From the Heritable Disorders Branch, NICHD and the
¶ Laboratory of Metabolism, NCI, National Institutes of Health,
Bethesda, Maryland 20892
Received for publication, November 21, 2000, and in revised form, December 14, 2000
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ABSTRACT |
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The clinical manifestations of type 1 glycogen
storage disease (GSD-1) in patients deficient in the
glucose-6-phosphatase (G6Pase) system (e.g. growth
retardation, hepatomegaly, hyperlipidemia, and renal dysfunction) are
shared by Hnf1 Glycogen storage disease type 1 (GSD-1), also know as von Gierke
disease, is a group of autosomal recessive disorders that occurs
approximately once in every 100,000 live births (1, 2). These disorders
are caused by deficiencies in the activity of the glucose-6-phosphatase
(G6Pase)1 system that
consists of two integral membrane proteins, glucose 6-phosphate
transporter (G6PT) and the G6Pase catalytic unit (1-3). G6PT
translocates glucose 6-phosphate (G6P), the terminal product of
gluconeogenesis and glycogenolysis, from the cytoplasm to the lumen of
the endoplasmic reticulum (ER). Inside the ER, G6Pase with its active
site facing the lumen (4) catalyzes the hydrolysis of G6P to glucose
and phosphate. Therefore, G6PT and G6Pase work in concert to maintain
glucose homeostasis. Deficiencies in G6Pase and G6PT cause GSD-1a and
GSD-1b, respectively (1, 2). Both groups of patients manifest growth
retardation, hepatomegaly, hyperlipidemia, and renal dysfunction,
clinical features associated with Hnf1 Hnf1 Construction of Promoter-CAT Fusion Genes, Transfection, and CAT
Assays--
The G6PT promoter-chloramphenicol
acetyltransferase (CAT) fusion gene constructs were synthesized by
polymerase chain reaction using the G6PT gene (26) as the
template. The 3' primer for the G6PT 5' deletion mutants
consisted of nucleotides
HepG2 human hepatoma cells were grown at 37 °C in Electromobility Shift Assays--
HepG2 nuclear extracts were
prepared essentially as described (28). End-labeled oligonucleotide
probes (2 ng; 0.2-0.5 × 106 cpm) were incubated for
20 min at room temperature in binding reaction buffer (10 mM Tris-HCl, pH 7.5, 50 mM NaCl, 0.05% Nonidet P-40, 1 mM EDTA, 0.5 mM dithiothreitol, and
10% glycerol) containing 0.4-1 µg of poly(dI-dC) and 3 µg of
nuclear extracts. Following binding, the mixture was electrophoresed
through a 5% nondenaturing polyacrylamide gel, dried, and
autoradiographed. For competition experiments, competitor DNA was
incubated in the mixture prior to the addition of probe. For gel
supershift assays, specific antisera were preincubated with HepG2
extracts at 4 °C for 20 min before the addition of probe.
Animals--
Hnf1 Northern Blot, Phosphohydrolase, and G6P Uptake
Analyses--
Total RNA was isolated by the guanidinium
thiocyanate/CsCl method, fractionated by electrophoresis through 1.2%
agarose gels containing 2.2 M formaldehyde and transferred
to a Nytran membrane by electroblotting. The membranes were hybridized
to cDNA probes for G6Pase, G6PT, or
Phosphohydrolase assays were performed as previously described (4).
Disrupted microsomal membranes were prepared by incubating intact
microsomes in 0.2% deoxycholate for 20 min at 0 °C. Nonspecific phosphatase activity was estimated by preincubating microsomal preparations at pH 5 for 10 min at 37 °C, a condition that
inactivates the thermally labile G6Pase. G6P uptake measurements were
performed as previously described (26). Microsomes permeabilized with 0.2% deoxycholate, which abolished G6P uptake, were used as negative controls. Statistical analysis using the unpaired t test was
performed with the GraphPad Prism Program (GraphPad Software, San
Diego, CA).
