In:
Diabetes, American Diabetes Association, Vol. 50, No. 7 ( 2001-07-01), p. 1515-1521
Kurzfassung:
Mutations in the HNF4α 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)-4α is a transcription factor that plays a critical role in the transcriptional regulation of genes involved in glucose metabolism in both hepatocytes and pancreatic β-cells. Recent evidence has implicated AMP-activated protein kinase (AMPK) in the modulation of both insulin secretion by pancreatic β-cells and the control of glucose-dependent gene expression in both hepatocytes and β-cells. Therefore, the question could be raised as to whether AMPK plays a role in these processes by modulating HNF-4α function. In this study, we show that activation of AMPK by 5-amino-4-imidazolecarboxamide riboside (AICAR) in hepatocytes greatly diminished HNF-4α protein levels and consequently downregulates the expression of HNF-4α target genes. Quantitative evaluation of HNF-4α target gene expression revealed diminished mRNA levels for HNF-1α, GLUT2, l-type pyruvate kinase, aldolase B, apolipoprotein (apo)-B, and apoCIII. Our data clearly demonstrate that the MODY1/HNF-4α transcription factor is a novel target of AMPK in hepatocytes. Accordingly, it can be suggested that in pancreatic β-cells, AMPK also acts by decreasing HNF-4α protein level, and therefore insulin secretion. Hence, the possible role of AMPK in the physiopathology of type 2 diabetes should be considered.
Materialart:
Online-Ressource
ISSN:
0012-1797
,
1939-327X
DOI:
10.2337/diabetes.50.7.1515
Sprache:
Englisch
Verlag:
American Diabetes Association
Publikationsdatum:
2001
ZDB Id:
1501252-9
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