• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Study of glucose metabolism by HNF4α with knockout mouse

Research Project

Project/Area Number 15590938
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Metabolomics
Research InstitutionOsaka University

Principal Investigator

YAMAGATA Kazuya  Osaka University, Graduate School of Medicine, Assistant Professor, 医学系研究科, 助手 (70324770)

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
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2004: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 2003: ¥2,600,000 (Direct Cost: ¥2,600,000)
KeywordsDiabetes Mellitus / gene / transcription factor / insulin / hepatocyte nuclear factor / MODY / HNF4α / HNF-4α / ノックアウトマウス
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.

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (17 results)

All 2005 2004 2003 Other

All Journal Article (12 results) Publications (5 results)

  • [Journal Article] Functional characterization of the HNF4α isoform (HNF4α8) expressed in pancreatic β-cells2005

    • Author(s)
      Ihara A, Yamagata K et al.
    • Journal Title

      BBRC 329

      Pages: 984-990

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The endoplasmic reticulum chaperone improves insulin resistance in type 2 diabetes.2005

    • Author(s)
      Ozawa K, Yamagata K et al.
    • Journal Title

      Diabetes 54

      Pages: 657-663

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] The endoplasmic reticulum chaperone improves insulin resistance in type 2 diabetes.2005

    • Author(s)
      Ozawa K et al.
    • Journal Title

      Diabetes 54

      Pages: 657-663

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Functional characterization of the HNF4α isoform (HNF4α8) expressed in pancreatic β-cells.2005

    • Author(s)
      Ihara A et al.
    • Journal Title

      BBRC 329

      Pages: 984-990

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Functional characterization of the HNF4α isoform(HNF4α8) expressed in pancreatic β-cells2005

    • Author(s)
      Ihara A, Yamagata K et al.
    • Journal Title

      BBRC (in press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] The ER chaperone 150 kDa Oxygen Regulated Protein(ORP150) improves insulin resistance in type 2 diabetes mellitus2005

    • Author(s)
      Ozawa K, Yamagata K et al.
    • Journal Title

      Diabetes (in press)

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Inhibitory effect of small heterodimer partner on hepatocyte nuclear factor 4 mediates bile acid-induced repression of human angiotensinogen gene.2004

    • Author(s)
      Shimamoto Y, Yamagata K et al.
    • Journal Title

      J.Biol.Chem. 279

      Pages: 7770-7776

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Overexpression of pituitary adenylate cyclase-activating polypeptide in islets inhibits hyperinsulinemia and islet hyperplasia in agouti yellow mice.2004

    • Author(s)
      Tomimoto S, Yamagata K et al.
    • Journal Title

      J.Pharmacol.Exp.Ther. 309

      Pages: 796-803

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Inhibitory effect of small heterodimer partner on hepatocyte nuclear factor 4 mediates bile acid-induced repression of human angiotensinogen gene.2004

    • Author(s)
      Shimamoto Y et al.
    • Journal Title

      J.Biol.Chem. 279

      Pages: 7770-7776

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Overexpression of pituitary adenylate cyclase-activating polypeptide in islets inhibits hyperinsulinemia and islet hyperplasia in agouti yellow mice.2004

    • Author(s)
      Tomimoto S et al.
    • Journal Title

      J.Pharmacol.Exp.Ther. 309

      Pages: 796-803

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] T130I mutation in HNF-4α gene is a loss-of-function mutation In hepatocytes and is associated with late-onset Type 2 diabetes mellitus in Japanese subjects.2003

    • Author(s)
      Zhu Q, Yamagata K et al.
    • Journal Title

      Diabetologia 46

      Pages: 567-573

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] T130I mutation in HNF-4α gene is a loss-of-function mutation in hepatocytes and is associated with late-onset Type 2 diabetes mellitus in Japanese subjects.2003

    • Author(s)
      Zhu Q et al.
    • Journal Title

      Diabetologia 46

      Pages: 567-573

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Zhu Q, Yamagata K et al.: "T130I mutation in HNF-4α gene is a loss-of-function mutation in hepatocytes an is associated with late-onset Type 2 diabetes mellitus in Japanese subjects"Diabetologia. 46. 567-573 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yamamoto K, Yamagata K et al.: "Overexpression of PACAP in transgenic mouse pancreatic β cells enhances insulin secretion and ameliorates streptozotocin-induced diabetes"Diabetes. 52. 1155-1162 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Yamagata K: "Regulation of pancreatic β-cell function by the HNF transcription network : Lessons from maturity-onset diabetes of the young (MODY)"Endocr J. 50. 491-499 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Li M, Yamagata K et al.: "Analysis of expression profiles of islet-associated transcription and growth factors during β-cell neogenesis from duct cells in partially duct-ligated mice"Pancreas. 27. 345-355 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Shimamoto Y, Yamagata K: "Inhibitory effect of small heterodimer partner on hepatocyte nuclear factor 4 rediates bile acid-induced repression of human angiotensinogen gene"J Biol Chem. (in press).

    • Related Report
      2003 Annual Research Report

URL: 

Published: 2003-04-01   Modified: 2016-04-21  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi