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: 13.77). 05/2005; 115(4):1006-15. DOI: 10.1172/JCI22365
Source: PubMed

ABSTRACT 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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Available from: Klaus H Kaestner, Aug 27, 2015
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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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    ABSTRACT: Congenital hyperinsulinism (CHI) is a complex heterogeneous condition in which insulin secretion from pancreatic β-cells is unregulated and inappropriate for the level of blood glucose. The inappropriate insulin secretion drives glucose into the insulin sensitive tissues, such as the muscle, liver and adipose tissue leading to severe hyperinsulinaemic hypoglycaemia (HH). At a molecular level, genetic abnormalities in 9 different genes (ABCC8, KCNJ11, GLUD1, GCK, HNF4A, HNF1A, SLC16A1, UCP2, HADH) have been identified which cause CHI. Autosomal recessive and dominant mutations in ABCC8/KCNJ11 are the commonest cause of medically-unresponsive CHI. Mutations in GLUD1 and HADH lead to leucine-induced HH and these two genes encode for the key enzymes (glutamate dehydrogenase and short chain 3-hydroxyacyl-CoA dehydrogenase) which play a key role in amino acid and fatty acid regulation of insulin secretion, respectively. Genetic abnormalities in HNF4A and HNF1A lead to a dual phenotype of HH in the newborn period and maturity onset diabetes later in life. This state of the art review provides an update on the molecular basis of CHI.
    Journal of Molecular Endocrinology 03/2015; 54(2). DOI:10.1530/jme-15-0016 · 3.62 Impact Factor
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    • "A study in Drosophila using an HNF4α ligand-binding domain (LBD) sensor found that HNF4α LBD activation was highly modulated, although the nature of the ligand remained undetermined (Palanker et al., 2009). Because of the limited evidence indicating that ligand binding influences the state of transcriptional activity mediated by HNF4α (Yuan et al., 2009), studies of HNF4α have been restricted to genetic deletion (Chen et al., 1994; Duncan et al., 1997; Gupta et al., 2005; Hayhurst et al., 2001) or overexpression (Carter et al., 1993; Harnish et al., 1996; Inoue et al., 2002). "
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    ABSTRACT: Hepatocyte nuclear factor (HNF)4α is a central regulator of gene expression in cell types that play a critical role in metabolic homeostasis, including hepatocytes, enterocytes, and pancreatic β cells. Although fatty acids were found to occupy the HNF4α ligand-binding pocket and were proposed to act as ligands, there is controversy about both the nature of HNF4α ligands as well as the physiological role of the binding. Here, we report the discovery of potent synthetic HNF4α antagonists through a high-throughput screen for effectors of the human insulin promoter. These molecules bound to HNF4α with high affinity and modulated the expression of known HNF4α target genes. Notably, they were found to be selectively cytotoxic to cancer cell lines in vitro and in vivo, although in vivo potency was limited by suboptimal pharmacokinetic properties. The discovery of bioactive modulators for HNF4α raises the possibility that diseases involving HNF4α, such as diabetes and cancer, might be amenable to pharmacologic intervention by modulation of HNF4α activity.
    Chemistry & biology 07/2012; 19(7):806-18. DOI:10.1016/j.chembiol.2012.05.014 · 6.59 Impact Factor
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    • "Others are less so, including the clear beneficial impact of estrogen receptor activation (Mauvais-Jarvis, 2011), and the well documented insulin sensitizing effects of phenobarbital in human type 2 diabetes (Lahtela et al., 1985; Sotaniemi and Karvonen, 1989). The beneficial impact of HNF-4α is revealed by the genetic consequences of its mutation in human patients with Mature Onset Diabetes of the Young type 1 (MODY-1) (Vaxillaire and Froguel, 2008), and also in mice with β-cell specific deletion of HNF-4α (Gupta et al., 2005; Miura et al., 2006). The potential antidiabetic effects of vitamin D in human patients remain controversial (Takiishi et al., 2010). "
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