Bovine growth hormone-transgenic mice have major alterations in hepatic expression of metabolic genes
Bob Olsson,1,3
Mohammad Bohlooly-Y,1,3
Ola Brusehed,1,3
Olle G. P. Isaksson,3
Bo Ahrén,6
Sven-Olof Olofsson,2,4
Jan Oscarsson,1,4 and
Jan Törnell1,5
Departments of 1Physiology and
2Medical Biochemistry, Göteborg University,
SE-405 30 Goteborg; 3Research Center for Endocrinology
and Metabolism, Department of Internal Medicine and
4Wallenberg Laboratory for Cardiovascular Disease,
Sahlgrenska University Hospital, SE-413 45 Goteborg;
5AstraZeneca Transgenics and Comparative Genomics
Center, AstraZeneca Research and Development, SE-431 83 Molndal; and
6Department of Medicine, Lund University, SE-221 84
Lund, Sweden
Submitted 16 November 2002
; accepted in final form 26 April 2003
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ABSTRACT
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Transgenic mice overexpressing growth hormone (GH) have been extensively
used to study the chronic effects of elevated serum levels of GH. GH is known
to have many acute effects in the liver, but little is known about the chronic
effects of GH overexpression on hepatic gene expression. Therefore, we used
DNA microarray to compare gene expression in livers from bovine GH
(bGH)-transgenic mice and littermates. Hepatic expression of peroxisome
proliferator-activated receptor-
(PPAR
) and genes involved in
fatty acid activation, peroxisomal and mitochondrial
-oxidation, and
production of ketone bodies was decreased. In line with this expression
profile, bGH-transgenic mice had a reduced ability to form ketone bodies in
both the fed and fasted states. Although the bGH mice were hyperinsulinemic,
the expression of sterol regulatory element-binding protein (SREBP)-1 and most
lipogenic enzymes regulated by SREBP-1 was reduced, indicating that these mice
are different from other insulin-resistant models with respect to expression
of SREBP-1 and its downstream genes. This study also provides several
candidate genes for the well-known association between elevated GH levels and
cardiovascular disease, e.g., decreased expression of scavenger receptor class
B type I, hepatic lipase, and serum paraoxonase and increased expression of
serum amyloid A-3 protein. We conclude that bGH-transgenic mice display marked
changes in hepatic genes coding for metabolic enzymes and suggest that GH
directly or indirectly regulates many of these hepatic genes via decreased
expression of PPAR
and SREBP-1.
fatty acids; transgenic mice; DNA microarray; peroxisome proliferator-activated receptor-
; sterol regulatory element-binding protein
MANY DIFFERENT TRANSGENIC MODELS with chronic elevation of
growth hormone (GH) levels have been used to study the long-term effects of
GH. Mice transgenic for GH have increased size due to increased lean body
mass, linear growth, and organomegaly
(13,
67). The GH-transgenic mice
have decreased fat mass (20,
45) and changed serum levels
of several hormones other than GH. The bovine GH (bGH)-transgenic mice used in
this study have elevated serum levels of corticosterone
(4), triiodothyronine
(T3) (4), insulin
(20), and IGF-I
(20) but decreased levels of
thyroxine (T4) (4)
compared with littermate controls. Moreover, hyperinsulinemia and insulin
resistance, but normal or nearly normal glucose tolerance, have also been
described in GH-transgenic mice
(29). Furthermore, these
bGH-transgenic mice have impaired cardiac function
(5) and increased locomotor
activity (60). Regarding the
lipid and lipoprotein metabolism in GH-transgenic models, both GH-releasing
factor- and bGH-transgenic mice revealed elevated serum cholesterol levels and
normal or decreased serum triglyceride levels
(6,
20,
46). We have recently shown
(20) that bGH-transgenic mice
have increased HDL-cholesterol and LDL-apolipoprotein B (apoB) levels but
decreased VLDL-apoB and triglyceride levels. Moreover, these mice showed
decreased hepatic triglyceride secretion and increased lipoprotein lipase
activity in adipose tissue, heart, and skeletal muscle but unchanged LDL
receptor activity (20).
Patients with acromegaly have many features that are similar to those of
GH-transgenic mice, including organomegaly, decreased body fat
(3), insulin resistance
(19), and disturbed
lipoprotein metabolism. However, these patients have elevated serum
triglycerides and, in some individuals, increased hepatic triglyceride
secretion (39,
44).
