GRP78 Expression Inhibits Insulin and ER Stress-Induced SREBP-1c Activation and Reduces Hepatic Steatosis in Mice

J Clin Invest. 2009 May;119(5):1201-15. doi: 10.1172/JCI37007. Epub 2009 Apr 13.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism*
  • Fatty Liver / metabolism
  • Fatty Liver / pathology
  • Fatty Liver / therapy*
  • Gene Expression / drug effects
  • Gene Expression / genetics
  • Glucose / metabolism
  • Heat-Shock Proteins / genetics*
  • Heat-Shock Proteins / metabolism
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism
  • Insulin / pharmacology*
  • Insulin Receptor Substrate Proteins / metabolism
  • Insulin Resistance / physiology
  • Lipid Metabolism / genetics
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Obese
  • Models, Biological
  • Molecular Chaperones / genetics*
  • Molecular Chaperones / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Obesity / metabolism
  • Rats
  • Rats, Wistar
  • Rats, Zucker
  • 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 / genetics
  • Transcription Factors / metabolism

Substances

  • Heat-Shock Proteins
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Mlxipl protein, mouse
  • Molecular Chaperones
  • Nuclear Proteins
  • Sterol Regulatory Element Binding Protein 1
  • Sterol Regulatory Element Binding Protein 2
  • Transcription Factors
  • Thapsigargin
  • Glucose
  • molecular chaperone GRP78