Effects of diet and diabetes on gene expression in the liver

  • Dennis, Michael M.D (PI)

Project: Research project

Project Details


DESCRIPTION (provided by applicant): The proposed project will test the hypothesis that hyperglycemia and diabetes, acting alone or in combination, cause increased flux of glucose through the hexosamine biosynthetic pathway which results in increased O-GlcNAcylation, decreased ubiquitination, and decreased proteosomal-mediated degradation of the 4E-BP1 in the liver. The upregulated expression of 4E-BP1, in turn, produces a shift from cap-dependent to cap-independent mRNA translation. Mammalian eIF4E binding proteins (4E- BPs) inhibit cap-dependent translation by binding to the cap-binding protein eIF4E and preventing its association with eIF4G. 5'-cap binding by eIF4E is typically thought of as the rate-limiting step in translation initiation, and as such the reversible phosphorylation of 4E-BP1 is one of the best characterized mechanisms for regulating mRNA binding. An unexplored mechanism that also likely contributes to the regulation of mRNA cap-binding is altered expression of one or more of the 4E-BPs. Upregulated expression of 4E-BP1 likely contributes to pathologies associated with maladapted metabolism, as a result of altered hepatic protein expression due to the shift from cap-dependent to cap-independent translation. In the proposed studies, we will use diabetic rats and HepG2 cells in culture to evaluate the mechanism through which hyperglycemia leads to upregulated expression of 4E-BP1 in the liver.
Effective start/end date12/1/106/30/13


  • National Institute of Diabetes and Digestive and Kidney Diseases: $53,942.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $50,474.00
  • National Institute of Diabetes and Digestive and Kidney Diseases: $32,474.00


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