The control of glucose homeostasis is critical to human health. Central to this process is the regulation of gluconeogenesis by the liver and kidney cortex. The rate limiting enzyme in glucose synthesis is phosphoenolpyruvate carboxykinase (GTP) (PEPCK; the overexpression of the gene for PEPCK in the liver of mice has, by itself, been shown to induce the symptoms of diabetes. The level of PEPCK in tissues is controlled by the rate of its gene transcription, which is acutely and markedly increased by starvation and by a diet devoid of carbohydrate and is inhibited by a diet high in carbohydrate. The mechanism of regulation of PEPCK gene transcription by hormones and diet is the topic of this grant application. The proposed research will focus on the interaction between cAMP (the signal of the catabolic state), glucocorticoids and other regulatory factors such as Nuclear Factor I, Steroid regulatory Co-activator-1 (SRC-1) and CREB binding protein (CBP). Recent work in Dr. Hanson's laboratory has shown that CREB Binding protein (CBP) can integrate the multiple signals that control PEPCK gene transcription in mammals and may thus hold the key to understanding the interaction between cAMP and glucocorticoids in controlling glucose output from the liver. Dr. Hanson plans to elucidate the manner in which the complex set of signals that control PEPCK gene transcription coordinated, using an in vitro transcription system. Based on the results, he will attempt to establish a physiological model of much greater resolution to explain the complex pattern of hormonal regulation of PEPCK gene transcription in mammals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK025541-27
Application #
6691653
Study Section
Biochemistry Study Section (BIO)
Program Officer
Laughlin, Maren R
Project Start
1978-08-01
Project End
2004-12-31
Budget Start
2004-01-01
Budget End
2004-12-31
Support Year
27
Fiscal Year
2004
Total Cost
$404,719
Indirect Cost
Name
Case Western Reserve University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Yang, Jianqi; Kong, Xiaoying; Martins-Santos, Maria Emilia S et al. (2009) Activation of SIRT1 by resveratrol represses transcription of the gene for the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) by deacetylating hepatic nuclear factor 4alpha. J Biol Chem 284:27042-53
Yang, Jianqi; Reshef, Lea; Cassuto, Hanoch et al. (2009) Aspects of the control of phosphoenolpyruvate carboxykinase gene transcription. J Biol Chem 284:27031-5
Nye, Colleen K; Hanson, Richard W; Kalhan, Satish C (2008) Glyceroneogenesis is the dominant pathway for triglyceride glycerol synthesis in vivo in the rat. J Biol Chem 283:27565-74
Montano, Monica M; Doughman, Yong Qui; Deng, Huayun et al. (2008) Mutation of the HEXIM1 gene results in defects during heart and vascular development partly through downregulation of vascular endothelial growth factor. Circ Res 102:415-22
Liu, George E; Weirauch, Matthew T; Van Tassell, Curtis P et al. (2008) Identification of conserved regulatory elements in mammalian promoter regions: a case study using the PCK1 promoter. Genomics Proteomics Bioinformatics 6:129-43
Hanson, Richard W; Hakimi, Parvin (2008) Born to run;the story of the PEPCK-Cmus mouse. Biochimie 90:838-42
Chalhoub, Elie; Hanson, Richard W; Belovich, Joanne M (2007) A computer model of gluconeogenesis and lipid metabolism in the perfused liver. Am J Physiol Endocrinol Metab 293:E1676-86
Chakravarty, Kaushik; Hanson, Richard W (2007) Insulin regulation of phosphoenolpyruvate carboxykinase-c gene transcription: the role of sterol regulatory element-binding protein 1c. Nutr Rev 65:S47-56
Hakimi, Parvin; Yang, Jianqi; Casadesus, Gemma et al. (2007) Overexpression of the cytosolic form of phosphoenolpyruvate carboxykinase (GTP) in skeletal muscle repatterns energy metabolism in the mouse. J Biol Chem 282:32844-55
Xu, Chuan; Chakravarty, Kaushik; Kong, Xiaoying et al. (2007) Several transcription factors are recruited to the glucose-6-phosphatase gene promoter in response to palmitate in rat hepatocytes and H4IIE cells. J Nutr 137:554-9

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