Journal Article

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

Ferré, Pascal, Hainault, Isabelle, Foufelle, Fabienne, Chabanon, Hervé, Koike, Tatsuro, Kammoun, Hélène L., Luquet, Serge, Magnan, Christophe

2009

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: 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