Mammals regulate the expression of their genetic information in response to nutritional and metabolic signals, providing the optimal protein repertoire to meet metabolic and energy needs of the organism. The intracellular signaling pathways and molecular mechanisms involved in nutrient control of gene expression are only beginning to be unraveled. The long-range goal of this proposal is to understand one system of metabolic regulation: the transcriptional induction of lipogenic enzyme genes that occurs in the hepatocyte in response to increased glucose metabolism. At least 16 gene products involved directly or indirectly in the process of ctenovo lipogenesis are induced in response to glucose in the liver. We have previously defined a conserved regulatory sequence, the carbohydrate response element or ChoRE, in several of these genes that is necessary and sufficient for this regulation. In the past funding period, a novel hepatic nuclear complex composed of the transcription factors ChREBP (ChoRE-Binding Protein) and Mix (Max-like factor X) has been shown to bind to the ChoRE and mediate the effects of elevated glucose. We hypothesize that increased glucose metabolism leads to the covalent modification of the ChREBP-Mix complex to activate its transcriptional potential. Furthermore, we hypothesize that the ChREBP-MIx complex is an important transcriptional regulator in the hepatocyte that controls other metabolic pathways in response to glucose. To test these hypotheses and further characterize the role of the glucose-responsive transcription complex, the following specific aims are proposed: (1) to evaluate the post-translational modification of ChREBP and the effect of changes in glucose metabolism on its modification and activity; (2) to explore the function of the ChREBP partner, Mix, in the glucose regulatory pathway; (3) to examine the functional roles of ChREBP-MIx in hepatocytes by gene expression analysis. These studies should allow us to decipher the signaling pathway by which the hepatocyte can 'sense' increased glucose metabolism and respond by changing its transcriptional program. Given the critical position of the ChREBP-MIx complex in the metabolic conversion of carbohydrate to lipid, its potential role in contributing to the complications of obesity, type 2 diabetes, and the 'metabolic syndrome' is of significant biomedical relevance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK026919-27
Application #
7322530
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Laughlin, Maren R
Project Start
1980-04-01
Project End
2009-11-30
Budget Start
2007-12-01
Budget End
2008-11-30
Support Year
27
Fiscal Year
2008
Total Cost
$258,202
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Biochemistry
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Aipoalani, Derrick L; O'Callaghan, Brennon L; Mashek, Douglas G et al. (2010) Overlapping roles of the glucose-responsive genes, S14 and S14R, in hepatic lipogenesis. Endocrinology 151:2071-7
Davies, Michael N; O'Callaghan, Brennon L; Towle, Howard C (2010) Activation and repression of glucose-stimulated ChREBP requires the concerted action of multiple domains within the MondoA conserved region. Am J Physiol Endocrinol Metab 299:E665-74
Davies, Michael N; O'Callaghan, Brennon L; Towle, Howard C (2008) Glucose activates ChREBP by increasing its rate of nuclear entry and relieving repression of its transcriptional activity. J Biol Chem 283:24029-38
Tsatsos, Nikolas G; Augustin, Lance B; Anderson, Grant W et al. (2008) Hepatic expression of the SPOT 14 (S14) paralog S14-related (Mid1 interacting protein) is regulated by dietary carbohydrate. Endocrinology 149:5155-61
Tsatsos, Nikolas G; Davies, Michael N; O'Callaghan, Brennon L et al. (2008) Identification and function of phosphorylation in the glucose-regulated transcription factor ChREBP. Biochem J 411:261-70
Ma, Lin; Sham, Yuk Y; Walters, Kylie J et al. (2007) A critical role for the loop region of the basic helix-loop-helix/leucine zipper protein Mlx in DNA binding and glucose-regulated transcription. Nucleic Acids Res 35:35-44
Tsatsos, Nikolas G; Towle, Howard C (2006) Glucose activation of ChREBP in hepatocytes occurs via a two-step mechanism. Biochem Biophys Res Commun 340:449-56
Ma, Lin; Tsatsos, Nikolas G; Towle, Howard C (2005) Direct role of ChREBP.Mlx in regulating hepatic glucose-responsive genes. J Biol Chem 280:12019-27
Towle, Howard C (2005) Glucose as a regulator of eukaryotic gene transcription. Trends Endocrinol Metab 16:489-94
Stoeckman, Angela K; Ma, Lin; Towle, Howard C (2004) Mlx is the functional heteromeric partner of the carbohydrate response element-binding protein in glucose regulation of lipogenic enzyme genes. J Biol Chem 279:15662-9

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