Deletion of the Gene Encoding the Ubiquitously Expressed Glucose-6-phosphatase Catalytic Subunit-related Protein (UGRP)/Glucose-6-phosphatase Catalytic Subunit-β Results in Lowered Plasma Cholesterol and Elevated Glucagon

Wang, Yingda; Oeser, James K.; Yang, Chunmei; Sarkar, Sagartirtha; Hackl, Seija I; Hasty, Alyssa H.; McGuinness, Owen P.; Paradee, William; Hutton, John C.; Powell, David R.; O’Brien, Richard M.

doi:10.1074/jbc.m605858200

Cited by 21 publications

(18 citation statements)

References 43 publications

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“…G6P hydrolytic activity is decreased by ϳ50% in homogenates of G6pc3 Ϫ/Ϫ mouse brain and testis relative to wild-type tissue, consistent with the ability of G6PC3 to hydrolyze G6P (48). In addition, female, but not male, G6pc3 Ϫ/Ϫ mice exhibit growth retardation, as do G6pc Ϫ/Ϫ mice and patients with GSD type 1a (48). However, in contrast to G6pc Ϫ/Ϫ mice and patients with GSD type 1a, G6pc3 Ϫ/Ϫ mice exhibit no change in hepatic glycogen content or blood glucose or triglyceride levels.…”

Section: G6pc3mentioning

confidence: 71%

“…Although G6pc3 Ϫ/Ϫ mice are not hypoglycemic, female G6pc3 Ϫ/Ϫ mice have elevated (ϳ60%) plasma glucagon and reduced (ϳ20%) plasma cholesterol. We hypothesize that the hyperglucagonemia prevents hypoglycemia and that the hypocholesterolemia is secondary to the hyperglucagonemia (48). As such, the phenotype of G6pc3 Ϫ/Ϫ mice is mild, indicating that G6PC is the major glucose-6-phosphatase of physiological importance for glucose homeostasis in vivo.…”

Section: G6pc3mentioning

confidence: 99%

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Glucose-6-phosphatase Catalytic Subunit Gene Family

Hutton

O’Brien

2009

Journal of Biological Chemistry

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157

138

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Glucose-6-phosphatase catalyzes the hydrolysis of glucose 6-phosphate (G6P) to glucose and inorganic phosphate. It is a multicomponent system located in the endoplasmic reticulum that comprises several integral membrane proteins, namely a catalytic subunit (G6PC) and transporters for G6P, inorganic phosphate, and glucose. The G6PC gene family contains three members, designated G6PC, G6PC2, and G6PC3. The tissuespecific expression patterns of these genes differ, and mutations in all three genes have been linked to distinct diseases in humans. This minireview discusses the disease association and transcriptional regulation of the G6PC genes as well as the biological functions of the encoded proteins.

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Section: G6pc3mentioning

confidence: 71%

Section: G6pc3mentioning

confidence: 99%

Glucose-6-phosphatase Catalytic Subunit Gene Family

Hutton

O’Brien

2009

Journal of Biological Chemistry

Self Cite

157

138

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“…À / À mice 21 were transduced with an ER-Hoxb8 retrovirus and cell lines were established. Cell lines from wt and G6PC3…”

Section: Resultsmentioning

confidence: 99%

Survival and differentiation defects contribute to neutropenia in glucose-6-phosphatase-β (G6PC3) deficiency in a model of mouse neutrophil granulocyte differentiation

