Content area
Full Text
OBJECTIVE-The Vhlh gene codes for the von Hippel-Lindau protein (VHL), a tumor suppressor that is a key player in the cellular response to oxygen sensing. In humans, a germline mutation in the VHL gene leads to the von Hippel-Lindau disease, a familial syndrome characterized by benign and malignant tumors of the kidney, central nervous system, and pancreas.
RESEARCH DESIGN AND METHODS-We use Cre-lox recombination to eliminate Vhlh in adult mouse pancreatic β-cells. Morphology of mutant islets is assessed by immunofluorescence analysis. To determine the functional state of Vhlh^sup -/-^ islets, insulin secretion is measured in vivo and in vitro, and quantitative PCR is used to identify changes in gene expression.
RESULTS-Loss of VHL in β-cells leads to a severe glucose-intolerant phenotype in adult animals. Although VHL is not required for β-cell specification and development, it is critical for β-cell function. Insulin production is normal in β-cells lacking VHL; however, insulin secretion in the presence of high concentrations of glucose is impaired. Furthermore, the loss of VHL leads to dysregulation of glycolytic enzymes, pointing to a perturbation of the intracellular energy homeostasis.
CONCLUSIONS-We show that loss of VHL in β-cells leads to defects in glucose homeostasis, indicating an important and previously unappreciated role for VHL in β-cell function. We believe that the β-cell-specific Vhlh-deficient mice might be a useful tool as a "genetic hypoxia" model, to unravel the possible link between hypoxia signaling and impairment of β-cell function. Diabetes 58:433-441, 2009
Oxygen homeostasis is essential to cellular func- tion, and low O2 pressure (hypoxia) has a profound impact on cell metabolism and phys- iological processes. The von Hippel-Lindau tu- mor suppressor protein (VHL) is a key player in the cellular response to oxygen sensing. Hypoxia inducible factors (HIFs) are global regulators of oxygen homeosta- sis, allowing cellular adaptation to oxygen deprivation by transcriptionally modulating genes involved in cellular energy metabolism, angiogenesis, apoptosis, and prolifer- ation, among other biological processes (rev. in 1-5). During normoxia, prolyl hydroxylases hydroxylate specific residues on HIF-α, a modification that is oxygen dependent (6,7). VHL specifically recognizes these modified residues, targeting HIF-α for ubiquitination via E3 ubiquitin ligase and subsequent proteasonial degradation (8,9). Under hypoxic conditions, HIF-α is stabilized and forms a complex with the β-subunit of a transcriptional complex (HIF-1β,...