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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    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 · 3.08 Impact Factor
    • "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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    ABSTRACT: Congenital hyperinsulinism (CHI) is the result of unregulated insulin secretion from the pancreatic β-cells leading to severe hypoglycaemia. In these patients it is important to make an accurate diagnosis and initiate the appropriate management so as to avoid hypoglycemic episodes and prevent the potentially associated complications like epilepsy, neurological impairment and cerebral palsy. At a genetic level abnormalities in eight different genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A and UCP2) have been reported with CHI. Loss of function mutations in ABCC8/KCNJ11 lead to the most severe forms of CHI which are usually medically unresponsive. At a histological level there are two major subgroups, diffuse and focal, each with a different genetic etiology. The focal form is sporadic in inheritance and is localized to a small region of the pancreas whereas the diffuse form is inherited in an autosomal recessive (or dominant) manner. Imaging using a specialized positron emission tomography scan with the isotope fluroine-18 L-3, 4-dihydroxyphenyalanine (18F-DOPA-PET-CT) is used to accurately locate the focal lesion pre-operatively and if removed can cure the patient from hypoglycemia. Understanding the molecular mechanisms, the histological basis, improvements in imaging modalities and surgical techniques have all improved the management of patients with CHI.
    03/2013; 17(1):19-30. DOI:10.4103/2230-8210.107822
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    • "Maturity onset diabetes of the young 1 (MODY1) is an autosomal dominant disease that develops as a result of hepatocyte nuclear factor‐4α (HNF4α) heterozygous mutations1,2 and is characterized by a primary defect in insulin response to glucose3,4. A number of heterozygous HNF4α mutations causing MODY1 have been identified, and some of which are C‐terminal truncated mutants, such as Q268X and R154X. "
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    ABSTRACT: Aims/Introduction: Mutations in hepatocyte nuclear factor‐4α (HNF4α) lead to various diseases, among which C‐terminal deletions of HNF4α are exclusively responsible for maturity onset diabetes of the young 1 (MODY1). MODY is an autosomal dominant disease characterized by a primary defect in insulin response to glucose, suggesting that the C‐terminus of HNF4α is important for pancreatic β‐cell function. To clarify the role of the C‐terminus of HNF4α, changes in cellular localization and the binding ability to its regulator were examined, specifically in the region containing Q268, which deletion causes MODY1. Materials and Methods: Cellular localization of mutant HNF4α were examined in monkey kidney 7 (COS7), Chinese hamster ovary, rat insulinoma and mouse insulinoma cells, and their binding activity to other proteins were examined by fluorescence resonance energy transfer (FRET) in COS7 cells. Results: Although wild‐type HNF4α was localized in the nucleoplasm in transfected cultured cells, Q268X‐HNF4α was located predominantly in the nucleolus. Deletion analysis of the C‐terminus of HNF4α showed that the S337X‐HNF4α mutant, and other mutants with shorter amino acid sequences (S337‐K194), were mostly localized in the nucleolus. HNF4α mutants with amino acid sequences shorter than the W192X‐HNF4α mutant gradually spread to the nucleoplasm in accordance with their lengths. The A250X‐HNF4α mutant was capable of causing the accumulation of HNF4α or the small heterodimer partner (SHP), one of the HNF4α regulators, in the nucleolus. However, the R154X‐HNF4α mutant did not have binding ability to wild‐type HNF4α or SHP, and thus was seen in the nucleus. Conclusions: The C‐terminus sites might play a key role in facilitating the nucleolar and subnucleolar localization of HNF4α. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2012.00210.x, 2012)
    10/2012; 3(5):449-56. DOI:10.1111/j.2040-1124.2012.00210.x
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