ABSTRACT
The molecular mechanisms of β-cell compensation to metabolic stress are poorly understood. Previously we observed that nutrient-induced β-cell proliferation in rats is dependent on epidermal growth factor receptor (EGFR) signaling. The aim of this study was to determine the role of the EGFR ligand heparin-binding epidermal growth factor-like growth factor (HB-EGF) in the β-cell proliferative response to glucose, a β-cell mitogen and key regulator of β-cell mass in response to increased insulin demand. We show that exposure of isolated rat islets to HB-EGF stimulated β-cell proliferation, whereas inhibition of EGFR or HB-EGF blocked the proliferative response not only to HB-EGF but also to glucose. Furthermore, knockdown of HB-EGF in islets blocked β-cell proliferation in response to glucose ex vivo and in vivo in transplanted glucose-infused rats. Mechanistically, we demonstrate that HB-EGF mRNA levels were increased in β cells in response to glucose in a carbohydrate response element binding protein (ChREBP)-dependent manner. In addition, chromatin-immunoprecipitation studies identified ChREBP binding sites in proximity to the HB-EGF gene. Finally, inhibition of Src family kinases, known to be involved in HB-EGF processing, abrogated glucose-induced β-cell proliferation. Our findings identify a novel glucose/HB-EGF/EGFR axis implicated in β-cell compensation to increased metabolic demand.
ABBREVIATIONS
- 3C
- Chromosome conformation capture
- BTC
- betacellulin
- ChIP
- Chromatin immunoprecipitation
- ChREBP
- Carbohydrate response element binding protein
- EGF
- Epidermal growth factor
- EGFR
- Epidermal growth factor receptor
- FACS
- Fluorescent activated cell sorting
- GIR
- Glucose infusion rate
- HB-EGF
- Heparin-binding epidermal growth factor-like growth factor
- mTORC1
- Mammalian target of rapamycin complex 1
- TSS
- Transcriptional start site