The influence of GH on hepatic metabolism has also been investigated in
GH-deficient states, such as in GH-deficient adults and hypophysectomized
rats. In terms of lipoprotein metabolism, GH treatment of hypophysectomized
rats increases HDL- but decreases LDL-cholesterol levels
(41), increases hepatic VLDL
secretion (14,
58), and increases LDL
receptor expression (2).
Lipoprotein lipase activity was increased in skeletal muscle and heart but was
unchanged in adipose tissue by GH treatment of hypophysectomized rats
(43). On the other hand, GH
treatment of GH-deficient adults decreased adipose tissue lipoprotein lipase
activity (42). Thus the effect
of GH treatment is different depending on the model of investigation and may
also depend on the time course of treatment.
Several hepatic genes that are influenced by GH on a transcriptional level
have been identified, e.g., the GH receptor (GHR), IGF-I, signal transducer
and activator of transcription 5, members of the CYP family, major urinary
proteins, serine proteinase inhibitor 2.1 (SPI2.1), and the prolactin receptor
(26,
27,
34,
38,
47). Also, the short-term
effect of GH on the expression of several hepatic genes in the normal and
aging rat and in hypophysectomized rats has recently been described
(16,
62-64).
However, the long-term effect of GH on hepatic metabolic genes has not
previously been described. Therefore, in this study, we investigated hepatic
gene expression by DNA microarray in mice with chronic elevation of GH. We
conclude that the livers of bGH-transgenic mice display marked changes in the
expression of genes coding for metabolic enzymes and suggest that many of
these changes are mediated via peroxisome proliferator-activated
receptor-
(PPAR
) and sterol regulatory element-binding protein
(SREBP)-1. Moreover, the reduced expression of SREBP-1, despite
hyperinsulinemia, shows that these mice are different from other
insulin-resistant models with respect to expression of SREBP-1 and its
downstream genes.
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MATERIAL AND METHODS
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Animals. In this study, we used 6-mo-old male bGH-transgenic mice
and littermates. The bGH-transgenic mice have been described previously
(20,
50). The mice were housed with
a light cycle of 14 h of light (0500-1900) and 10 h dark (1900-0500) and had
free access to mouse standard chow and tap water (Rat/Mouse Standard Diet;
B&K Universal, Sollentuna, Sweden). The mice were anesthetized with
ketamine hydrochloride (77 mg/kg Ketalar; Parke-Davis, Detroit, MI) and
xylazine (9 mg/kg Rompun; Bayer, Lever-Kusen, Germany) and killed by heart
puncture. The livers used for RNA preparations were excised and immediately
frozen in liquid nitrogen and stored at -135°C. The study was performed
after approval from the regional ethics committee for animal
experimentation.
RNA preparation. Total RNA from livers of four male bGH-transgenic
mice and four male littermate controls were extracted by Tri Reagent (Sigma
Diagnostics, St. Louis, MO) and further purified using an RNeasy Total RNA
Isolation Kit (Qiagen, Valencia, CA) according to the manufacturer's
instructions. The integrity of RNA was examined by agarose gel electrophoresis
and ethidium bromide staining. The total RNA from the four mice in each group
was pooled using equal amounts of RNA from each mouse. Reverse transcription
was performed with Superscript Choice System (GIBCO-BRL, Rockville, MD),
followed by an in vitro transcription using BioArray HighYield Transcript
Labeling Kit (Enzo Diagnostics, Farmingdale, NY) according to the Affymetrix
(Affymetrix, Santa Clara, CA) user manual. After this procedure, the integrity
of the samples was examined by agarose gel electrophoresis and ethidium
bromide staining. The hybridization and washing procedures were performed
using an Affymetrix hybridization oven and fluidics station according to the
Affymetrix user manual. The duplicate microarrays started from the same
livers, but two separate RNA preparations and cDNA syntheses and in vitro
transcriptions were performed. The microarrays were scanned with a
Hewlett-Packard confocal laser scanner and visualized using Affymetrix
Genechip 3.1 software (Affymetrix).
