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

118 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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