HNF1
To demonstrate whether HNF1
To determine whether binding of HNF1
Sequence analysis also predicts the presence of a binding site for HNF3
at nucleotides Expression of G6PT and G6Pase Genes in Hnf1
It has been demonstrated that HNF1
The active site of G6Pase faces the lumen of the ER (4) and for G6Pase
catalysis in vivo, G6P must be translocated from the
cytoplasm into the lumen by the G6PT (3, 26). Biochemically, G6Pase
activity in intact hepatic microsomes of GSD-1b patients, deficient in
G6PT, is low or nondetectable, consistent with a functional G6Pase
deficiency manifested by these patients. On the other hand, high levels
of G6Pase activity were detected in disrupted hepatic microsomes of
GSD-1b patients where G6PT function was abolished. The difference in
G6Pase enzymatic activity in intact versus disrupted
microsomes is best evaluated by measuring the G6Pase latency value,
defined as the portion of enzymatic activity that is not expressed
unless the microsomes are disrupted (33). G6Pase latency values in
hepatic microsomes of GSD-1b patients are significantly higher than
that in normal individuals (34). The apparent G6PT deficiency
manifested by Hnf1 In this study, we have investigated the molecular mechanisms of
phenotypic similarities between GSD-1 patients deficient in the G6Pase
system (1, 2) and Hnf1 G6PT, encoded by a single copy gene located on human chromosome 11q23
(35), is expressed in nearly all tissues examined, including liver,
kidney, pancreas, and digestive tract (36). In this study, we
demonstrate that nucleotides In addition to functional G6Pase deficiency, GSD-1b patients suffer
additional infectious complications because of heritable neutropenia
and functional deficiencies of neutrophils and monocytes (37), clinical
features not associated with Hnf1 It is noteworthy that overexpression of G6Pase in primary hepatocytes
creates the metabolic profile of liver cells derived from NIDDM
patients (40). Moreover, rats overexpressing the G6Pase gene
manifest glucose intolerance and hyperinsulinemia (23). Transient
expression studies have shown that HNF1 Glucose 6-phosphate, the substrate of the G6Pase system, plays a
pivotal role in metabolism. It is at the branch point of lipid
biosynthesis and glycogen biosynthesis as well as facilitating energy
homeostasis through glucose. Kinetic studies have suggested that G6P
uptake is the rate-limiting step in G6Pase catalysis (3). This notion
is further supported by functional G6Pase deficiency manifested by
GSD-1b patients carrying inactivating mutations in the G6PT
gene (26). Similarly, in Hnf1/
mice deficient of a
transcriptional activator, hepatocyte nuclear factor 1
(HNF1
).
However, the molecular mechanism is unknown. The G6Pase system,
essential for the maintenance of glucose homeostasis, is comprised of
glucose 6-phosphate transporter (G6PT) and G6Pase. G6PT translocates
G6P from the cytoplasm to the lumen of the endoplasmic reticulum where
it is metabolized by G6Pase to glucose and phosphate. Deficiencies in
G6Pase and G6PT cause GSD-1a and GSD-1b, respectively. Hnf1
/
mice also develop
noninsulin-dependent diabetes mellitus caused by defective
insulin secretion. In this study, we sought to determine whether there
is a molecular link between HNF1
deficiency and function of the
G6Pase system. Transactivation studies revealed that HNF1
is
required for transcription of the G6PT gene. Hepatic G6PT
mRNA levels and microsomal G6P transport activity are also markedly
reduced in Hnf1
/
mice as compared with
Hnf1
+/+ and
Hnf1
+/
littermates. On the other hand,
hepatic G6Pase mRNA expression and activity are up-regulated in
Hnf1
/
mice, consistent with observations
that G6Pase expression is increased in diabetic animals.
Taken together, the results strongly suggest that metabolic
abnormalities in HNF1
-null mice are caused in part by G6PT
deficiency and by perturbations of the G6Pase system.
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
/
mice (5-7) that are completely deficient in hepatocyte nuclear factor
1
(HNF1
), a dimeric homeodomain-containing transcriptional activator (8-10). HNF1
is expressed in the liver, kidney, pancreas, and digestive tract (5, 8, 10) and is required for the expression of
many liver genes (11-14). In this study, we establish a molecular link
between HNF1
deficiency and function of the G6Pase system. We show
that HNF1
binds to the G6PT promoter and is required for
activation of G6PT gene transcription. Further, we show that
hepatic G6PT mRNA expression in Hnf1
/
mice is markedly reduced, resulting in a near abolishment of microsomal
G6P transport activity. These data indicate that
Hnf1
/
mice, similar to GSD-1b patients,
are deficient in the G6PT.