Calculations. The mouse 11ka and 11kb (Affymetrix microassays)
contain 11,000 genes and expressed sequence tags (ESTs) together. To study all
well-known genes, we decided to use both chips, since the well-known genes
were divided onto both chips. To allow cross-comparisons between different
samples, the mean target signal on each microarray was scaled to an average
intensity of 500. Both the mouse 11ka and the mouse 11kb microarrays were run
in duplicates for each group (bGH and control). Each bGH microarray was
compared with each control microarray for either 11ka or 11kb, creating four
comparison files. The differences were selected solely on the difference call
(DC) parameter, determined by an algorithm based on signal intensity and
quality. Only the genes that differed in three or four of the comparisons (DC
3-4) were set as a significant change. The fold change given was calculated as
the average fold change of all comparisons. EST accessions were identified
using the TIGR Mouse Gene Index database and compared with GenBank with NCBI
BLAST.
Real-time PCR. Livers from four transgenic males and four
littermate controls were dissected. Total RNA was extracted with Tri Reagent
(Sigma). First-strand cDNA was synthesized from total RNA using the
Superscript preamplification system (Life Technologies). Real-time (Rt)-PCR
analysis was performed in individual mice (n = 6) with an ABI Prism
7900 Sequence Detection System (Perkin Elmer Applied Biosystems) using
6-carboxyfluorescein- and 6-carboxy-tetramethylrhodamine-labeled fluorogenic
probes. The expression data were normalized against mouse acidic ribosomal
phosphoprotein P0 (M36B4). The SREBP-1 total (including 1a and 1c isoforms),
SREBP-1a, SREBP-2, PPAR
, fatty acid synthetase, hepatic lipase, and
M36B4-specific primers amplified nucleotides 600-648 (GenBank accesion no.
U09103
[GenBank]
), 1053-1120 (acc. no. U09103
[GenBank]
), 1037-1106 (acc. no. X57638), 1053-1120
(acc. no. X13135
[GenBank]
), 1053-1120 (acc. no. X58426), and 986-1059 (acc. no.
X15267
[GenBank]
), respectively (Table
1). The relative expression levels were calculated according to
the formula 2-
CT, where
CT is the
difference in threshold cycle (CT) values between the target and the M36B4
internal control (User Bulletin no. 2, Perkin Elmer).
Serum analysis. Plasma
-hydroxybutyrate (
-HB) and free
fatty acid (FFA) levels were determined before and after a 16-h fast using a
-HB kit (Sigma) and NEFA C kit (Wako Chemicals, Neuss, Germany)
according to the manufacturer's instructions. Plasma insulin was determined
radioimmunochemically with the use of a guinea pig anti-rat insulin antibody,
125I-labeled human insulin as tracer, and rat insulin as standard
(Linco Research, St. Charles, MO). Plasma glucose was determined with the
glucose oxidase method.
Statistics. Values are given as means ± SE. Comparisons
between independent groups were performed with the Mann-Whitney
U-test, and comparisons of repeated measurements within groups were
performed with the Wilcoxon signed rank pair test. P values <0.05
were considered significant.
 |
RESULTS
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Microarray. GH is a potent regulator of metabolism and has been
shown to influence hepatic lipid, cholesterol, and carbohydrate metabolism
(2,
7,
10,
12,
17,
27,
46,
49,
56). However, few molecular
targets for the effect of GH on metabolism in the liver have been identified.
To study the effect of chronic elevation of GH on genes involved in hepatic
metabolism, we performed microarray analysis on pooled RNA from livers of
bGH-transgenic mice and littermate controls. To validate the use of DNA
microarray to detect differences between bGH-transgenic mice and littermates,
we first investigated the expression of well-known GH-regulated genes. In
agreement with previous observations, the elevated GH levels in bGH-transgenic
mice increased the hepatic gene expression of the GHR, IGF-I, and SPI2.1
(35,
40,
70)
(Table 2).
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Table 2. Difference in expression of classic GH-responsive genes between
bGH-transgenic mice and littermate controls
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Several regulated metabolic genes were identified and classified into
regulators of transcription, fatty acid synthesis and oxidation, scavenger
receptors, lipoprotein metabolism, cholesterol metabolism, and carbohydrate
and amino acid metabolism (Tables
3 and
4). The most striking findings
were that the expression of genes involved in all aspects of fatty acid
metabolism were decreased, e.g., fatty acid activation,
-oxidation,
ketone body formation, and fatty acid synthesis and esterification, with the
exception of diacylglycerol acyltransferase (DGAT), which was increased. Also,
SREBP-1 and PPAR
, two important regulators of transcription of genes
involved in fatty acid metabolism, were decreased. Furthermore, genes involved
in amino acid and HDL metabolism showed decreased gene expression.
