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.
Wang
Yingda
Y
Department of Molecular Physiology and Biophysics, Vanderbilt University Medical School, Nashville, Tennessee 37232, USA.
Oeser
James K
JK
Yang
Chunmei
C
Sarkar
Suparna
S
Hackl
Seija I
SI
Hasty
Alyssa H
AH
McGuinness
Owen P
OP
Paradee
William
W
Hutton
John C
JC
Powell
David R
DR
O'Brien
Richard M
RM
D000818:Animals; D020134:Catalytic Domain / Q000235:genetics*; D002784:Cholesterol / Q000097:blood*; D015536:Down-Regulation / Q000235:genetics*; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000235:genetics; D005934:Glucagon / Q000096:biosynthesis*; D005947:Glucose / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D005953:Glycogen Storage Disease Type I / Q000201:enzymology / Q000235:genetics; D006706:Homeostasis / Q000235:genetics; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D021122:Protein Subunits / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D011506:Proteins / Q000235:genetics* / Q000502:physiology; D060765:Secretoglobins; D015854:Up-Regulation / Q000235:genetics*
D007527:Isoenzymes; D021122:Protein Subunits; D011506:Proteins; C449818:Scgb3a2 protein, mouse; D060765:Secretoglobins; D005934:Glucagon; D002784:Cholesterol; D005952:Glucose-6-Phosphatase; D005947:Glucose