Hepatocyte nuclear factor-4alpha involved in type 1 maturity-onset diabetes of the young is a novel target of AMP-activated protein kinase.
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.
Leclerc
I
I
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, 24 Rue de Faubourg Saint-Jacques, 75014 Paris, France.
Lenzner
C
C
Gourdon
L
L
Vaulont
S
S
Kahn
A
A
Viollet
B
B
D055372:AMP-Activated Protein Kinases; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D053305:Apolipoprotein C-III; D001055:Apolipoproteins B / Q000096:biosynthesis / Q000235:genetics; D001056:Apolipoproteins C / Q000096:biosynthesis / Q000235:genetics; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D004789:Enzyme Activation; D005634:Fructose-Bisphosphate Aldolase / Q000096:biosynthesis / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D051273:Glucose Transporter Type 2; D051557:Hepatocyte Nuclear Factor 4; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000201:enzymology; D008099:Liver / Q000201:enzymology; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000378:metabolism; D009097:Multienzyme Complexes / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011770:Pyruvate Kinase / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012265:Ribonucleotides / Q000494:pharmacology; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic
D053305:Apolipoprotein C-III; D001055:Apolipoproteins B; D001056:Apolipoproteins C; D004268:DNA-Binding Proteins; D051273:Glucose Transporter Type 2; D051557:Hepatocyte Nuclear Factor 4; C496594:Hnf4a protein, rat; D007328:Insulin; D009004:Monosaccharide Transport Proteins; D009097:Multienzyme Complexes; D010750:Phosphoproteins; D012333:RNA, Messenger; D012265:Ribonucleotides; D014157:Transcription Factors; D000620:Aminoimidazole Carboxamide; D011770:Pyruvate Kinase; D017346:Protein Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D005634:Fructose-Bisphosphate Aldolase; C031143:AICA ribonucleotide