2004 Fiscal Year Final Research Report Summary
Study of glucose metabolism by HNF4α with knockout mouse
| Project/Area Number |
15590938
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Metabolomics
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| Research Institution | Osaka University |
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Principal Investigator |
YAMAGATA Kazuya Osaka University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (70324770)
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| Co-Investigator(Kenkyū-buntansha) |
MIYAGAWA Junichiro Hyogo College of Medicine, Associate Professor, 助教授 (00127721)
IWAHASHI Hiromi Osaka University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手
OKITA Kohei Osaka University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手
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| Project Period (FY) |
2003 – 2004
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| Keywords | Diabetes Mellitus / gene / transcription factor / insulin / hepatocyte nuclear factor / MODY |
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| Research Abstract |
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.
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