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The MODY1 gene HNF-4α regulates selected genes involved in insulin secretion
Rana K. Gupta, … , Stephen A. Duncan, Klaus H. Kaestner
Rana K. Gupta, … , Stephen A. Duncan, Klaus H. Kaestner
Published April 1, 2005
Citation Information: J Clin Invest. 2005;115(4):1006-1015. https://doi.org/10.1172/JCI22365.
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Article Metabolism

The MODY1 gene HNF-4α regulates selected genes involved in insulin secretion

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Abstract

Mutations in the gene encoding hepatocyte nuclear factor-4α (HNF-4α) result in maturity-onset diabetes of the young (MODY). To determine the contribution of HNF-4α to the maintenance of glucose homeostasis by the β cell in vivo, we derived a conditional knockout of HNF-4α using the Cre-loxP system. Surprisingly, deletion of HNF-4α in β cells resulted in hyperinsulinemia in fasted and fed mice but paradoxically also in impaired glucose tolerance. Islet perifusion and calcium-imaging studies showed abnormal responses of the mutant β cells to stimulation by glucose and sulfonylureas. These phenotypes can be explained in part by a 60% reduction in expression of the potassium channel subunit Kir6.2. We demonstrate using cotransfection assays that the Kir6.2 gene is a transcriptional target of HNF-4α. Our data provide genetic evidence that HNF-4α is required in the pancreatic β cell for regulation of the pathway of insulin secretion dependent on the ATP-dependent potassium channel.

Authors

Rana K. Gupta, Marko Z. Vatamaniuk, Catherine S. Lee, Reed C. Flaschen, James T. Fulmer, Franz M. Matschinsky, Stephen A. Duncan, Klaus H. Kaestner

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Figure 6

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HNF-4α directly activates the Kir6.2 gene. (A) The consensus binding sit...
HNF-4α directly activates the Kir6.2 gene. (A) The consensus binding site for HNF-4α is 13 bp long and was derived from 71 known HNF-4α binding sequences from the literature (55) using the program Weblogo (http://weblogo.berkeley.edu/). The size of the letters reflects the frequency at which the nucleotide appears at that position in the binding site. (B) Putative HNF-4α binding site in the Kir6.2 promoter identified using NUBIScan, which uses a transcription factor–binding site–identification algorithm to identify nuclear receptor binding sites. Note that the site located at position –2,300 matches all determinant nucleotides in the HNF-4α consensus site shown in A. (C) EMSA demonstrates that HNF-4α binds to the identified binding site in the Kir6.2 gene as well as the HNF-4α consensus site. In supershift experiments using 2 different antibodies raised against HNF-4α, the identity of the bound protein is confirmed to be HNF-4α. (D) Cotransfection of BHK cells with HNF-4α and pGL3-Kir6.2, expressing luciferase under the control of the 237-bp region of Kir6.2 containing the binding site, results in a dose-dependent increase in luciferase activity, indicating that this element serves as an HNF-4α–dependent enhancer. Mutation of this binding site abolishes the transcriptional activation. Statistical analysis was performed by ANOVA; n = 3 for each transfection condition.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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