We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Hepatocyte nuclear factor-4alpha involved in type 1 maturity-onset diabetes of the young is a novel target of AMP-activated protein kinase.
- Authors
Leclerc, Isabelle; Lenzner, Claudia; Gourdon, Laurence; Vaulont, Sophie; Kahn, Axel; Viollet, Benoit; Leclerc, I; Lenzner, C; Gourdon, L; Vaulont, S; Kahn, A; Viollet, B
- 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.
- Subjects
GENETIC regulation; PROTEIN kinases; CELLULAR signal transduction; GLUCOSE; METABOLISM
- Publication
Diabetes, 2001, Vol 50, Issue 7, p1515
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/diabetes.50.7.1515