PMID- 11423471
OWN - NLM
STAT- MEDLINE
DCOM- 20010719
LR  - 20220227
IS  - 0012-1797 (Print)
IS  - 0012-1797 (Linking)
VI  - 50
IP  - 7
DP  - 2001 Jul
TI  - Hepatocyte nuclear factor-4alpha involved in type 1 maturity-onset diabetes of 
      the young is a novel target of AMP-activated protein kinase.
PG  - 1515-21
AB  - 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.
FAU - Leclerc, I
AU  - Leclerc I
AD  - Cochin Institute of Molecular Genetics, Department of Genetics, Development, and 
      Molecular Pathology, Institut National de la Sante et de la Recherche Medicale 
      (INSERM) Unit 129, 24 Rue de Faubourg Saint-Jacques, 75014 Paris, France.
FAU - Lenzner, C
AU  - Lenzner C
FAU - Gourdon, L
AU  - Gourdon L
FAU - Vaulont, S
AU  - Vaulont S
FAU - Kahn, A
AU  - Kahn A
FAU - Viollet, B
AU  - Viollet B
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (Apolipoprotein C-III)
RN  - 0 (Apolipoproteins B)
RN  - 0 (Apolipoproteins C)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Glucose Transporter Type 2)
RN  - 0 (Hepatocyte Nuclear Factor 4)
RN  - 0 (Hnf4a protein, rat)
RN  - 0 (Insulin)
RN  - 0 (Monosaccharide Transport Proteins)
RN  - 0 (Multienzyme Complexes)
RN  - 0 (Phosphoproteins)
RN  - 0 (RNA, Messenger)
RN  - 0 (Ribonucleotides)
RN  - 0 (Transcription Factors)
RN  - 360-97-4 (Aminoimidazole Carboxamide)
RN  - EC 2.7.1.40 (Pyruvate Kinase)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.31 (AMP-Activated Protein Kinases)
RN  - EC 4.1.2.13 (Fructose-Bisphosphate Aldolase)
RN  - F0X88YW0YK (AICA ribonucleotide)
SB  - IM
MH  - AMP-Activated Protein Kinases
MH  - Aminoimidazole Carboxamide/*analogs & derivatives/pharmacology
MH  - Animals
MH  - Apolipoprotein C-III
MH  - Apolipoproteins B/biosynthesis/genetics
MH  - Apolipoproteins C/biosynthesis/genetics
MH  - Cells, Cultured
MH  - *DNA-Binding Proteins
MH  - Diabetes Mellitus, Type 1/genetics/*metabolism
MH  - Down-Regulation
MH  - Enzyme Activation
MH  - Fructose-Bisphosphate Aldolase/biosynthesis/genetics
MH  - Gene Expression Regulation/drug effects
MH  - Glucose Transporter Type 2
MH  - Hepatocyte Nuclear Factor 4
MH  - Insulin/metabolism
MH  - Insulin Secretion
MH  - Islets of Langerhans/enzymology
MH  - Liver/enzymology
MH  - Monosaccharide Transport Proteins/genetics/metabolism
MH  - Multienzyme Complexes/*metabolism
MH  - Phosphoproteins/*metabolism
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - Pyruvate Kinase/biosynthesis/genetics
MH  - RNA, Messenger/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Ribonucleotides/pharmacology
MH  - Time Factors
MH  - Transcription Factors/*metabolism
MH  - Transcription, Genetic
EDAT- 2001/06/26 10:00
MHDA- 2001/07/20 10:01
CRDT- 2001/06/26 10:00
PHST- 2001/06/26 10:00 [pubmed]
PHST- 2001/07/20 10:01 [medline]
PHST- 2001/06/26 10:00 [entrez]
AID - 10.2337/diabetes.50.7.1515 [doi]
PST - ppublish
SO  - Diabetes. 2001 Jul;50(7):1515-21. doi: 10.2337/diabetes.50.7.1515.