Effects of diet and diabetes on gene expression in the liver

描述(申请人提供)：建议的项目将测试这一假设，即高血糖和糖尿病单独或联合作用，导致通过己糖胺生物合成途径的葡萄糖流量增加，从而导致肝脏中O-GlcN酰化增加，泛素化减少，以及蛋白酶体介导的4E-BP1降解减少。4E-BP1的上调表达反过来又导致了从帽子依赖到帽子非依赖的mRNA翻译。哺乳动物eIF4E结合蛋白(4E-Bps)通过与帽结合蛋白eIF4E结合并阻止其与eIF4G结合来抑制帽依赖的翻译。EIF4E与5‘-帽的结合通常被认为是翻译启动的限速步骤，因此4E-BP1的可逆磷酸化是调节mRNA结合的最佳机制之一。一个未知的机制，也可能有助于调节mRNA帽结合是改变表达的一个或多个4E-BP。4E-BP1的上调表达可能参与了与适应不良代谢相关的病理过程，这是由于从帽依赖翻译转变为帽非依赖翻译导致肝脏蛋白表达改变的结果。在拟议的研究中，我们将使用糖尿病大鼠和培养的HepG2细胞来评估高血糖导致4E-BP1在肝脏上调表达的机制。 公共卫生相关性：拟议的项目将探索高血糖和/或糖尿病状态诱导肝脏4E-BP1上调表达的机制(S)。尽管4E-BP1可逆磷酸化对翻译启动的调控已经得到了广泛的表征，但翻译抑制因子的表达变化在很大程度上还没有被探索。由于营养过剩和糖尿病状态，4E-BP1在肝脏中的表达增加可能会导致与代谢功能障碍相关的病理变化，因此是公共卫生领域的关键探索领域。

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.