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Article

Insulin Receptor at the Mouse Hepatocyte Nucleus after a Glucose Meal Induces Dephosphorylation of a 30-kDa Transcription Factor and a Concomitant Increase in Malic Enzyme Gene Expression¹

Nana Gletsu^*,, W. Dixon and M. T. Clandinin^*,,**2

^* Nutrition and Metabolism Research Group, Department of Agricultural, Food and Nutritional Science, ^** Department of Medicine, University of Alberta, Edmonton, AB, Canada T6G 2P5

²To whom correspondence should be addressed.

Insulin receptor translocation to the nucleus may represent a mechanism for activation of transcription factors controlling lipogenic gene expression in the mouse hepatocyte. Insulin stimulation was achieved in vivo by oral glucose feeding of mice deprived of food for 24 h. Hepatocytes were fractionated after the glucose meal and nuclei were purified. Insulin receptor levels and phosphorylation state in nuclei were assessed by immunoassay. Insulin receptor significantly increased from basal levels in hepatocyte nuclei within 15 min of the glucose meal. Immunoassay using antiphosphotyrosine indicated that phosphorylation of nuclear insulin receptor increased, whereas phosphorylation of a 30-kDa DNA-binding protein significantly decreased within 15 min of the glucose meal. Glucose treatment significantly increased expression of malic enzyme within the time frame of insulin receptor translocation to the nucleus. Nuclear protein binding to an insulin response element (IRE) within the malic enzyme gene promoter significantly increased within 15 min of the glucose meal. When cell nuclei were isolated from mice that had been deprived of food and treated in vitro with purified, activated insulin receptor, changes were observed in DNA-binding protein phosphorylation and IRE-binding in the absence of cytoplasmic insulin signaling. In vitro incubation of nuclei with activated insulin receptor significantly decreased phosphorylation of a 30-kDa DNA-binding protein compared with basal levels. Increased binding of nuclear proteins to malic enzyme IRE was observed upon stimulation of isolated nuclei with activated insulin receptor. These results suggest that nuclear insulin receptors induce malic enzyme gene expression by regulating phosphorylation of IRE transcription factors.

KEY WORDS: • insulin receptor • hepatocyte • mice • lipogenesis

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