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Expansion of adult beta-cell mass in response to increased metabolic demand is dependent on HNF-4alpha.

Publication ,  Journal Article
Gupta, RK; Gao, N; Gorski, RK; White, P; Hardy, OT; Rafiq, K; Brestelli, JE; Chen, G; Stoeckert, CJ; Kaestner, KH
Published in: Genes Dev
April 1, 2007

The failure to expand functional pancreatic beta-cell mass in response to increased metabolic demand is a hallmark of type 2 diabetes. Lineage tracing studies indicate that replication of existing beta-cells is the principle mechanism for beta-cell expansion in adult mice. Here we demonstrate that the proliferative response of beta-cells is dependent on the orphan nuclear receptor hepatocyte nuclear factor-4alpha (HNF-4alpha), the gene that is mutated in Maturity-Onset Diabetes of the Young 1 (MODY1). Computational analysis of microarray expression profiles from isolated islets of mice lacking HNF-4alpha in pancreatic beta-cells reveals that HNF-4alpha regulates selected genes in the beta-cell, many of which are involved in proliferation. Using a physiological model of beta-cell expansion, we show that HNF-4alpha is required for beta-cell replication and the activation of the Ras/ERK signaling cascade in islets. This phenotype correlates with the down-regulation of suppression of tumorigenicity 5 (ST5) in HNF-4alpha mutants, which we identify as a novel regulator of ERK phosphorylation in beta-cells and a direct transcriptional target of HNF-4alpha in vivo. Together, these results indicate that HNF-4alpha is essential for the physiological expansion of adult beta-cell mass in response to increased metabolic demand.

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Published In

Genes Dev

DOI

ISSN

0890-9369

Publication Date

April 1, 2007

Volume

21

Issue

7

Start / End Page

756 / 769

Location

United States

Related Subject Headings

  • ras Proteins
  • Tumor Suppressor Proteins
  • Transcription, Genetic
  • Signal Transduction
  • Pregnancy
  • Molecular Sequence Data
  • Models, Genetic
  • Mice, Transgenic
  • Mice
  • Islets of Langerhans
 

Citation

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Gupta, R. K., Gao, N., Gorski, R. K., White, P., Hardy, O. T., Rafiq, K., … Kaestner, K. H. (2007). Expansion of adult beta-cell mass in response to increased metabolic demand is dependent on HNF-4alpha. Genes Dev, 21(7), 756–769. https://doi.org/10.1101/gad.1535507
Gupta, Rana K., Nan Gao, Regina K. Gorski, Peter White, Olga T. Hardy, Kiran Rafiq, John E. Brestelli, Guang Chen, Christian J. Stoeckert, and Klaus H. Kaestner. “Expansion of adult beta-cell mass in response to increased metabolic demand is dependent on HNF-4alpha.Genes Dev 21, no. 7 (April 1, 2007): 756–69. https://doi.org/10.1101/gad.1535507.
Gupta RK, Gao N, Gorski RK, White P, Hardy OT, Rafiq K, et al. Expansion of adult beta-cell mass in response to increased metabolic demand is dependent on HNF-4alpha. Genes Dev. 2007 Apr 1;21(7):756–69.
Gupta, Rana K., et al. “Expansion of adult beta-cell mass in response to increased metabolic demand is dependent on HNF-4alpha.Genes Dev, vol. 21, no. 7, Apr. 2007, pp. 756–69. Pubmed, doi:10.1101/gad.1535507.
Gupta RK, Gao N, Gorski RK, White P, Hardy OT, Rafiq K, Brestelli JE, Chen G, Stoeckert CJ, Kaestner KH. Expansion of adult beta-cell mass in response to increased metabolic demand is dependent on HNF-4alpha. Genes Dev. 2007 Apr 1;21(7):756–769.

Published In

Genes Dev

DOI

ISSN

0890-9369

Publication Date

April 1, 2007

Volume

21

Issue

7

Start / End Page

756 / 769

Location

United States

Related Subject Headings

  • ras Proteins
  • Tumor Suppressor Proteins
  • Transcription, Genetic
  • Signal Transduction
  • Pregnancy
  • Molecular Sequence Data
  • Models, Genetic
  • Mice, Transgenic
  • Mice
  • Islets of Langerhans