/
mice also develop
noninsulin-dependent diabetes mellitus (NIDDM) (6) caused
by defective insulin secretion and
-cell glycolytic signaling (15,
16). This finding is consistent with observations showing that
mutations in the Hnf1
/
gene in humans
cause type 3 maturity-onset diabetes of the young, an autosomal
dominant form of NIDDM characterized by impaired insulin secretion
(17-20). It has been speculated that overexpression of G6Pase might
contribute to the pathophysiology of NIDDM. In animal models of
diabetes, G6Pase mRNA expression and enzymatic activity are
increased, resulting in an elevation in hepatic glucose production (21,
22). Moreover, rats overexpressing the G6Pase gene exhibit
several metabolic abnormalities associated with NIDDM, including
glucose intolerance and hyperinsulinemia (23). Insulin has been shown
to inhibit G6Pase gene transcription, and this effect is
mediated through a cluster of insulin-response elements in the
G6Pase promoter (24). Further, HNF1
is required for maximal repression of G6Pase gene transcription by insulin
(25). In this study, we show that G6Pase activity and mRNA levels
are elevated in Hnf1
/
mice. Taken
together, our data indicate that metabolic abnormalities in
Hnf1
/
mice are caused in part by
perturbation of the G6Pase system.
MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
21 to
1, and the 5' primers consisted of
nucleotides
609 to
589,
200 to
180, and
152 to
132. Each
primer contained an additional HindIII or XbaI
site at the 5'-end. After digestion with HindIII and
XbaI, the amplified fragments were inserted upstream of the bacterial CAT gene of a modified promoter- and enhancer-less
pCAT-Basic-N plasmid (27). The G6PT(
200/
1M)CAT construct was
generated by site-directed mutagenesis using a pair of primers
(nucleotides
172 to
149) that contain TAA
GGG mutations at
nucleotides
163/
161. All constructs were verified by DNA
sequencing. The pSVCAT, which contains both the SV40 enhancer and
promoter and pCAT-Basic-N plasmids were used as positive and negative
controls, respectively. Additionally, we constructed G6PT
promoter-CAT constructs in the reverse orientation, G6PT(
1/
609)CAT,
and showed that it directed no CAT expression (data not shown).
-modified
minimal essential medium supplemented with 4% fetal bovine serum. Cells in 25-cm2 flasks were transfected with the
G6PT promoter-CAT constructs by the calcium phosphate-DNA
coprecipitate method as previously described (27). The CAT activity was
assayed by incubating total cellular protein in a buffer containing 250 mM Tris-HCl, pH 7.8, 4 mM acetyl coenzyme A,
and 0.1 µCi [14C]chloramphenicol (56 µCi/mmol,
Amersham Pharmacia Biotech). The acetylated compounds were separated
from chloramphenicol by thin-layer chromatography (95% chloroform, 5%
methanol; v/v) on silica gel IB2 (Gilman Sciences). Spots were
quantitated on an AMBIS Radioanalytic Imaging System (San Diego, CA).
/
mice were generated by
Cre-loxP-mediated deletion to remove exon 1 of the
Hnf1
gene (6). All animal studies were conducted under an
animal protocol approved by the NIH Animal Care and Use Committee.
-actin.
RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
Binds to the G6PT Promoter and Transactivates G6PT Gene
Transcription--
To determine whether HNF1
regulates
G6PT gene expression, we analyzed the 5'-flanking region of
the gene and identified a HNF1 motif at nucleotides
165 to
153
followed by a TATA-box at nucleotides
141 to
136 upstream of the
translation start site at +1 (Fig.
1A). To determine whether
HNF1
activates transcription of the G6PT gene, we
examined expression of the CAT gene directed by the
G6PT promoter. Whereas both G6PT(
609/
1)CAT and
G6PT(
200/
1)CAT constructs directed significant levels of CAT
expression, CAT activity was found to be barely detectable with the
G6PT(
152/
1)CAT construct (Fig. 1B). These data indicate
that nucleotides
200 to
1 constitute a minimal G6PT
promoter, which contains an activating element at nucleotides
200 to
153 encompassing the HNF1 motif (
165/
153).
