Effects of diet and diabetes on gene expression in the liver

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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. PUBLIC HEALTH RELEVANCE: The proposed project will explore the mechanism(s) through which hyperglycemia and/or the diabetic state induce upregulated expression of 4E-BP1 in the liver. Although the regulation of translation initiation by the reversible phosphorylation of 4E-BP1 has been extensively characterized, changes in the expression of the translational repressor are largely unexplored. Increased expression of the 4E-BP1 in the liver due to excess nutrients and the diabetic state likely contributes to pathologies associated with metabolic dysfunction and as a result is a critical area for exploration in regards to public health.