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Table 3. Difference in expression of genes in lipid metabolism between
bGH-transgenic mice and littermate controls
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Table 4. Difference in expression of genes in lipoprotein, carbohydrate, amino
acid, and cholesterol metabolism between bGH-transgenic mice and littermate
controls
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Rt-PCR. To verify the results found in the microarray experiment,
we performed Rt-PCR on five key genes in six bGH-transgenic mice and six
littermate controls. PPAR
was decreased 2.1 times on the microarray in
the bGH-transgenic mice and 1.6 times in the Rt-PCR
(Fig. 1). SREBP-1 exists in two
different isoforms, SREBP-1a and -1c, which are transcribed from a single gene
by the use of alternate promoters
(24,
54). SREBP-1a is a potent
activator of the cholesterol and lipogenic pathways, whereas SREBP-1c
activates only the lipogenic pathway
(24). SREBP-1 was decreased
2.6 times on the microarray, and the Rt-PCR showed a twofold decrease by use
of primers directed to the common part of the SREBP-1 detecting both SREBP-1a
and -1c (P < 0.05; Fig.
1). However, specific primers for the SREBP-1a isoform showed no
difference between the bGH-transgenic mice and littermate controls
(Fig. 1). Hence, the decrease
in SREBP-1 is due to the decreased expression of SREBP-1c. SREBP-2 showed no
difference in expression level between the bGH-transgenic mice and littermate
controls. Fatty acid synthase and hepatic lipase were decreased 2.5 and 22.2
times, respectively, on the microarray, and Rt-PCR revealed a decrease of 2.4
times for fatty acid synthase and a decrease of 25.3 times for hepatic lipase
(Fig. 1).

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Fig. 1. Real-time PCR verification in individual mice of some of the genes found
differently expressed by microarray. Relative expression is shown in an
arbitrary scale. bGH, bovine growth hormone-transgenic mice; SREBP, sterol
regulatory element-binding protein; PPAR, peroxisome proliferator-activated
receptor- ; FAS, fatty acid synthetase; HL, hepatic lipase. Values are
expressed as means ± SE (n = 6). Comparisons between independent groups
were performed with a Mann-Whitney U-test (*significant
change). P < 0.05 was considered significant.
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Serum analysis. Because the gene expression of enzymes involved in
-oxidation and ketone body formation was decreased, we conducted an
experiment to study the plasma and serum levels of ketone bodies and fatty
acids in response to fasting (Fig. 2,
A and B). In the fed state, the levels of
-HB were undetectable in five of the seven bGH-transgenic mice. Fasting
induced a rise in plasma
-HB levels in the bGH mice but to a markedly
lower level than in littermate controls
(Fig. 2A), indicating
that the hepatic fatty acid
-oxidation and subsequent ketone body
formation were impaired in bGH-transgenic mice. FFA levels were lower in the
bGH-transgenic mice in the fed state, but they were not different from the
littermate controls in the fasted state
(Fig. 2B). The
bGH-transgenic mice were clearly hyperinsulinemic
(Fig. 2C) but showed
normal blood glucose levels (Fig.
2D). Furthermore, bGH-transgenic mice as used in this
study (same strain) had previously been shown to have elevated levels of IGF-I
(bGH 526 µg/l vs. controls 262 µg/l)
(20), T3 (bGH 7.2
pmol/l vs. controls 5.4 pmol/l)
(4), and corticosterone (bGH
745 µg/l vs. controls 199 µg/l)
(4) but decreased levels of
T4 (bGH 9.3 µg/l vs. controls 13.7 µg/l)
(4).
