Nur77 modulates hepatic lipid metabolism through suppression of SREBP1c activity.
ABSTRACT NR4A nuclear receptors are induced in the liver upon fasting and regulate hepatic gluconeogenesis. Here, we studied the role of nuclear receptor Nur77 (NR4A1) in hepatic lipid metabolism. We generated mice expressing hepatic Nur77 using adenoviral vectors, and demonstrate that these mice exhibit a modulation of the plasma lipid profile and a reduction in hepatic triglyceride. Expression analysis of >25 key genes involved in lipid metabolism revealed that Nur77 inhibits SREBP1c expression. This results in decreased SREBP1c activity as is illustrated by reduced expression of its target genes stearoyl-coA desaturase-1, mitochondrial glycerol-3-phosphate acyltransferase, fatty acid synthase and the LDL receptor, and provides a mechanism for the physiological changes observed in response to Nur77. Expression of LXR target genes Abcg5 and Abcg8 is reduced by Nur77, and may suggest involvement of LXR in the inhibitory action of Nur77 on SREBP1c expression. Taken together, our study demonstrates that Nur77 modulates hepatic lipid metabolism through suppression of SREBP1c activity.
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ABSTRACT: Abstract The NR4A subfamily is orphan nuclear receptors that belong to the larger nuclear receptors (NRs) superfamily of eukaryotic transcription factors. The NR4A subfamily includes three members, namely Nur77 (NR4A1), Nurr1 (NR4A2) and Nor1 (NR4A3) which are gene regulators and participate in diverse biological functions. Though the ligands for these receptors are presently unidentified, they are thought to be constitutively active. NR4A acts as molecular switches in gene regulation and their action is increasingly seen to be modulated by complex network of cellular signaling pathways. Members of the NR4A are expressed in tissue-specific fashion which indicates their selective control of various biological processes. Data reveal a host of functions governed by the NR4A subfamily members including general metabolism, immunity, cellular stress, memory, insulin sensitivity and cardiac homeostasis by regulating specific target genes whose products participates in such processes. Moreover, these receptors have a role in the onset and progression of various diseases such as various types of cancer, inflammation, atherosclerosis and obesity. In this review, a concise overview of the current understanding of the important metabolic roles governed by NR4A members including their participation in a number of diseases shall be provided.Journal of Receptor and Signal Transduction Research 08/2014; · 1.63 Impact Factor
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ABSTRACT: The orphan nuclear receptor subfamily 4 group A member 1 (NR4A1) is a transcription factor stimulated by many factors and plays pivotal roles in metabolism, proliferation, and apoptosis. The expression of NR4A1 in Huh7.5.1 cells was significantly upregulated by HCV infection. The silencing of NR4A1 inhibited the entry of HCV and reduced the specific infectivity of secreted HCV particles, but had only minor or no effect on the genome replication and translation, virion assembly, and viral release steps of the virus life cycle. Further experiments demonstrated that the silencing of NR4A1 affected virus entry through pan-downregulation of the expression of HCV receptors SR-BI, Occludin, Claudin-1, and EGFR, but not CD81. The reduced specific infectivity of HCV in the knockdown cells was due to the decreased apolipoprotein E (ApoE) expression. These results explained the delayed spread of HCV in NR4A1 knockdown Huh7.5.1 cells. Thus, NR4A1 plays a role in HCV replication through regulating the expression of HCV receptors and ApoE and facilitates HCV entry and spread.Journal of General Virology 04/2014; · 3.13 Impact Factor
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ABSTRACT: The NR4A subfamily of nuclear receptors consists of three mammalian members: Nur77, Nurr1, and NOR-1. The NR4A receptors are involved in essential physiological processes such as adaptive and innate immune cell differentiation, metabolism and brain function. They act as transcription factors that directly modulate gene expression, but can also form trans-repressive complexes with other transcription factors. In contrast to steroid hormone nuclear receptors such as the estrogen receptor or the glucocorticoid receptor, no ligands have been described for the NR4A receptors. This lack of known ligands might be explained by the structure of the ligand-binding domain of NR4A receptors, which shows an active conformation and a ligand-binding pocket that is filled with bulky amino acid side-chains. Other mechanisms, such as transcriptional control, post-translational modifications and protein-protein interactions therefore seem to be more important in regulating the activity of the NR4A receptors. For Nur77, over 80 interacting proteins (the interactome) have been identified so far, and roughly half of these interactions have been studied in more detail. Although the NR4As show some overlap in interacting proteins, less information is available on the interactome of Nurr1 and NOR-1. Therefore, the present review will describe the current knowledge on the interactomes of all three NR4A nuclear receptors with emphasis on Nur77.Biochimica et biophysica acta. 06/2014;
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Chapter 2: Nur77 modulates hepatic lipid metabolism through suppression of SREBP-1c
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TitleNR4A nuclear receptors in atherosclerosis
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Nur77 modulates hepatic lipid metabolism
through suppression of SREBP-1c activity
Thijs WH Pols1, Roelof Ottenhoff1, Mariska Vos1, Johannes HM Levels2,
Paul HA Quax4,5, Joost CM Meijers2,3, Hans Pannekoek1,
Albert K Groen1, and Carlie JM de Vries1.
