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

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 an...

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Published in:	The Journal of clinical investigation Vol. 119; no. 5; pp. 1201 - 1215
Main Authors:	Kammoun, Hélène L., Chabanon, Hervé, Hainault, Isabelle, Luquet, Serge, Magnan, Christophe, Koike, Tatsuro, Ferré, Pascal, Foufelle, Fabienne
Format:	Journal Article
Language:	English
Published:	United States American Society for Clinical Investigation 01.05.2009
Subjects:	Animals Biomedical research Carbohydrates Care and treatment Endoplasmic reticulum Endoplasmic Reticulum - drug effects Endoplasmic Reticulum - metabolism Fatty acids Fatty Liver - metabolism Fatty Liver - pathology Fatty Liver - therapy Gene Expression - drug effects Gene Expression - genetics Genes Genetic aspects Glucose Glucose - metabolism Health aspects Heat shock proteins Heat-Shock Proteins - genetics Heat-Shock Proteins - metabolism Hepatocytes - drug effects Hepatocytes - metabolism Hyperglycemia Insulin - pharmacology Insulin Receptor Substrate Proteins - metabolism Insulin resistance Insulin Resistance - physiology Kinases Lipid Metabolism - genetics Liver - metabolism Liver diseases Male Metabolism Mice Mice, Obese Models, Biological Molecular Chaperones - genetics Molecular Chaperones - metabolism Nuclear Proteins - genetics Nuclear Proteins - metabolism Obesity - metabolism Phosphorylation Physiological aspects Proteins Rats Rats, Wistar Rats, Zucker Risk factors Signal Transduction - genetics Sterol Regulatory Element Binding Protein 1 - genetics Sterol Regulatory Element Binding Protein 1 - metabolism Sterol Regulatory Element Binding Protein 2 - metabolism Thapsigargin - pharmacology Transcription factors Transcription Factors - genetics Transcription Factors - metabolism Triglycerides United States
ISSN:	0021-9738, 1558-8238, 1558-8238
Online Access:	Get full text
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Summary:	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-1c 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.
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ISSN:	0021-9738 1558-8238 1558-8238
DOI:	10.1172/JCI37007