 |
DISCUSSION
|
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In this study, we used DNA microarray to investigate the effect of chronic
elevation of GH on hepatic gene expression in bGH-transgenic mice. Gene
expression of lipogenic enzymes was decreased. We also noted a decrease in the
expression of SREBP-1, which is a potent regulator of lipogenic enzymes,
indicating that decreased expression of SREBP-1 may be responsible for the
decreased gene expression of these enzymes. The expression of genes involved
in fatty acid oxidation and ketone body formation was also decreased in
bGH-transgenic mice. In line with these findings, bGH-transgenic mice had a
reduced ability to form ketone bodies in both the fed and fasted states. This
decrease coincided with decreased gene expression of PPAR
. This finding
suggests that decreased PPAR
expression mediates the downregulation of
the genes involved in fatty acid oxidation and ketone body formation. An
alternative explanation is that enzymes involved in fatty acid oxidation and
ketone body formation are downregulated in bGH-transgenic mice by an increased
action of insulin on the liver. In line with this possibility, the liver seems
to be less affected by the diabetogenic action of GH than is muscle tissue in
GH-transgenic mice (11,
12).
Concerning the validation of our animal model, the gene expressions of GHR,
IGF-I, and SPI2.1 were increased on the microarray, which is in line with
previous reports (35,
40,
70). The decreased gene
expression of enzymes involved in the catabolism of amino acids observed in
the bGH-transgenic mice most likely reflects the known anabolic effects of GH.
Thus, apart from a decreased supply of amino acids for gluconeogenesis and
ketogenesis by the anabolic action of GH in skeletal muscle, GH also decreases
the hepatic expression of genes involved in the catabolism of amino acids.
The expression of SREBP-1 was decreased in bGH-transgenic livers. In
addition, we noted a decreased expression of genes regulated by SREBP-1, i.e.,
the HDL receptor scavenger receptor class B type I (SR-BI)
(31), fatty acid synthetase
(32,
57), ATP-citrate lyase
(51), glycerol-3-phosphate
acyltransferase (GPAT) (15),
stearoyl-CoA desaturase (SCD1)
(57), and spot 14
(33). These findings indicate
that SREBP-1 may be an important mediator of GH's long-term effect on the gene
expression of enzymes involved in fatty acid metabolism.
Recent studies have shown that SREBP-1 is an important mediator of insulin
action, since SREBP-1 mRNA and protein were directly stimulated by insulin in
rat hepatocytes (18) and
introduction of a dominant negative form of SREBP-1 in hepatocytes abolished
insulin's ability to induce transcription of glucokinase
(17). Furthermore,
introduction of a dominant positive SREBP-1 in hepatocytes induced glucokinase
without insulin stimulation
(17), and dominant positive
SREBP-1-transgenic mice did not show a decrease in lipogenic enzymes when
fasted (23). Moreover, in mice
with streptozotocin-induced diabetes, hepatic SREBP-1c was undetectable but
was rapidly induced after insulin administration
(55). The stimulatory effect
of insulin on SREBP-1c has been shown to be mediated by an increase in gene
expression (17,
55). Our finding of decreased
SREBP-1 mRNA expression indicates that SREBP-1 is resistant to the stimulatory
effect of hyperinsulinemia in bGH-transgenic mice, in contrast to other
hyperinsulinemic mouse models such as the ob/ob mouse
(56). Thus the decreased
expression of SREBP-1 may be a direct effect of chronic overexpression of GH
in the liver or, alternatively, an indirect effect via other accompanying
hormonal or metabolic alterations than hyperinsulinemia such as elevated
levels of T3 or corticosterone. It is less likely that SREBP-1
levels decreased via changed hepatic cholesterol levels, because they are
unchanged in these mice (20).
Our findings therefore indicate that the effect of chronic overexpression of
GH is dominant over the effect of hyperinsulinemia in the regulation of
SREBP-1c gene expression.
We observed a contradiction in the GH-mediated regulation of two key
enzymes in the triglyceride biosynthesis; i.e., the gene expression of GPAT
decreased whereas the expression of DGAT increased. A decreased triglyceride
biosynthesis is suggested to occur in these mice by the observations of normal
hepatic triglyceride content and a decreased hepatic triglyceride secretion
rate in bGH-transgenic mice
(20), indicating that the
decreased DGAT gene expression is of less importance for the hepatic
triglyceride synthesis in these mice. The physiological role of DGAT has been
questioned, because the
DGAT-/- mice showed normal
triglyceride formation and amount of adipose tissue
(59). Furthermore, other
enzymes with DGAT activity have recently been identified and cloned
(8).