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Fig. 1.
The G6PT promoter.
A, nucleotides 200 to +3 of the 5'-flanking region of the
human G6PT gene. The numbers indicate the distance in
nucleotides from the translation start site (+1). The TATA-box and
motifs for HNF1, HNF3, and C/EBP are boxed. The
transcription start site is denoted by an arrow.
B, promoter activity of the G6PT 5'-flanking
region. The G6PT promoter-CAT fusion genes (10 µg/25-cm2 flask) were transfected into HepG2 cells, and
CAT activity was expressed as percentage of activity expressed by the
G6PT(
609/
1)CAT construct. Specific CAT activities directed by
G6PT(
609/
1)CAT, pSVCAT, and pCAT-Basic-N plasmids were 7.6, 4.8, and 0.02 nmol/min/mg protein, respectively. Five independent
experiments were conducted with two preparations of each
construct.
is the protein factor that binds to this
activating element, electromobility shift assays were performed using
HepG2 nuclear extracts. A protein-DNA complex, C1, was formed between
the G6PT(
173/
145) oligo and HepG2 extracts (Fig.
2A, lane 2). The
formation of complex C1 was efficiently blocked by the addition of an
excess of unlabeled target DNA (lanes 3-5) and by an
oligonucleotide containing the HNF1 motif (lanes 6-8), but
not by an unrelated HNF4 (lane 21) and C/EBP oligonucleotide (lane 22). An HNF1-M1 oligonucleotide containing a mutated
HNF1 site (TAA
GGG) had markedly reduced ability to block complex C1 formation (lanes 9-13) and an HNF1-M2 oligonucleotide that
disrupts the entire DNA binding motif (TAA
GGG and TAA
GGG
conversions) was completely incapable of blocking complex C1 formation
(lanes 14-18). Further, an antiserum to HNF1
(lane
19), but not HNF1
(lane 20), caused a shift in the
mobility of complex C1, demonstrating that a protein factor in this
complex is HNF1
.
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Fig. 2.
Activation of G6PT transcription
by HNF1 . A, binding of HepG2 nuclear proteins to
nucleotides
173/
145 in the G6PT promoter. The
G6PT(
173/
145) fragment encompassing a HNF1 site (
165/
153) was
labeled and used in electromobility shift assays with HepG2 nuclear
extracts. Reaction mixtures were preincubated with a competitor
oligonucleotide, an antiserum to HNF1
(supershift), or antiserum to
HNF1
(supershift), and analyzed on a 5% nondenaturing
polyacrylamide gel. Consensus sequences that bind to transcription
factors are underlined. B, stimulation of CAT expression
directed by G6PT promoter constructs by HNF1
.
G6PT promoter-CAT constructs (5 µg/25-cm2
flask)) were transfected into HepG2 cells in the presence of 1 µg
each of pBJ5 (solid bar) or pBJ5-HNF1
(open
bar). The G6PT(
200/
1M)CAT construct contains a mutated HNF1
site (TAA
GGG conversion at nucleotides
163/
161). Specific CAT
activities directed by G6PT(
609/
1)CAT, pSVCAT, and pCAT-Basic-N
plasmids were 0.55, 0.33, and 0.001 nmol/min/mg protein, respectively.
Four independent experiments were conducted with two preparations of
each construct.
to the G6PT promoter
activates gene transcription, we examined CAT expression after cotransfecting G6PT promoter-CAT fusion genes with pBJ5 or
pBJ5-HNF1
. HNF1
elicited a 9.2-fold increase in CAT expression
directed by the G6PT(
200/
1)CAT construct (Fig. 2B). In
contrast, HNF1
elicited only a 3.8-fold increase in CAT activity
directed by G6PT(
200/
1M)CAT, which contains a mutated HNF1 site
(TAA
GGG conversion at nucleotides
163 to
161). Moreover, CAT
expression directed by G6PT(
200/
1M)CAT was also markedly reduced
when compared with G6PT(
200/
1)CAT in the absence of a cotransfected
HNF1
(Fig. 2B). Thus, our data indicate that HNF1
binds to its cognate site within the promoter and activates
G6PT gene transcription.
