1. Molecular mechanisms of neutrophil dysfunction in glycogen storage disease type Ib.
- Author
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Jun HS, Weinstein DA, Lee YM, Mansfield BC, and Chou JY
- Subjects
- Adenosine Triphosphate metabolism, Adolescent, Adult, Antiporters deficiency, Antiporters metabolism, Child, Child, Preschool, Enzyme Activation, Glucose metabolism, Glucose-6-Phosphatase metabolism, Humans, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Immunophenotyping, Intracellular Space metabolism, Lactic Acid metabolism, Monosaccharide Transport Proteins deficiency, Monosaccharide Transport Proteins metabolism, NADP metabolism, NADPH Oxidases metabolism, Neutrophils drug effects, Neutrophils pathology, PPAR gamma metabolism, Phenotype, Signal Transduction, Young Adult, Glycogen Storage Disease Type I genetics, Glycogen Storage Disease Type I metabolism, Neutrophils metabolism
- Abstract
Glycogen storage disease type Ib (GSD-Ib) is an autosomal-recessive syndrome characterized by neutropenia and impaired glucose homeostasis resulting from a deficiency in the glucose-6-phosphate (G6P) transporter (G6PT). The underlying cause of GSD-Ib neutropenia is an enhanced neutrophil apoptosis, but patients also manifest neutrophil dysfunction of unknown etiology. Previously, we showed G6PT interacts with the enzyme glucose-6-phosphatase-β (G6Pase-β) to regulate the availability of G6P/glucose in neutrophils. A deficiency in G6Pase-β activity in neutrophils impairs both their energy homeostasis and function. We now show that G6PT-deficient neutrophils from GSD-Ib patients are similarly impaired. Their energy impairment is characterized by decreased glucose uptake and reduced levels of intracellular G6P, lactate, adenosine triphosphate, and reduced NAD phosphate, whereas functional impairment is reflected in reduced neutrophil respiratory burst, chemotaxis, and calcium mobilization. We further show that the mechanism of neutrophil dysfunction in GSD-Ib arises from activation of the hypoxia-inducible factor-1α/peroxisome-proliferators-activated receptor-γ pathway.
- Published
- 2014
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