Expression of several genes involved in lipid metabolism, including fatty
acid activation, peroxisomal and mitochondrial
-oxidation, and
production of ketone bodies, was decreased in bGH-transgenic mice. This
finding coincided with decreased gene expression of PPAR
. PPAR
has been shown to direct the activity of
-oxidation and subsequent
ketone body formation in the liver via changed expression of mitochondrial
3-hydroxy-3-methylglutaryl-CoA synthetase
(48), acyl-CoA oxidase
(28,
66), long-chain acyl-CoA
synthetase (52), and
medium-chain acyl-CoA dehydrogenase
(21). PPAR
also
regulates the expression of SCD1, which mainly converts palmitic acid and
stearic acid to their monounsaturated forms
(36). All of these known
PPAR
target genes showed reduced expression. Moreover, we showed that
bGH-transgenic mice have a reduced ability to produce ketone bodies in both
the fed and fasted states.
GH has previously been shown to decrease the expression of PPAR
and
the effect of peroxisome proliferators on peroxisomal
-oxidation
activity in hepatocytes (7,
64,
68,
69). Furthermore, insulin has
been shown to decrease peroxisomal
-oxidation
(22), indicating that GH may
decrease the expression of enzymes in peroxisomal
-oxidation via
decreased PPAR
expression and via elevated insulin levels.
Glucocorticoids have a stimulatory effect on PPAR
expression
(30), and even though
bGH-transgenic mice have a threefold increase in serum corticosterone levels
(9), the expression of
PPAR
was reduced. This finding suggests that the levels of
glucocorticoids are subordinate to the levels of GH in the regulation of
PPAR
in this mouse model. The decreased expression of genes involved in
-oxidation and formation of ketone bodies, together with a reduced
ability to form ketone bodies in response to fasting where fatty acids are
ample, suggests that that the hepatic fatty acid
-oxidation and
subsequent ketone body formation are impaired in bGH-transgenic mice.
Epidemiological studies of patients with chronic elevation of GH in humans
(acromegaly) indicate that increased levels of GH result in an increased risk
for cardiovascular disease (1).
One explanation for this effect of GH may be major alterations in the
lipoprotein metabolism induced by the hormone
(20). There are several
observations in the present study that connect chronic elevation of GH with
risk factors for atherosclerosis and cardiovascular disease. Thus our data
indicate that the expression of SR-BI is decreased in the bGH-transgenic mice.
Recent studies in mice show that SR-BI deficiency resulted in elevated
HDL-cholesterol levels, reduced biliary cholesterol levels, and drastically
accelerated onset of atherosclerosis
(65). Epidemiological studies
indicate that elevated HDL-cholesterol levels are beneficial. However,
increased HDL levels have to be related to the presumed function of HDL. Thus
the elevated HDL levels in bGH-transgenic male mice
(20) may therefore not be
associated with an increase in reverse cholesterol transport, the transport
that has been suggested to be one reason for the antiatherogenic effects of
HDL. Other factors associated with atherosclerosis and cardiovascular disease
that connect chronic elevation of GH with the development of the diseases are
the reduced gene expression of hepatic lipase
(37,
71) and serum paraoxonase
(25,
53) and the increased gene
expression of serum amyloid A-3 protein
(61).
We conclude that bGH-transgenic mice display marked changes in genes coding
for metabolic enzymes and suggest that many of these hepatic effects by GH are
mediated via PPAR
and SREBP-1. The decreased expression of SREBP-1 and
its target genes indicates that GH may impair this insulin-dependent
pathway.
 |
DISCLOSURES
|
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This work was supported by grants from Swedish Cancer Foundation,
AstraZeneca Research and Development, Swedish Medical Research Council 14291,
the Sahlgrenska University Foundation, Novo Nordisk Foundation, Gustaf V's,
Queen Victoria's Foundation, and the Swedish Heart and Lung Foundation.
 |
ACKNOWLEDGMENTS
|
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We thank Barbro Basta for excellent technical assistance.
 |
FOOTNOTES
|
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Address for reprint requests and other correspondence: B. Olsson, Research
Center, Endocrinology and Metabolism, Dept. of Internal Medicine,
Göteborg Univ., Vita Straket 12, SE-405 30 Goteborg, Sweden (E-mail:
bob.olsson{at}medic.gu.se).
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.
 |
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