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

  1. Rana K. Gupta1,3,
  2. Nan Gao1,3,
  3. Regina K. Gorski1,2,
  4. Peter White1,
  5. Olga T. Hardy1,
  6. Kiran Rafiq1,
  7. John E. Brestelli1,
  8. Guang Chen2,
  9. Christian J. Stoeckert, Jr.1,2, and
  10. Klaus H. Kaestner1,4
  11. 1 Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA;
  12. 2 Center for Bioinformatics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA
  13. ↵3 These authors contributed equally to this work.

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-4_α (_HNF-4_α), 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-4_α 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-4_α 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-4_α 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.

Footnotes