Hepatocyte nuclear factor-4α involved in type 1 maturity-onset diabetes of the young is a novel target of AMP-activated protein kinase

Mutations in the HNF4 alpha 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 (KNF)-4 alpha 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-4 alpha function, In this study, we show that activation of AMPK by 5-amino-4-imidazolecarboxamide riboside (AICAR) in hepatocytes greatly diminished HNF-4 alpha protein levels and consequently downregulates the expression of HNF-4 alpha target genes. Quantitative evaluation of HNF-4 alpha target gene expression revealed diminished mRNA levels for HNF-1 alpha, GLUT2, L-type pyruvate kinase, aldolase B, apolipoprotein (apo)-B, and apoCIII, Our data clearly demonstrate that the MODY1/HNF-4 alpha 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-4 alpha protein level, and therefore insulin secretion. Hence, the possible role of AMPK in the physiopathology of type 2 diabetes should be considered.