The research aim of this laboratory is to elucidate biochemical mechanisms for regulation of carbohydrate metabolism and lipogenesis. A high carbohydrate diet leads to post-translational activation of many enzymes involved in carbohydrate metabolism and conversion to storage fat. Until recently it was thought that hormones such as insulin and glucagon regulate the transcription of genes. More recently it has been shown that nutrients themselves play an important role in the activation of lipogenesis.
We have recently purified and identified from liver a transcription factor which responds to high glucose by specifically binding to the carbohydrate responsive element of the liver pyruvate kinase gene and activates transcription. We have demonstrated that the transcription factor, termed "carbohydrate responsive element binding protein, ChREBP" is regulated at two levels, nuclear localization and DNA binding, through phosphorylation-mediated mechanisms in response to signals from high glucose and cAMP. The nuclear import is regulated by phosphorylation and dephosphorylation. Glucose stimulates nuclear import of ChREBP after dephosphorylation catalyzed by xylulose5P activated protein phosphatase. Fatty acids also inhibit ChREBP by phosphorylation of another site on the ChREBP by AMP-activated protein kianse. We are currently investigating the mechanism of the glucose signaling pathway, and roles of ChREBP in brain in regulation of appetite.
RESEARCH INTERESTS
Regulation of carbohydrate metabolism and lipogenesis in various mammalian tissues.
Short term regulation such as allosteric controls of key enzymes in glucose metabolism and fat synthesis.
Long term regulation which includes transcriptional controls by hormones, nutrients and stress factors.
Glucose signaling pathway and its signaling mechanism in lipogenesis.
RECENT PUBLICATIONS
Iizuka, K., Miller, B., and Uyeda, K., "Deficiency of carbohydrate-activated transcription factor ChREBP prevents obesity and improves plasma glucose control in leptin-deficient (ob/ob) mice." Am. J. of Physiol. Endcrinol. Metab., 291:E358-E364, 2006
Iizuka K, Bruick RK, Liang G, Horton JD, Uyeda K., "Deficiency of carbohydrate response element-binding protein (ChREBP) reduces lipogenesis as well as glycolysis." Proc. Natl..Acad. Sci., 101(19):7281-6, May 2004
Kabashima T, Kawaguchi T, Wadzinski BE, Uyeda K., "Xylulose 5-phosphate mediates glucose-induced lipogenesis by xylulose 5-phosphate-activated protein phosphatase in rat liver." Proc. Natl. Acad. Sci. USA, 100(10):5578-80, May 2003
Kawaguchi, T., Osatomi, K, Yamashita, H., Kabashima, T., and Uyeda, K., "Mechanism of Fatty Acids Sparing Effect on Glucose-induced Transcription: Regulation of Carbohydrate Response Element Binding Protein by AMP-Activated Protein Kinase." J. Biol. Chem, 277:3829- 3835, 2002
Uyeda, K., and Repa, J.J., "Carbohydrate response element binding protein, ChREBP, a transcription factor coupling hepatic glucose utilization and lipid synthesis." Cell Metabolism, 4:107-110, 2006
SIGNIFICANT PUBLICATIONS
Yamashita, H.,Takenoshita, M., Sakurai, M., Bruick, R.K., Henzel, W.J., Shillinglaw, W., Arnot, D., and Uyeda, K., "A Glucose-Responsive Transcription Factor that regulates Carbohydrate Metabolism in the liver." Proc Natl. Acad. Sci., 98:9116-9121, 2001
Kawaguchi, T., Takenoshita, M., Kabashima, T., and Uyeda, K., "Glucose and cAMP Regulate L-type Pyruvate Kinase Gene by Phosphorylation/Dephosphorylation of the Carbohydrate Response Element Binding Protein." Proc. Natl..Acad. Sci., 98:13710 13715, 2001
Nishimura, M. and Uyeda, K., "Catalyzing Dephosphorylation of Fructose 6-phosphate,2-kinase:Fructose 2,6-bisphosphatase" J. Biol. Chem., 270:9116-9121, 1995
Nishimura, M., Fedorov, S., and Uyeda, K., "Glucose-stimulated Synthesis of Fructose 2,6-Bisphosphate in Rat Liver" J. Biol. Chem., 269:26100-26106, 1994
Istvan, E.S., Hasemann, C.A., Kurumbail, R.G., Uyeda, K., and Deisenhofer, J., "Crystallization and Preliminary X-ray Analysis of Fructose 6-phosphate,2-kinase:Fructose 2,6-bisphosphatase." Protein Sci., 4:2439-2441, 1995
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