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Expansion of adult β-cell mass in response to increased metabolic demand is dependent on HNF-4α
Open accessAbstract
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.
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“Our work also suggests that Mapk/Erk regulation links Pdgfr activation to Ezh2 induction and β-cell proliferation, consistent with studies demonstrating Erk regulation of Ezh2 in cancer cells33, and Erk activation that accompanies mouse β-cell expansion in pregnancy34.”
From PDGF signalling controls age-dependent proliferation in pancreatic β-cells (2011) · cites this paper as [34]
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“Additionally, a recent study showed that the orphan nuclear receptor hepatocyte nuclear factor-4 (HNF-4)α is required in β-cells for the proliferative response of pregnancy through activation of the Ras/ERK signaling cascade, at least in part through the regulation of the guanine nucleotide exchange factor ST5 (Figure 3) [55].”
From Expansion of β-cell mass in response to pregnancy (2010) · cites this paper as [55]
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Metadata
- Authors
- Gupta, R. K., Gao, N., Gorski, R. K., White, P., Hardy, O. T., Rafiq, K., Brestelli, J. E., Chen, G., Stoeckert, C. J., & Kaestner, K. H.
- Affiliations
- University of Pennsylvania (US)
- ORCID
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2007-04-01
- Volume
- 21
- Issue
- 7
- Pages
- 756-769
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- PMC
- PMC1838528
- OpenAlex
- W2158386353
- Cited by
- 161
- References
- 62
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 4 · 2023: 3 · 2022: 4 · 2021: 9 · 2020: 4 · 2019: 5 · 2018: 6 · 2017: 6 · 2016: 6 · 2015: 9 · 2014: 9 · 2013: 17 · 2012: 10
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Pennsylvania (NIH DK19525)
- National Institutes of Health (DK 19525)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 19525, DK-56947, R24DK056947, DK-55342, R01DK055342, U01DK056947, P30DK019525)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- HNF4α, beta-cell proliferation, type 2 diabetes, MODY1, ST5, Ras/ERK signaling, ERK1/2 phosphorylation, orphan nuclear receptor, transcriptional regulation, metabolic demand, islets
- MeSH terms
- Animals, Base Sequence, DNA-Binding Proteins, Female, Islets of Langerhans, Mice, Transgenic, Models, Genetic, Molecular Sequence Data, Pregnancy, Transcription, Genetic, Signal Transduction, ras Proteins, Tumor Suppressor Proteins, Extracellular Signal-Regulated MAP Kinases, Cell Proliferation, Insulin-Secreting Cells, Mice, Hepatocyte Nuclear Factor 4
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