinatorial actions of SREBP, LXR, Sp-1 and NF-Y cis-acting elements [J].
Cagen, LM ;
Deng, X ;
Wilcox, HG ;
Park, EA ;
Raghow, R ;
Elam, MB .
BIOCHEMICAL JOURNAL, 2005, 385 :207-216
[6]   Central role for liver X receptor in insulin-mediated activation of Srebp-1c transcription and stimulation of fatty acid synthesis in liver [J].
Chen, GX ;
Liang, GS ;
Ou, JF ;
Goldstein, JL ;
Brown, MS .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (31) :11245-11250
[7]   Endoplasmic reticulum stress causes the activation of sterol regulatory element binding protein-2 [J].
Colgan, Stephen M. ;
Tang, Darnu ;
Werstuck, Geoff H. ;
Austin, Richard C. .
INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY, 2007, 39 (10) :1843-1851
[8]   Hepatic glucokinase is required for the synergistic action of ChREBP and SREBP-1c on glycolytic and lipogenic gene expression [J].
Dentin, R ;
Pégorier, JP ;
Benhamed, F ;
Foufelle, F ;
Ferré, P ;
Fauveau, V ;
Magnuson, MA ;
Girard, J ;
Postic, C .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (19) :20314-20326
[9]  
Donnelly KL, 2005, J CLIN INVEST, V115, P1343, DOI [10.1172/JCI23621, 10.1172/JCI200523621]
[10]   Sterol regulatory element binding protein-1c is a major mediator of insulin action on the hepatic expression of glucokinase and lipogenesis-related genes [J].
Foretz, M ;
Guichard, C ;
Ferré, P ;
Foufelle, F .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1999, 96 (22) :12737-12742