Hepatic gluconeogenesis is one of the critical factors in the development of hyperglycemia in diabetes. The sustained production of glucose by the liver requires sufficient metabollc substrates such as pyruvate, lactate, and alanine. Among them, pyruvate is the most direct substrate used for hepatic gluconeogenesis. Since substrate availability is one of the most important driving forces in gluconeogenesis, regulation of pyruvate metabolism may be a critical switch for glucose oxidation or gluconeogenesis. Pyruvate dehydrogenase kinases (PDK) normally inhibits pyruvate oxidation through phosphorylation and inactivation of the pyruvate dehydrogenase complex. One of the PDK kinases, PDK4, is elevated in the liver under starvation or diabetic conditions, suggesting that regulation of PDK4 may be an essential component of gluconeogenesis because of its effects on substrate availability. To elucidate the mechanisms of glucose homeostasis and PDK4 gene regulation under normal and diabetic conditions, the following specific aims are proposed.
Aim 1, The role of PDKs in gluconeogenesis in the development of diabetes will be examined using animal models.
Aim 2, Regulation of PDK4 gene expression by nutrient signals will be investigated by both in vitro and in vivo approaches.
Aim 3, Role of Foxol in the regulation of PDK4 and hepatic glucose homeostasis will be investigated using mouse genetic approaches.
The goal of this project is to elucidate the mechanism how blood glucose levels are elevated above a normal range in the development of diabetes, which has reached an epidemic level in the U.S. and worldwide.
|He, Guifen; Zhang, Yi-Wei; Lee, Jun-Ho et al. (2014) AMP-activated protein kinase induces p53 by phosphorylating MDMX and inhibiting its activity. Mol Cell Biol 34:148-57|
|Xiong, Xiwen; Tao, Rongya; DePinho, Ronald A et al. (2013) Deletion of hepatic FoxO1/3/4 genes in mice significantly impacts on glucose metabolism through downregulation of gluconeogenesis and upregulation of glycolysis. PLoS One 8:e74340|
|Riehle, Christian; Wende, Adam R; Sena, Sandra et al. (2013) Insulin receptor substrate signaling suppresses neonatal autophagy in the heart. J Clin Invest 123:5319-33|
|Tao, Rongya; Xiong, Xiwen; DePinho, Ronald A et al. (2013) FoxO3 transcription factor and Sirt6 deacetylase regulate low density lipoprotein (LDL)-cholesterol homeostasis via control of the proprotein convertase subtilisin/kexin type 9 (Pcsk9) gene expression. J Biol Chem 288:29252-9|
|Tao, Rongya; Xiong, Xiwen; DePinho, Ronald A et al. (2013) Hepatic SREBP-2 and cholesterol biosynthesis are regulated by FoxO3 and Sirt6. J Lipid Res 54:2745-53|
|Tao, Rongya; Xiong, Xiwen; Harris, Robert A et al. (2013) Genetic inactivation of pyruvate dehydrogenase kinases improves hepatic insulin resistance induced diabetes. PLoS One 8:e71997|
|Dhurandhar, Emily J; Krishnapuram, Rashmi; Hegde, Vijay et al. (2012) E4orf1 improves lipid and glucose metabolism in hepatocytes: a template to improve steatosis & hyperglycemia. PLoS One 7:e47813|
|Dong, X Charlie (2012) Sirtuin biology and relevance to diabetes treatment. Diabetes Manag (Lond) 2:243-257|
|Zhang, Sheng; Liu, Sijiu; Tao, Rongya et al. (2012) A highly selective and potent PTP-MEG2 inhibitor with therapeutic potential for type 2 diabetes. J Am Chem Soc 134:18116-24|
|Xiong, Xiwen; Tao, Rongya; DePinho, Ronald A et al. (2012) The autophagy-related gene 14 (Atg14) is regulated by forkhead box O transcription factors and circadian rhythms and plays a critical role in hepatic autophagy and lipid metabolism. J Biol Chem 287:39107-14|
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