Journal article
Deletion of the gene encoding the ubiquitously expressed glucose-6-phosphatase catalytic subunit-related protein (UGRP)/glucose-6-phosphatase catalytic subunit-beta results in lowered plasma cholesterol and elevated glucagon
The Journal of biological chemistry, Vol.281(52), pp.39982-39989
12/29/2006
DOI: 10.1074/jbc.M605858200
PMID: 17023421
Abstract
In liver, glucose-6-phosphatase catalyzes the hydrolysis of glucose-6-phosphate (G6P) to glucose and inorganic phosphate, the final step in the gluconeogenic and glycogenolytic pathways. Mutations in the glucose-6-phosphatase catalytic subunit (G6Pase) give rise to glycogen storage disease (GSD) type 1a, which is characterized in part by hypoglycemia, growth retardation, hypertriglyceridemia, hypercholesterolemia, and hepatic glycogen accumulation. Recently, a novel G6Pase isoform was identified, designated UGRP/G6Pase-beta. The activity of UGRP relative to G6Pase in vitro is disputed, raising the question as to whether G6P is a physiologically important substrate for this protein. To address this issue we have characterized the phenotype of UGRP knock-out mice. G6P hydrolytic activity was decreased by approximately 50% in homogenates of UGRP(-/-) mouse brain relative to wild type tissue, consistent with the ability of UGRP to hydrolyze G6P. In addition, female, but not male, UGRP(-/-) mice exhibit growth retardation as do G6Pase(-/-) mice and patients with GSD type 1a. However, in contrast to G6Pase(-/-) mice and patients with GSD type 1a, UGRP(-/-) mice exhibit no change in hepatic glycogen content, blood glucose, or triglyceride levels. Although UGRP(-/-) mice are not hypoglycemic, female UGRP(-/-) mice have elevated ( approximately 60%) plasma glucagon and reduced ( approximately 20%) plasma cholesterol. We hypothesize that the hyperglucagonemia prevents hypoglycemia and that the hypocholesterolemia is secondary to the hyperglucagonemia. As such, the phenotype of UGRP(-/-) mice is mild, indicating that G6Pase is the major glucose-6-phosphatase of physiological importance for glucose homeostasis in vivo.
Details
- Title: Subtitle
- Deletion of the gene encoding the ubiquitously expressed glucose-6-phosphatase catalytic subunit-related protein (UGRP)/glucose-6-phosphatase catalytic subunit-beta results in lowered plasma cholesterol and elevated glucagon
- Creators
- Yingda Wang - Vanderbilt UniversityJames K Oeser - Vanderbilt UniversityChunmei Yang - Lexicon PharmaceuticalsSuparna SarkarSeija I Hackl - University of Colorado HealthAlyssa H Hasty - Vanderbilt UniversityOwen P McGuinness - Vanderbilt UniversityWilliam Paradee - Lexicon PharmaceuticalsJohn C Hutton - University of Colorado HealthDavid R Powell - Lexicon PharmaceuticalsRichard M O'Brien
- Resource Type
- Journal article
- Publication Details
- The Journal of biological chemistry, Vol.281(52), pp.39982-39989
- DOI
- 10.1074/jbc.M605858200
- PMID
- 17023421
- ISSN
- 0021-9258
- eISSN
- 1083-351X
- Grant note
- P60 DK20593 / NIDDK NIH HHS DK56374 / NIDDK NIH HHS P30 DK57516 / NIDDK NIH HHS U24 DK059637 / NIDDK NIH HHS DK61645 / NIDDK NIH HHS DK59637 / NIDDK NIH HHS DK064877 / NIDDK NIH HHS
- Language
- English
- Date published
- 12/29/2006
- Academic Unit
- Medicine Administration
- Record Identifier
- 9984622755802771
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