Abstract
Mutations in the HNF4alpha 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)-4alpha is a transcription factor that plays a critical role in the transcriptional regulation of genes involved in glucose metabolism in both hepatocytes and pancreatic beta-cells. Recent evidence has implicated AMP-activated protein kinase (AMPK) in the modulation of both insulin secretion by pancreatic beta-cells and the control of glucose-dependent gene expression in both hepatocytes and beta-cells. Therefore, the question could be raised as to whether AMPK plays a role in these processes by modulating HNF-4alpha function. In this study, we show that activation of AMPK by 5-amino-4-imidazolecarboxamide riboside (AICAR) in hepatocytes greatly diminished HNF-4alpha protein levels and consequently downregulates the expression of HNF-4alpha target genes. Quantitative evaluation of HNF-4alpha target gene expression revealed diminished mRNA levels for HNF-1alpha, GLUT2, L-type pyruvate kinase, aldolase B, apolipoprotein (apo)-B, and apoCIII. Our data clearly demonstrate that the MODY1/HNF-4alpha transcription factor is a novel target of AMPK in hepatocytes. Accordingly, it can be suggested that in pancreatic beta-cells, AMPK also acts by decreasing HNF-4alpha protein level, and therefore insulin secretion. Hence, the possible role of AMPK in the physiopathology of type 2 diabetes should be considered.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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AMP-Activated Protein Kinases
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Aminoimidazole Carboxamide / analogs & derivatives*
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Aminoimidazole Carboxamide / pharmacology
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Animals
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Apolipoprotein C-III
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Apolipoproteins B / biosynthesis
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Apolipoproteins B / genetics
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Apolipoproteins C / biosynthesis
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Apolipoproteins C / genetics
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Cells, Cultured
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DNA-Binding Proteins*
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Diabetes Mellitus, Type 1 / genetics
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Diabetes Mellitus, Type 1 / metabolism*
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Down-Regulation
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Enzyme Activation
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Fructose-Bisphosphate Aldolase / biosynthesis
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Fructose-Bisphosphate Aldolase / genetics
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Gene Expression Regulation / drug effects
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Glucose Transporter Type 2
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Hepatocyte Nuclear Factor 4
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Insulin / metabolism
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Insulin Secretion
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Islets of Langerhans / enzymology
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Liver / enzymology
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Monosaccharide Transport Proteins / genetics
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Monosaccharide Transport Proteins / metabolism
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Multienzyme Complexes / metabolism*
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Phosphoproteins / metabolism*
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Protein Serine-Threonine Kinases / metabolism*
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Pyruvate Kinase / biosynthesis
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Pyruvate Kinase / genetics
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RNA, Messenger / metabolism
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Rats
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Rats, Sprague-Dawley
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Ribonucleotides / pharmacology
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Time Factors
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Transcription Factors / metabolism*
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Transcription, Genetic
Substances
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Apolipoprotein C-III
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Apolipoproteins B
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Apolipoproteins C
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DNA-Binding Proteins
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Glucose Transporter Type 2
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Hepatocyte Nuclear Factor 4
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Hnf4a protein, rat
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Insulin
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Monosaccharide Transport Proteins
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Multienzyme Complexes
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Phosphoproteins
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RNA, Messenger
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Ribonucleotides
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Transcription Factors
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Aminoimidazole Carboxamide
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Pyruvate Kinase
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Protein Serine-Threonine Kinases
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AMP-Activated Protein Kinases
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Fructose-Bisphosphate Aldolase
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AICA ribonucleotide