Functional characterization of the HNF4alpha isoform (HNF4alpha8) expressed in pancreatic beta-cells

Biochem Biophys Res Commun. 2005 Apr 15;329(3):984-90. doi: 10.1016/j.bbrc.2005.02.072.


Mutations in the hepatocyte nuclear factor (HNF) 4alpha gene cause a form of maturity-onset diabetes of the young (MODY1), which is a monogenic form of type 2 diabetes characterized by impaired insulin secretion by pancreatic beta-cells. HNF4alpha is a transcription factor expressed in the liver, kidney, intestine, and pancreatic islet. Multiple splice variants of the HNF4alpha gene have been identified and an isoform of HNF4alpha8, an N-terminal splice variant, is expressed in pancreatic beta-cells. However, expression levels of HNF4alpha protein in pancreatic beta-cells and the transcriptional activity of HNF4alpha8 are not yet understood. In the present study, we investigated the expression of HNF4alpha in beta-cells and examined its functional properties. Western blotting and immunohistochemical analysis revealed that the expression of HNF4alpha protein in pancreatic islets and INS-1 cells was much lower than in the liver. A reporter gene assay showed that the transactivation potential of HNF4alpha8 was significantly weaker than that of HNF4alpha2, which is a major isoform in the liver, suggesting that the total level of HNF4alpha activity is very weak in pancreatic beta-cells. We also showed that the N-terminal A/B region of HNF4alpha8 possessed no activation function and C-terminal F region negatively regulated the transcriptional activity of HNF4alpha8. The information presented here would be helpful for the better understanding of MODY1/HNF4alpha diabetes.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Substitution
  • Animals
  • Cell Line
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Hepatocyte Nuclear Factor 4
  • Humans
  • Islets of Langerhans / metabolism*
  • Mice
  • Mutagenesis, Site-Directed
  • Phosphoproteins / genetics
  • Phosphoproteins / metabolism*
  • Protein Isoforms / metabolism
  • Rats
  • Structure-Activity Relationship
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*


  • DNA-Binding Proteins
  • HNF4A protein, human
  • Hepatocyte Nuclear Factor 4
  • Hnf4a protein, mouse
  • Hnf4a protein, rat
  • Phosphoproteins
  • Protein Isoforms
  • Transcription Factors