HNF1alpha controls renal glucose reabsorption in mouse and man.
Recently it has been shown that dominant mutations in the human hepatocyte nuclear factor 1alpha (HNF1alpha) gene, encoding for a homeoprotein that is expressed in liver, kidney, pancreas and intestine, result in maturity onset diabetes of the young type 3 (MODY3). HNF1alpha-null mice are diabetic, but at the same time suffer from a renal Fanconi syndrome characterized by urinary glucose loss. Here we show that MODY3 patients are also characterized by a reduced tubular reabsorption of glucose. The renal murine defect is due to reduced expression of the low affinity/high capacity glucose cotransporter (SGLT2). Our results show that HNF1alpha directly controls SGLT2 gene expression. Together these data indicate that HNF1alpha plays a key role in glucose homeostasis in mammals.
Unité des Virus Oncogènes, URA 1644 CNRS, Département des Biotechnologies, Institut Pasteur, Paris, France. marcop@pasteur.fr
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Pontoglio
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Prié
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Cheret
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Doyen
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Leroy
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Froguel
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Velho
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Yaniv
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Friedlander
D000042:Absorption; D000328:Adult; D000818:Animals; D001692:Biological Transport; D001786:Blood Glucose / Q000378:metabolism; D015152:Blotting, Northern; D017931:DNA Primers / Q000737:chemistry; D004268:DNA-Binding Proteins; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015698:Genomic Library; D005947:Glucose / Q000378:metabolism*; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009004:Monosaccharide Transport Proteins / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051297:Sodium-Glucose Transporter 2; D014157:Transcription Factors / Q000235:genetics* / Q000502:physiology*; D014162:Transfection
D001786:Blood Glucose; D017931:DNA Primers; D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; C496496:Hnf1b protein, mouse; D009004:Monosaccharide Transport Proteins; D009687:Nuclear Proteins; C089180:SLC5A2 protein, human; C490299:Slc5a2 protein, mouse; D051297:Sodium-Glucose Transporter 2; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta; D008156:Luciferases; D005947:Glucose