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

doi:10.1074/jbc.m605858200

Abstract

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

Highlights

We hypothesize that the hyperglucagonemia prevents hypoglycemia and that the hypocholesterolemia is secondary to the hyperglucagonemia
Glucose-6-phosphatase is located in the endoplasmic reticulum membrane and is postulated to exist as a multi-component enzyme system in which a glucose-6-phosphatase catalytic subunit has its catalytic site directed toward the lumen of the endoplasmic reticulum, and a G6P transporter serves to deliver G6P from the cytosol to the active site of the catalytic subunit (3– 6)
In contrast to G6PaseϪ/Ϫ mice and patients with glycogen storage disease (GSD) type 1a, UGRPϪ/Ϫ mice exhibit no change in hepatic glycogen content (Fig. 2C), blood glucose, or plasma triglyceride levels (Table 1)

Summary

The abbreviations used are

G6P, glucose-6-phosphate; G6Pase, glucose-6phosphatase catalytic subunit; GSD, glycogen storage disease; KOS, knockout shuttle; ES, embryonic stem; ORF, open reading frame; PBS, phosphate-buffered saline. The first, islet-specific G6Pase-related protein (IGRP or G6PC2) (13–15) is expressed in islet ␤ cells (18). Questions arise as to whether the physiologically important substrate that UGRP hydrolyzes is something other than G6P or whether a low rate of G6P hydrolysis by UGRP might influence glucose production in vivo because of the wide tissue distribution of the enzyme. To address these possibilities, this study describes the generation and characterization of UGRP knock-out mice. The results demonstrate that, deletion of UGRP reduces glucose-6-phosphatase activity in tissue extracts, the phenotype of UGRP knock-out mice is mild, indicating that G6Pase is the major glucose-6phosphatase of physiological importance for glucose homeostasis in vivo

EXPERIMENTAL PROCEDURES

RESULTS

DISCUSSION