Departments of 1Medical Biochemistry, 2Experimental Vascular
Medicine, 3Vascular Medicine, Academic Medical Center, Amsterdam;
4TNO-Quality of Life, Gaubius Laboratory, Leiden; 5Department
of Surgery, Leiden University Medical Center, Leiden, The Netherlands.
Biochem. Biophys. Res. Commun. 2008; 366(4):910-916
NR4A nuclear receptors are induced in the liver upon fasting and regulate hepatic
gluconeogenesis. Here, we studied the role of nuclear receptor Nur77 (NR4A1)
in hepatic lipid metabolism. We generated mice expressing hepatic Nur77 using
adenoviral vectors, and demonstrate that these mice exhibit a modulation of the
plasma lipid profile and a reduction in hepatic triglyceride. Expression analysis of
>25 key genes involved in lipid metabolism revealed that Nur77 inhibits SREBP-
1c expression. This results in decreased SREBP-1c activity as is illustrated by
reduced expression of its target genes stearoyl-coA desaturase-1, mitochondrial
glycerol-3-phosphate acyltransferase, fatty acid synthase and the LDL receptor,
and provides a mechanism for the physiological changes observed in response to
Nur77. Expression of LXR target genes Abcg5 and Abcg8 is reduced by Nur77, and
may suggest involvement of LXR in the inhibitory action of Nur77 on SREBP-1c
expression. Taken together, our study demonstrates that Nur77 modulates hepatic
lipid metabolism through suppression of SREBP-1c activity.
Nur77 in hepatic lipid metabolism
Nuclear receptor Nur77 (NR4A1) belongs together with Nurr1 (NR4A2) and NOR-1
(NR4A3) to the NR4A subfamily of the nuclear receptor superfamily. NR4A nuclear
receptors consist, like most other nuclear receptors, of an N-terminal activating-
function-1 domain, a central DNA binding domain, and a C-terminal ligand-binding
domain (LBD) (Mangelsdorf et al., 1995). It has been demonstrated that the ligand
binding pocket of Nurr1, located within the LBD domain, is filled with bulky side-
chains of hydrophobic amino acids (Wang et al., 2003). Although an induced fit of
at present unknown ligands may not be excluded, it is very well possible that all
three NR4A nuclear receptors are regulated independent of ligand binding to the
LBD. Nur77 is a so-called ‘immediate-early response gene’ and is rapidly induced in
response to various stimuli, among which growth factors, inflammatory stimuli and
mechanical stimuli (Pols et al., 2007).
Nur77 initiates gene transcription by binding the so called NGFI-B consensus
response element (NBRE; AAAGGTCA) (Wilson et al., 1991). Furthermore,
Nur77 can form homo- or heterodimers with NR4A subfamily members
or with Retinoid X Receptor (RXR), to bind the Nurr1 response element
(NurRE; TGATATTTn6AAATGCCA) or the DR5 consensus response element
(GGTTCACCGAAAGGTCA), respectively (Perlmann and Jansson, 1995; Philips
et al., 1997). In addition to directly modulating transcription, NR4A nuclear
receptors have been described to trans-repress other transcription factors, such as
E26 transformation specific sequence (ETS-1), nuclear factor κ beta (NFκB) and
estrogen related receptor-1 (ERR1) (Mix et al., 2007; Hong et al., 2004; Lammi et
Nur77 regulates distinct cellular processes in a tissue-specific manner. For
example, we have previously demonstrated that Nur77 is expressed in atherosclerotic
lesions and inhibits neointima formation (Pols et al., 2007). More recently, Nur77
has been shown to regulate lipolysis, energy expenditure, and glucose metabolism
in skeletal muscle, to enhance insulin sensitivity in 3T3-L1 cells, and to increase
energy expenditure in murine brown adipocytes (Maxwell et al., 2005; Chao et al.,
2007; Fu et al., 2007; Kanzleiter et al., 2005).
