Hepatocyte Nuclear Factor-4α Involved in Type 1 Maturity-Onset Diabetes of the Young Is a Novel Target of AMP-Activated Protein Kinase

Abstract

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 lev-els 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.