Study of glucose metabolism by HNF4α with knockout mouse

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Mutations in the hepatocyte nuclear factor (HNF) 4α 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 β-cells. Expression levels of HNF4α protein in pancreatic β-cells and the transcriptional activity of HNF4α are not yet understood. In the present study, we showed that the expression of HNF4α protein in pancreatic islets and INS-1 cells was much lower than in the liver by Western blotting and immunohistochemistry. A reporter gene assay showed that the transactivation potential of HNF4α8 was significantly weaker than that of HNF4α2, which is a major isoform in the liver, suggesting that the total level of HNF4α activity is very weak in pancreatic β-cells.T130I mutation in the HNF4α gene is a rare missense mutation, which affects a conserved amino acid in a DNA binding domain. The significance in the development of late-onset type 2 diabetes is unknown. We found that the frequency of T130I mutation was significantly higher in type 2 diabetic patients (p=0.015, odds ratio 4.3, 95%CI 1.24-14.98) than control subjects. Reporter gene analysis showed that T130I-HNF-4α transcriptional activity was significantly reduced in HepG2 and primary cultured mouse hepatocytes (27-78% of wild type, p<0.05). These findings suggest that T130I-HNF-4α is a loss-of-function mutation in hepatocytes and that this mutation is associated with late-onset type 2 diabetes in Japanese population.