62 to
56 and a C/EBP motif at nucleotides
50 to
42 of the G6PT promoter (Fig. 1A). HNF3 belongs
to the forkhead or winged helix family of transcription factors (29, 30), and it has been shown that HNF3
is required for transcription of the G6Pase gene (27). The C/EBP family belongs to the
bZIP class of transcription factors that contain a basic DNA-binding region adjacent to a leucine zipper dimerization domain (31, 32). The
roles of HNF3 and C/EBP in G6PT gene transcription are
currently under investigation.
/
Mice--
The vital role of HNF1
in transactivation of the
G6PT gene and the clinical features common to both GSD-1
patients and Hnf1
/
mice suggest that the
expression of the G6PT gene is likely to be perturbed in
these mice. We therefore examined G6PT mRNA expression in the liver
of Hnf1
/
mice by Northern blot analysis.
The results show that the levels of hepatic G6PT mRNA were markedly
reduced in Hnf1
/
mice as compared with
their wild-type and heterozygous littermates (Fig.
3). Additionally, whereas hepatic
microsomes isolated from Hnf1
+/+ or
Hnf1
+/
mice actively transported G6P, G6P
uptake activities in intact hepatic microsomes from
Hnf1
/
animals were markedly reduced (Fig.
4), confirming that G6P transport function of G6PT is impaired in Hnf1
/
mice.
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Fig. 3.
Expression of G6PT and G6Pase mRNA in the
liver of Hnf1 /
mice. Total RNAs (10 µg/lane), isolated from livers of 2-3
month old Hnf1
/
mice and their
Hnf1
+/+ and
Hnf1
+/
littermates, were separated on
formaldehyde-agarose gels and hybridized with a uniformly labeled
antisense probe of G6PT, G6Pase, or
-actin.
View larger version (15K):
[in a new window]
Fig. 4.
Uptake of
[U-14C]G6P into liver microsomes of
Hnf1 +/+,
Hnf1
+/
and
Hnf1
/
mice.
A, time course of hepatic microsomal
[U-14C]G6P uptake in
Hnf1
+/+ (154) and
Hnf1
/
(152) mice. B, the 3-min
G6P uptake values in
Hnf1
+/+/Hnf1
+/
(n = 5) and Hnf1
/
(n = 5) mice. Data are presented as the mean ± S.E. Hepatic microsomal G6P uptake activities are similar in
Hnf1
+/+ and
Hnf1
+/
mice.
is required for transactivation
of the G6Pase gene (27), and it acts as an accessory factor
for maximal suppression of G6Pase transcription by insulin (25). In this study, we show that levels of hepatic G6Pase mRNA were increased by 2- to 6-fold in Hnf1
/
mice (Fig. 3), resulting in an increase in G6Pase enzymatic activity in
deoxycholate-disrupted microsomes where the G6PT function is not
required (Table I). The results suggest
that HNF1
is not required for transcription of the G6Pase
gene in vivo. On the other hand, the results are consistent
with observations that G6Pase expression is increased in diabetic
animals (21, 22) and that HNF1
is required for suppression of
G6Pase transcription by insulin (25).
Hepatic G6Pase activity in Hnf1+/+, Hnf1
+/
, and
Hnf1
/
mice
/
mice prompted us to
characterize the G6Pase system in these mice. As expected, G6Pase
activity in intact hepatic microsomes of
Hnf1
/
mice was only 53% of that found in
Hnf1
+/+ or Hnf1
+/
mice (Table I). Moreover, hepatic G6Pase latency value was 87.9% in
Hnf1
/
mice, which was markedly higher
than the value of 41.7% found in
Hnf1
+/+/Hnf1
+/
mice (Table I). Taken together, these results indicate that Hnf1
/
mice, like GSD-1b patients, are
deficient in the G6PT.
DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
/
mice lacking the
transactivator, HNF1
(5-7). We demonstrate that
Hnf1
/
mice, like GSD-1b patients, are
deficient in G6PT, an ER-associated membrane protein that translocates
G6P from cytoplasm to the lumen of ER and a member of the G6Pse system
required for the maintenance of glucose homeostasis (1-3). The results
establish for the first time a molecular link between the common
phenotypes of GSD-1 and Hnf1
/
mice.
