Expansion of adult β-cell mass in response to increased metabolic demand is dependent on HNF-4α

Rana K Gupta, Nan Gao, Regina K. Gorski, Peter White, Olga T Gupta, Kiran Rafiq, John E. Brestelli, Guang Chen, Christian J. Stoeckert, Klaus H. Kaestner

Research output: Contribution to journalArticle

117 Citations (Scopus)

Abstract

The failure to expand functional pancreatic β-cell mass in response to increased metabolic demand is a hallmark of type 2 diabetes. Lineage tracing studies indicate that replication of existing β-cells is the principle mechanism for β-cell expansion in adult mice. Here we demonstrate that the proliferative response of β-cells is dependent on the orphan nuclear receptor hepatocyte nuclear factor-4α (HNF-4α), 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-4α in pancreatic β-cells reveals that HNF-4α regulates selected genes in the β-cell, many of which are involved in proliferation. Using a physiological model of β-cell expansion, we show that HNF-4α is required for β-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-4α mutants, which we identify as a novel regulator of ERK phosphorylation in β-cells and a direct transcriptional target of HNF-4α in vivo. Together, these results indicate that HNF-4α is essential for the physiological expansion of adult β-cell mass in response to increased metabolic demand.

Original languageEnglish (US)
Pages (from-to)756-769
Number of pages14
JournalGenes and Development
Volume21
Issue number7
DOIs
StatePublished - Apr 1 2007

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Hepatocyte Nuclear Factor 4
Orphan Nuclear Receptors
Microarray Analysis
Type 2 Diabetes Mellitus
Genes

Keywords

  • β-cells
  • Extracellular regulated kinase
  • Gestational diabetes
  • HNF-4α
  • Mitogen activated protein kinase
  • Ras
  • Type 2 diabetes

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Expansion of adult β-cell mass in response to increased metabolic demand is dependent on HNF-4α. / Gupta, Rana K; Gao, Nan; Gorski, Regina K.; White, Peter; Gupta, Olga T; Rafiq, Kiran; Brestelli, John E.; Chen, Guang; Stoeckert, Christian J.; Kaestner, Klaus H.

In: Genes and Development, Vol. 21, No. 7, 01.04.2007, p. 756-769.

Research output: Contribution to journalArticle

Gupta, RK, Gao, N, Gorski, RK, White, P, Gupta, OT, Rafiq, K, Brestelli, JE, Chen, G, Stoeckert, CJ & Kaestner, KH 2007, 'Expansion of adult β-cell mass in response to increased metabolic demand is dependent on HNF-4α', Genes and Development, vol. 21, no. 7, pp. 756-769. https://doi.org/10.1101/gad.1535507
Gupta, Rana K ; Gao, Nan ; Gorski, Regina K. ; White, Peter ; Gupta, Olga T ; Rafiq, Kiran ; Brestelli, John E. ; Chen, Guang ; Stoeckert, Christian J. ; Kaestner, Klaus H. / Expansion of adult β-cell mass in response to increased metabolic demand is dependent on HNF-4α. In: Genes and Development. 2007 ; Vol. 21, No. 7. pp. 756-769.
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