The MODY1 gene HNF-4α regulates selected genes involved in insulin secretion. J Clin Invest

Department of Genetics, Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 05/2005; 115(4):1006-15. DOI: 10.1172/JCI22365
Source: PubMed


Mutations in the gene encoding hepatocyte nuclear factor-4alpha (HNF-4alpha) result in maturity-onset diabetes of the young (MODY). To determine the contribution of HNF-4alpha to the maintenance of glucose homeostasis by the beta cell in vivo, we derived a conditional knockout of HNF-4alpha using the Cre-loxP system. Surprisingly, deletion of HNF-4alpha in beta 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 beta 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-4alpha. Our data provide genetic evidence that HNF-4alpha is required in the pancreatic beta cell for regulation of the pathway of insulin secretion dependent on the ATP-dependent potassium channel.

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    • "It has been suggested that PPAR-a directs fatty acids to the b-oxidation pathway and promotes an elevation of insulin secretion during hypoglycaemia (Sugden & Holness 2004). This hypothesis is supported by the reduction in PPAR-a expression in b-cell Hnf4a-null mice (Gupta et al. 2005). Moreover, Ppara-null mice have also been reported to develop fasted HH (Gremlich et al. 2005). "
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    • "Candidate transcription factors which may possess a critical role in the molecular mechanisms responsible for reprogramming alpha cells to beta cells include transcription factors known to be important in beta cell differentiation and function during normal development. Hepatocyte nuclear factor 4α (HNF4α) represents a potential candidate as it has been identified as a key transcription factor required for regulation of many genes and pathways responsible for the maintenance and proliferation of adult beta cells (Gupta et al., 2005;Wollheim et al., 2000). The importance of HNF4α for beta cell function is also highlighted as Maturity-Onset Diabetes of the Young (MODY). "
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    • "PPARα is a transcription factor that is known to control the expression of genes encoding enzymes of the beta oxidation pathway of fatty acids. Low levels of PPARα are reported in HNF-4α deficient β-cells.[37] It can be postulated that HNF-4α deficiency causes lower levels of PPARα and a decrease in beta-oxidation of fatty acids resulting in the accumulation of lipids (such as malonyl-CoA) in the cytoplasm. "
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