Further, we show that the expression of the G6Pase gene is
also perturbed in Hnf1
/
mice.
200 to
1 upstream of the translation
start site constitute a minimal G6PT promoter and HNF1
is
required for transcription of the G6PT gene. The minimal
G6PT promoter contains an activating element at nucleotides
200 to
153 encompassing the HNF1 motif at nucleotides
165 to
153. We show that HNF1
activates transcription of the
G6PT gene following binding to its cognate site. Consistent
with this, hepatic G6PT mRNA expression was inhibited and
microsomal G6P transport function in the liver was impaired in
Hnf1
/
mice. In GSD-1b patients,
deficiency in G6PT results in an increase in hepatic G6Pase latency
values (34). Likewise, G6Pase latency values in
Hnf1
/
mice are also markedly increased.
Taken together, these data demonstrate that the G6PT function in
Hnf1
/
mice is impaired, resulting in a
phenotype that closely resembles that of GSD-1b.
/
mice.
The results of a recent study showed that GSD-1b patients carrying
either a homozygous splicing (794G
A) mutation or heterozygous G339D
and R415X mutations suffer no impairment in their
polymorphonuclear leukocyte functions (38). The 794G
A mutation was
shown to be leaky because the mutated G6PT gene of the
patient directed the expression of both mature and truncated G6PT
transcripts (38). Likewise, the R415X mutation was shown to
only partially inactive the transporter (39). These studies strongly
suggest that neutropenia as well as neutrophil and monocyte
dysfunctions occur only in patients that harbor null G6PT
mutations. Therefore, Hnf1
/
mice, which
express a low level of the G6PT gene, do not manifest neutropenia or polymorphonuclear leukocyte dysfunction.
is required for
transcription of the G6Pase gene (27). However, HNF1
is
also required for the maximal repression of G6Pase gene transcription by insulin (24, 25). The increase in G6Pase expression in Hnf1
/
mice strongly
suggests that the in vivo role of HNF1
is to act as an
accessory factor to enhance the inhibitory action of insulin on
G6Pase gene transcription (25). It has been shown that in diabetic rats, prolonged hyperglycemia increases G6Pase gene
expression independent of insulin (22) and that the glucose-stimulated increase in G6Pase mRNA depending upon the presence of
glucokinase (41). It appears that HNF1
deficiency compounded with
impaired insulin secretion and hyperglycemia contributes to G6Pase
overexpression in Hnf1
/
mice. Whether
perturbations in G6Pase expression contribute to the pathogenesis of
NIDDM in these mice remains to be elucidated.
/
mice, G6P
generated by glycogenolysis and gluconeogenesis could not be
efficiently translocated to the lumen of the ER, resulting in an
increase in hepatic glycogen deposition and stimulation of cholesterol
and fatty acid synthesis. Taken together, our study demonstrates, for
the first time that metabolic abnormalities in
Hnf1
/
mice are caused in part by G6PT
deficiency and disruption in the balance of the G6Pase system.
![]() |
ACKNOWLEDGEMENTS |
---|
We thank Drs. A. B. Mukherjee and I. S.
Owens for critical reading of the manuscript and Drs. L. Hansen and
G. R. Crabtree for gifts of expression vector for HNF1 and antisera
to HNF1
and HNF1
.
![]() |
FOOTNOTES |
---|
* The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
§ Both authors contributed equally to this work.
To whom correspondence should be addressed: Bldg. 10, Rm.
9S241, National Institutes of Health, Bethesda, MD 20892. Tel.: 301-496-1094; Fax: 301-402-6035; E-mail: chou@helix.nih.gov.
Published, JBC Papers in Press, December 19, 2000, DOI 10.1074/jbc.M010523200
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ABBREVIATIONS |
---|
The abbreviations used are: G6Pase, glucose-6-phosphatase; HNF1, hepatocyte nuclear factor; ER, endoplasmic reticulum; CAT, chloramphenicol acetyltransferase; G6P, glucose 6-phosphate; NIDDM, noninsulin-dependent diabetes mellitus; GSD-1, type 1 glycogen storage disease.
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REFERENCES |
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