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Papers In Press, published online ahead of print January 23, 2004
Biochemistry, Molecular Biology & Biophysics, University of Minnesota, Minneapolis, MN 55455
Corresponding Author: towle{at}mail.ahc.umn.edu
The expression of genes encoding enzymes involved in de novo triglyceride synthesis (lipogenesis) is transcriptionally induced in the liver in response to increased glucose metabolism. ChREBP is a newly identified basic/helix-loop-helix/leucine zipper (bHLH/LZ) transcription factor proposed to regulate the expression of the glucose-responsive gene pyruvate kinase. This gene contains a carbohydrate response element (ChoRE) consisting of two E box motifs separated by 5 bp that is necessary and sufficient for glucose regulation. We demonstrate that overexpression of ChREBP in primary rat hepatocytes activates other ChoRE-containing promoters in a manner consistent with their ability to respond to glucose. In vitro binding of ChREBP to ChoRE sequences was not detected. Since E box binding proteins function as obligate dimers, we performed a yeast two-hybrid screen of a mouse liver cDNA library to identify potential heteromeric partners. Max-like protein X (Mlx) was selected as the only bHLH/LZ interaction partner in this screen. When a plasmid expressing either Mlx or ChREBP was co-transfected with a ChoRE-containing reporter plasmid into HEK 293 cells, no increase in promoter activity was observed. However, expression of both proteins dramatically enhanced promoter activity. This activation was observed with reporters containing ChoREs from several different lipogenic enzyme genes. In contrast, reporters containing non-glucose-responsive E box elements were not activated by ChREBP/Mlx expression. In vitro binding of ChREBP to ChoRE-containing oligonucleotides was only observed in the presence of Mlx. ChREBP/Mlx binding discriminated between E box sites that are glucose-responsive and those that are not. We conclude that Mlx is a functional heteromeric partner of ChREBP in regulating the expression of glucose-responsive genes.
J. Biol. Chem, 10.1074/jbc.M311301200
Submitted on October 14, 2003
Revised on January 8, 2004
Accepted on January 23, 2004
Mlx is the functional heteromeric partner of ChREBP in glucose regulation of lipogenic enzyme genes
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