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Molecular mechanisms of neutrophil dysfunction in glycogen storage disease type Ib
- Publication Year :
- 2014
- Publisher :
- American Society of Hematology, 2014.
-
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.
- Subjects :
- Adult
medicine.medical_specialty
Adolescent
Monosaccharide Transport Proteins
Neutrophils
Immunology
Intracellular Space
Neutropenia
Glycogen Storage Disease Type I
Biochemistry
Energy homeostasis
Antiporters
Immunophenotyping
Young Adult
Phagocytes, Granulocytes, and Myelopoiesis
Adenosine Triphosphate
Internal medicine
Glycogen Storage Disease Type Ib
medicine
Glucose homeostasis
Humans
Lactic Acid
Child
Glycogen storage disease type I
NADPH oxidase
biology
NADPH Oxidases
Cell Biology
Hematology
medicine.disease
Hypoxia-Inducible Factor 1, alpha Subunit
Respiratory burst
Enzyme Activation
PPAR gamma
Endocrinology
Glucose
Phenotype
Child, Preschool
biology.protein
Glucose-6-Phosphatase
Glucose 6-phosphatase
NADP
Signal Transduction
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....2cd98910d3c5b0e517119876f8457b4c