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

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

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

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-β. 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 ∼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 (∼60%) plasma glucagon and reduced (∼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.

Original languageEnglish
Pages (from-to)39982-39989
Number of pages8
JournalJournal of Biological Chemistry
Volume281
Issue number52
DOIs
StatePublished - 29 Dec 2006
Externally publishedYes

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