Title

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

UMMS Affiliation

Department of Pediatrics

Date

4-4-2007

Document Type

Article

Medical Subject Headings

Animals; Base Sequence; Cell Proliferation; DNA-Binding Proteins; Extracellular Signal-Regulated MAP Kinases; Female; Hepatocyte Nuclear Factor 4; Insulin-Secreting Cells; Islets of Langerhans; Mice; Mice, Transgenic; Models, Genetic; Molecular Sequence Data; Pregnancy; Signal Transduction; Transcription, Genetic; Tumor Suppressor Proteins; ras Proteins

Disciplines

Endocrinology, Diabetes, and Metabolism | Pediatrics

Abstract

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.

Rights and Permissions

Citation: Genes Dev. 2007 Apr 1;21(7):756-69. Link to article on publisher's site

Comments

At the time of publication, Olga Hardy was not yet affiliated with the University of Massachusetts Medical School.

Related Resources

Link to Article in PubMed

PubMed ID

17403778