Laboratory of Kim Brint Pedersen
Assistant Professor, PhD,
Louisiana State University Health Sciences Center, 2003

Biography:
Kim Brint Pedersen received his Masters degree in Biology from the University of Copenhagen, Denmark in 1986. He was employed as a microbiologist in the Danish biotech company Novo Nordisk A/S 1986-1998. He received his Ph.D. degree from the Department of Biochemistry & Molecular Biology at LSUHSC, New Orleans in 2003. He continued his career in the Department of Biochemistry & Molecular Biology at LSUHSC, first as a postdoctoral researcher in the laboratory of Dr. Donald K. Scott 2003-2006, and from 2007 as an assistant professor.

Ongoing research in his lab
Metabolic conditions such as obesity and diabetes have reached epidemic proportions in the US and in much of the industrialized world. Currently, a third of the US population is obese, and 7% has diabetes. A thorough understanding of metabolism is required for developing effective treatments or prevention of these conditions. The research in Dr. Pedersen’s laboratory is focused on the regulation of enzymes involved in intermediary metabolism. The activity and expression of many such enzymes are dependent on whether the organism is in a fed or fasted state. As signals of the fed and fasted states, insulin and glucagon can affect the enzyme activity and/or gene expression. An elevated glucose concentration is another signal of the fed state that can elicit activation or repression of various genes. Glucose signaling thus promotes the conversion of glucose to triglycerides in the liver in the fed state in rodents.
     There are several ways whereby glucose can affect gene expression. A common way in which glucose induces genes in the liver is through the presence of a carbohydrate response element (ChoRE) in the promoter region. A ChoRE consists of two sequences related to the E-box motif (5’-CANNTG-3’) separated by 5 base pairs. The transcription factor Carbohydrate Response Element Binding Protein (ChREBP) together with its dimerization partner Mlx can mediate the induction of expression through a ChoRE, as an increased glucose concentration followed by enhanced glucose metabolism leads to increased binding of the ChREBP to the ChoRE and to enhanced activity of the ChREBP as a transcription factor.
    
Dr. Pedersen is currently studying the induction of the gene promoter for the catalytic subunit of glucose-6-phosphatase (G6Pase) by glucose. G6Pase catalyzes the hydrolysis of glucose 6-phosphate to glucose and is crucial for the ability of the liver to produce glucose. By opposing the first step in glucose utilization (catalyzed by glucokinase), G6Pase can also affect the rates of glycogen synthesis and glycolysis in hepatocytes. G6Pase is induced by glucose in both hepatocytes and pancreatic beta-cells. While this glucose regulation may be required for an adequate expression of G6Pase, it could also contribute to maintaining hyperglycemia in diabetics.
     Dr. Pedersen and his co-workers have mapped the cis-regulatory elements of the rat G6Pase gene promoter that mediate glucose responsiveness. Two distinct glucose-responsive regions of the promoter were found. A distal region ca. 3.7 kb upstream of the transcription start site functions as a typical ChoRE in a pancreatic beta-cell-derived cell line. A second, proximal region (-230/-112) is glucose-responsive in both hepatocyte- and beta-cell-derived cell lines. Within this region, a hepatocyte nuclear factor-1 binding site and two cAMP-reponse elements (CREs) are essential for glucose responsiveness.
     As shown in the diagram, the G6Pase gene promoters from rats and humans share homology in the non-repetitive regions. In the human promoter, sequences homologous to the glucose-responsive regions of the rat promoter can be located, but with only the proximal region supporting a robust glucose induction. There are thus species-specific differences with regards to the promoter elements mediating glucose responsiveness.  
     In a beta-cell-derived cell line, the two glucose-responsive regions respond to glucose by different mechanisms. ChREBP binds to the distal, but not the proximal, glucose-responsive region in a glucose-dependent manner, whereas transcription factors of the cAMP response element-binding protein (CREB) and CAAT/enhancer-binding protein (C/EBP) families are required for the glucose response from the proximal, but not the distal, glucose-responsive region. Dr. Pedersen intends to further investigate the mechanisms whereby glucose induces G6Pase.

Recent Publications

Collier, J.J., Zhang, P., Pedersen, K.B., Burke, S.J., Haycock, J.W., and Scott, D.K. c-Myc and ChREBP regulate glucose-mediated expression of the L-type pyruvate kinase gene in INS-1-derived 832/13 cells. Am. J. Physiol. Endocrinol. Metab. 293: E48-E56. (2007)

Pedersen, K.B., Zhang, P., Doumen, C., Charbonnet, M., Lu, D., Newgard, C., Haycock, J. W., Lange, A.J., and Scott, D. K. The promoter for the gene encoding the catalytic subunit of rat glucose-6-phosphatase contains two distinct glucose-responsive regions. Am. J. Physiol. Endocrinol. Metab. 292: E788-E801. (2007)

Geng, C.-d., Pedersen, K.B., Nunez, B.S., and Vedeckis, W.V. Human glucocorticoid receptor alpha transcript splice variants with exon 2 deletions: evidence for tissue- and cell type-specific functions. Biochemistry 44: 7395-7405. (2005)

Nunez, B.S., Geng, C.-d., Pedersen, K.B., Millro-Macklin, C.D., and Vedeckis W.V. Interaction between the interferon signaling pathway and the human glucocorticoid receptor gene 1A promoter. Endocrinology 146: 1449-1457. (2005)

Pedersen, K.B., Geng, C.-d., and Vedeckis W.V. Three mechanisms are involved in glucocorticoid receptor autoregulation in a human T-lymphoblast cell line. Biochemistry 43: 10851-10858 (2004)

Pedersen, K.B. and Vedeckis, W.V. Quantification and glucocorticoid regulation of glucocorticoid receptor transcripts in two human leukemic cell lines. Biochemistry 42: 10978-10990. (2003)

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