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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-beta results in lowered plasma cholesterol and elevated glucagon.

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.

Pubmed ID: 17023421

Authors

  • Wang Y
  • Oeser JK
  • Yang C
  • Sarkar S
  • Hackl SI
  • Hasty AH
  • McGuinness OP
  • Paradee W
  • Hutton JC
  • Powell DR
  • O'Brien RM

Journal

The Journal of biological chemistry

Publication Data

December 29, 2006

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK064877
  • Agency: NIDDK NIH HHS, Id: DK56374
  • Agency: NIDDK NIH HHS, Id: DK59637
  • Agency: NIDDK NIH HHS, Id: DK61645
  • Agency: NIDDK NIH HHS, Id: P30 DK57516
  • Agency: NIDDK NIH HHS, Id: P60 DK20593
  • Agency: NIDDK NIH HHS, Id: U24 DK059637

Mesh Terms

  • Animals
  • Catalytic Domain
  • Cholesterol
  • Down-Regulation
  • Female
  • Gene Deletion
  • Gene Expression Regulation
  • Glucagon
  • Glucose
  • Glucose-6-Phosphatase
  • Glycogen Storage Disease Type I
  • Homeostasis
  • Isoenzymes
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Protein Subunits
  • Proteins
  • Secretoglobins
  • Up-Regulation