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J. Biol. Chem., Vol. 279, Issue 15, 15662-15669, April 9, 2004

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Mlx Is the Functional Heteromeric Partner of the Carbohydrate Response Element-binding Protein in Glucose Regulation of Lipogenic Enzyme Genes^*

Angela K. Stoeckman, Lin Ma, and Howard C. Towle

From the Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455

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. The carbohydrate response element-binding protein (ChREBP) is a newly identified basic helix-loop-helix/leucine zipper 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. Because 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. Mlx (Max-like protein X) was selected as the only basic helix-loop-helix/leucine zipper interaction partner in this screen. When a plasmid expressing either Mlx or ChREBP was cotransfected with a ChoRE-containing reporter plasmid into human embryonic kidney 293 cells, no increase in promoter activity was observed. However, the 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 observed only 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.

Received for publication, October 14, 2003 , and in revised form, January 8, 2004.

^* This work was supported by National Institutes of Health Grant DK26919 and P30 DK50456 (Minnesota Obesity Center). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Both authors contributed equally to this work.

To whom correspondence should be addressed: Dept. of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, 6-155 Jackson Hall, 321 Church St. SE, Minneapolis, MN 55455. Tel.: 612-625-3662; Fax: 612-624-0432; E-mail: towle{at}mail.ahc.umn.edu.

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