Abstract
Mutations in the human homolog of the Vhlh gene [encoding the von-Hippel Lindau (VHL) protein] lead to tumor development. In mice, depletion of Vhlh in pancreatic ß-cells causes perturbed glucose homeostasis, but the role of this gene in other pancreatic cells is poorly understood. To investigate the function of VHL/HIF pathway in pancreatic cells, we inactivated Vhlh in the pancreatic epithelium as well as in the endocrine and exocrine lineages. Our results show that embryonic depletion of Vhlh within the pancreatic epithelium causes postnatal lethality due to severe hypoglycemia. The hypoglycemia is recapitulated in mice with endocrine-specific removal of Vhlh, while animals with loss of Vhlh predominantly in the exocrine compartment survive to adulthood with no overt defects in glucose metabolism. Mice with hypoglycemia display diminished insulin release in response to elevated glucose. Significantly, the glucagon response is impaired both in vivo (circulating glucagon levels) as well as in an in vitro secretion assay in isolated islets. Hypoxia also impairs glucagon secretion in a glucagon-expressing cell line in culture. Our results reveal a novel role for the hypoxia/HIF pathway in islet hormone secretion and maintenance of the fine balance that allows for the establishment of normoglycemia.
Highlights
The role of hypoxia in ß-cell formation and function has recently gained considerable interest [1]
Central to the hypoxic response is the transcription factor hypoxia-inducible factor (HIF) whose activity is regulated by proteasomal degradation in the presence of oxygen, a process mediated by the von Hippel-Lindau (VHL) tumor suppressor-containing ubiquitin ligase complex [1]
Efficient excision of the VhlhloxP/loxP allele by Cre recombinase was evidenced by significant accumulation of HIF1a in islet, acinar and ductal compartments of the pancreata from Pdx-1-Creearly;VhlhLoxP/LoxP animals (Figure 1B)
Summary
The role of hypoxia in ß-cell formation and function has recently gained considerable interest [1]. Central to the hypoxic response is the transcription factor hypoxia-inducible factor (HIF) whose activity is regulated by proteasomal degradation in the presence of oxygen, a process mediated by the von Hippel-Lindau (VHL) tumor suppressor-containing ubiquitin ligase complex [1]. Several studies, including our own, have uncovered a critical role for the HIF hypoxia response pathway in glucose homeostasis [2,3,4]. Hypoxia-responsive genes are upregulated in islets of pre-diabetic Zucker diabetic fatty (ZDF) and diabetic Goto-Kakizaki (GK) rats [5,6]. An increase in HIF1a is observed in islets of diabetic Goto-Kakizaki (GK) rats
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