Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Endoplasmic Reticulum / drug effects
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Endoplasmic Reticulum / metabolism*
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Endoplasmic Reticulum Chaperone BiP
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Fatty Liver / metabolism
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Fatty Liver / pathology
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Fatty Liver / therapy*
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Gene Expression / drug effects
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Gene Expression / genetics
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Glucose / metabolism
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Heat-Shock Proteins / genetics*
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Heat-Shock Proteins / metabolism
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Hepatocytes / drug effects
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Hepatocytes / metabolism
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Insulin / pharmacology*
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Insulin Receptor Substrate Proteins / metabolism
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Insulin Resistance / physiology
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Lipid Metabolism / genetics
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Liver / metabolism
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Male
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Mice
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Mice, Obese
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Models, Biological
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Molecular Chaperones / genetics*
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Molecular Chaperones / metabolism
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism
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Obesity / metabolism
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Rats
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Rats, Wistar
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Rats, Zucker
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Signal Transduction / genetics
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Sterol Regulatory Element Binding Protein 1 / genetics
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Sterol Regulatory Element Binding Protein 1 / metabolism*
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Sterol Regulatory Element Binding Protein 2 / metabolism
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Thapsigargin / pharmacology
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Transcription Factors / genetics
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Transcription Factors / metabolism
Substances
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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Endoplasmic Reticulum Chaperone BiP
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Heat-Shock Proteins
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Hspa5 protein, mouse
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Insulin
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Insulin Receptor Substrate Proteins
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Mlxipl protein, mouse
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Molecular Chaperones
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Nuclear Proteins
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Sterol Regulatory Element Binding Protein 1
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Sterol Regulatory Element Binding Protein 2
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Transcription Factors
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Thapsigargin
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Glucose