Hepatocyte Nuclear Factor-4 a Involved in Type 1 Maturity-Onset Diabetes of the Young Is a Novel Target of AMP-Activated Protein Kinase

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Author	Leclerc, Isabelle Lenzner, Claudia Gourdon, Laurence Vaulont, Sophie Kahn, Axel Viollet, Benoı̂t
Copyright Year	2001
Abstract	Mutations in the HNF4a gene are responsible for type 1 maturity-onset diabetes of the young (MODY1), which is characterized by a defect in insulin secretion. Hepatocyte nuclear factor (HNF)-4a is a transcription factor that plays a critical role in the transcriptional regulation of genes involved in glucose metabolism in both hepatocytes and pancreatic b-cells. Recent evidence has implicated AMP-activated protein kinase (AMPK) in the modulation of both insulin secretion by pancreatic b-cells and the control of glucose-dependent gene expression in both hepatocytes and b-cells. Therefore, the question could be raised as to whether AMPK plays a role in these processes by modulating HNF-4a function. In this study, we show that activation of AMPK by 5-amino-4-imidazolecarboxamide riboside (AICAR) in hepatocytes greatly diminished HNF-4a protein levels and consequently downregulates the expression of HNF4a target genes. Quantitative evaluation of HNF-4a target gene expression revealed diminished mRNA levels for HNF-1a, GLUT2, L-type pyruvate kinase, aldolase B, apolipoprotein (apo)-B, and apoCIII. Our data clearly demonstrate that the MODY1/HNF-4a transcription factor is a novel target of AMPK in hepatocytes. Accordingly, it can be suggested that in pancreatic b-cells, AMPK also acts by decreasing HNF-4a protein level, and therefore insulin secretion. Hence, the possible role of AMPK in the physiopathology of type 2 diabetes should be considered. Diabetes 50:1515–1521, 2001 Maturity-onset diabetes of the young (MODY) is a monogenic form of type 2 diabetes characterized by autosomal-dominant inheritance and early onset, usually before 25 years of age. Heterozygous mutations in genes encoding the glycolytic enzyme glucokinase and five different transcription factors, hepatocyte nuclear factor (HNF)-1a, HNF-1b, HNF4a, insulin promoter factor-1, and NeuroD-1, have been shown to be associated with different forms of MODY (1). The gene for type 1 MODY (MODY1) is encoded by the liver-enriched transcription factor HNF-4a that belongs to the nuclear receptors superfamily (2). Clinical studies have shown that MODY1 is characterized by a defect in nutrient-stimulated insulin secretion, suggesting that this disorder is caused by abnormal gene expression in pancreatic b-cells (3). HNF-4a was first identified for its role in regulating liver-specific gene expression, but it has also been found in other tissues, including kidney, intestine, and endocrine pancreas (4,5). Genes activated by HNF-4a encode serum proteins as well as enzymes involved in various metabolic pathways, including glucose, cholesterol, and fatty acid metabolism (4). Disruption of the murine HNF4a gene by homologous recombination causes defective gastrulation resulting from dysfunction of the visceral endoderm, thus indicating its crucial role for early development (6). Using visceral endoderm derived from HNF-4a–deficient embryonic stem cells, it has been shown that HNF-4a is essential for regulating genes involved in glucose transport and glycolysis, e.g., genes for GLUT2 and glycolytic enzymes such as aldolase B and liver-type pyruvate kinase (L-PK) (7). Moreover, HNF-4a is a key regulator of another liver-enriched transcription factor, HNF-1a, which is also associated to MODY (8). The existence of a transcriptional hierarchy responsible for early-onset type 2 diabetes has been strengthened by the finding of a MODY3 mutation in the HNF-4a binding site of the HNF-1a promoter (9). Although it is likely that dysregulation of glucose homeostasis in MODY1 patients is mainly caused by b-cell dysfunction, we cannot exclude the possibility that HNF-4a mutations have pleiotropic effects in other tissues expressing HNF-4a, especially in the liver. Significant alterations in triglyceride metabolism have been observed in MODY1 patients and have been considered to be an effect of impaired hepatic expression From the Cochin Institute of Molecular Genetics, Department of Genetics, Development, and Molecular Pathology, Institut National de la Santé et de la Recherche Médicale (INSERM) Unit 129, Paris, France. Address correspondence and reprint requests to Corresponding author: Dr. Benoı̂t Viollet, Institut Cochin de Génétique Moléculaire, Département de Génétique, Développement et Pathologie Moléculaire, Institut National de la Sante et de la Recherche Medicale (INSERM) Unit 129, 24 Rue du Faubourg Saint-Jacques, 75014 Paris, France. E-mail: viollet@cochin.inserm.fr. Received for publication 6 February 2001 and accepted 1 May 2001. Posted on the World Wide Web at www.diabetes.org/diabetes on 31 May 2001. AICAR, 5-amino-4-imiazolecarboxamide riboside; AMPK, AMP-activated protein kinase; apo, apolipoprotein; DTT, dithiothreitol; EMSA, electrophoretic mobility shift assays; HNF, hepatocyte nuclear factor; L-PK, liver-type pyruvate kinase; MODY, maturity-onset diabetes of the young; MODY1, type 1 MODY; NF-Y, nuclear factor Y; PCR, polymerase chain reaction; PPI, preproinsulin; RT, reverse transcription; TBST, Tris-buffered saline with Tween; USF, upstream stimulatory factor.
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Language	English
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Subject Keyword	AICA ribonucleotide Apolipoproteins Autosomal Dominant Emery-Dreifuss Muscular Dystrophy (disorder) B-Lymphocytes Beta normal form Body tissue Buffers Candidate Disease Gene Capability Maturity Model Cholesterol Diabetes Mellitus, Insulin-Dependent Diabetes Mellitus, Non-Insulin-Dependent Dithiothreitol ENCODE Electrophoretic Mobility Shift Assay Email Embryonic Stem Cells Emoticon Endoderm Fatty Acids Fructosediphosphate Aldolase Functional disorder Gastrulation Gene Expression Glucokinase Glucose Metabolism Disorders Glycolysis HNF1A wt Allele Hepatocyte Nuclear Factor 1-alpha Hepatocyte Nuclear Factors Hereditary fructose intolerance syndrome Homeostasis Homologous Recombination Intestinal Wall Tissue Intestines Islets of Langerhans Leukemia, B-Cell Lichen Sclerosus et Atrophicus Linear algebra Mail (macOS) Maturity onset diabetes mellitus in young Maturity-Onset Diabetes of the Young, Type 1 Modulation Mutation NSA product types Onset (audio) PRKAA2 gene Patients Pixel density Polymerase Chain Reaction Protein Kinases Proton Pump Inhibitors Public-key cryptography Pyruvate Kinase Pyruvates Receptors, Nuclear Renal Tissue Reprint Reverse Transcription SUPERFAMILY SalineOS Software bug Thioinosine Transcription (software) Transcription, Genetic Transcriptional Regulation Triglyceride Metabolism Triglycerides Tromethamine Tweens World Wide Web fatty acid metabolism glucose transport insulin secretion riboside transcription factor USF
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