et al. 2013

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Differentiation of neutrophil granulocytes (neutrophils) occurs through several steps in the bone marrow and requires a coordinate regulation of factors determining survival and lineage-specific development. A number of genes are known whose deficiency disrupts neutrophil generation in humans and in mice. One of the proteins encoded by these genes, glucose-6-phosphatase-b (G6PC3), is involved in glucose metabolism. G6PC3 deficiency causes neutropenia in humans and in mice, linked to enhanced apoptosis and ER stress. We used a model of conditional Hoxb8 expression to test molecular and functional differentiation as well as survival defects in neutrophils from G6PC3 À / À mice. Progenitor lines were established and differentiated into neutrophils when Hoxb8 was turned off. G6PC3À / À progenitor cells underwent substantial apoptosis when differentiation was started. Transgenic expression of Bcl-X L rescued survival; however, Bcl-X L -protected differentiated cells showed reduced proliferation, immaturity and functional deficiency such as altered MAP kinase signaling and reduced cytokine secretion. Impaired glucose utilization was found and was associated with ER stress and apoptosis, associated with the upregulation of Bim and Bax; downregulation of Bim protected against apoptosis during differentiation. ER-stress further caused a profound loss of expression and secretion of the main neutrophil product neutrophil elastase during differentiation. Transplantation of wild-type Hoxb8-progenitor cells into irradiated mice allowed differentiation into neutrophils in the bone marrow in vivo. Transplantation of G6PC3À / À cells yielded few mature neutrophils in bone marrow and peripheral blood. Transgenic Bcl-X L permitted differentiation of G6PC3À / À cells in vivo. However, functional deficiencies and differentiation abnormalities remained. Differentiation of macrophages from Hoxb8-dependent progenitors was only slightly disturbed. A combination of defects in differentiation and survival thus underlies neutropenia in G6PC3 À / À deficiency, both originating from a reduced ability to utilize glucose. Hoxb8-dependent cells are a model to study differentiation and survival of the neutrophil lineage.

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“…The height and weight of the boy described by Arostegui et al 2 were below the third percentile and at least 7 of the 12 patients reported by Boztug et al 3 demonstrated growth retardation or height/weight at the lower end of the normal range. We note that female g6pc3 À/À mice exhibit growth retardation, 12 but in humans this features seems not to be sex limited.…”

Section: Growthmentioning

confidence: 99%

Further delineation of the phenotype of severe congenital neutropenia type 4 due to mutations in G6PC3

et al. 2010

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Severe congenital neutropenia type 4 (SCN4) is an autosomal recessive condition, which was defined recently with identification of the causative mutations in G6PC3. To date there are only three reports in the literature describing patients with SCN4 with mutations in the G6PC3 gene. We report four individuals with SCN4 who belong to a single large consanguineous kindred. We provide an overview of the non-haematological features of the condition with a focus on the adult phenotype, which has not been previously described in detail. We show that the superficial venous changes seen in SCN4 patients can develop into varicose veins and venous ulcers in adulthood. We review the range of congenital anomalies associated with SCN4. We demonstrate that secundum atrial septal defect, patent ductus arteriosus and valvular defects are the most frequent cardiac anomalies in SCN4. Drawing parallels with type 1 glycogen storage disease, we propose that poor growth of prenatal onset, mild-to-moderate learning disability, primary pulmonary hypertension, delayed or incomplete puberty, hypothyroidism and dysmorphism likely represent features of this syndrome. We also suggest monitoring for lipid anomalies, and kidney and liver function in affected patients. Delineation of the SCN4 phenotype may help in appropriate treatment and management and provide further insights into the pathogenesis of this multisystem disease.

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Deletion of the Gene Encoding the Ubiquitously Expressed Glucose-6-phosphatase Catalytic Subunit-related Protein (UGRP)/Glucose-6-phosphatase Catalytic Subunit-β Results in Lowered Plasma Cholesterol and Elevated Glucagon

Cited by 21 publications

References 43 publications

Glucose-6-phosphatase Catalytic Subunit Gene Family

Glucose-6-phosphatase Catalytic Subunit Gene Family

Survival and differentiation defects contribute to neutropenia in glucose-6-phosphatase-β (G6PC3) deficiency in a model of mouse neutrophil granulocyte differentiation

Further delineation of the phenotype of severe congenital neutropenia type 4 due to mutations in G6PC3

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