The liver exhibits a key regulatory function in metabolism as it controls the
regulation of both glucose and lipid homeostasis. Nur77 is expressed in human
adult liver (Nakai et al., 1990), and has been shown to regulate gluconeogenesis
(Pei et al., 2006). In the current study we demonstrate, to our knowledge for the
first time, that Nur77 modulates hepatic lipid metabolism by repressing SREBP-1c
Materials and Methods
Full-length human Nur77 cDNA (GenBank D49728) was inserted into replication-
defective adenoviruses expressing cDNAs under control of the cytomegalovirus
promoter. The adenoviruses were purified by CsCl gradient centrifugation as
described before (Arkenbout et al., 2002).
Animal care and experimental procedures were approved by the Animal Experimental
Committee at our institute. Male 10-12 weeks old C57Bl/6 mice (n=6 per group; Charles
River Laboratories, Wilmington, MA) were fed a standard chow diet (Special diet
services, Witham, Essex, UK). Hepatic overexpression of Nur77 in mouse liver was
achieved by intravenous injection of recombinant adenovirus as described previously
(Schaap et al., 2004). Mice were sacrificed two days after adenoviral treatment, after
fasting for 4 hours. The liver was dissected and part of the liver was fixed in formalin
for immunohistochemistry, a part was used for lipid extraction, and a part was used
for RNA extraction. Triglycerides and cholesterol were extracted from mouse liver as
Gene symbol, GenBank no., primer sequence
Human Nur77 NM_002135.3
Fw: 5’- GTTCTCTGGAGGTCATCCGCAAG -3’
Rv: 5’- GCAGGGACCTTGAGAAGGCCA -3’
Fw: 5’- TCGGAGCGCAATATGAAGGT -3’
Rv: 5’-AAAAGGAAGACGACGGAGCC -3’
Fw: 5’- AGAAAGACCACGGAGGACGA -3’
Rv: 5’-CCCGCAGCCACGATGT -3’
Fw: 5’- TCCCGTGGTCTCCATTGAG -3’
Rv: 5’-CCACCCCAGAGAG GAATGAG -3’
Fw: 5’- CCTTAACGTGGGCCTAGTC-3’
Rv: 5’- TGTCCAGTTCGCACATCTC-3’
PrimerBank ID if applicable
Supplementary Table 1. Gene-specific primers for semi-quantitative real time RT-PCR analysis.
Nur77 in hepatic lipid metabolism
Gene symbol, GenBank no., Primer sequencePrimerBank ID if applicable
Fw: 5’-TCAAGAGAGGCTTGGCTAGCTT -3’
Uptake and Transport
Supplementary Table 2. Target genes hepatic lipid metabolism.
Gene-specific primers for semi-quantitative real time RT-PCR analysis.
described earlier (Aerts et al., 2007), and analyzed with a colorimetric assay (Wako
Chemicals, Neuss, Germany). Plasma cholesterol and triglyceride concentrations in
the main lipoprotein classes were determined using high performance gel filtration
chromatography (HPGC) as described before (Levels et al., 2003).
RNA extraction, cDNA synthesis, and RT-PCR analysis
RNA was extracted from mouse liver using Trizol (GIBCO-Invitrogen Life
Technology, Breda, The Netherlands), after which cDNA was synthesized from 1 μg
total RNA (iScript; Biorad, Veenendaal, The Netherlands). Semi-quantitative real-
time RT-PCR was performed using iQ SYBR-Green Super-Mix in the MyiQ RT-PCR
system (Biorad) using gene-specific primers. Primer sequences (see Supplementary
Table 1 and Supplementary Table 2) were obtained from literature, designed
(Beacon designer 3, Premier Biosoft International, Palo Alto, CA), or obtained from
the Harvard Primer Bank (pga.mgh.harvard.edu/primerbank). All expression levels
were corrected for expression of the housekeeping gene cyclophillin A. The heat
map was generated using Spotfire software (Spotfire Inc., MA, USA).
Immunohistochemistry was perfomed using the M210 Antibody against Nur77 (Santa
Cruz, Biotechnology, Santa Cruz, CA), a biotin-labeled goat-anti-rabbit IgG secondary
antibody incubation (DAKO, Glostrup, Denmark), followed by streptavidin-HRP
(DAKO) and AEC (Sigma, Zwijndrecht, The Netherlands) detection.
All data are shown as mean ± standard error (SD). The nonparametric Mann-Whitney
U test was used to calculate statistical significance. P values less than 0.05 were
considered statistically significant.
Adenoviral expression of Nur77 in C57Bl/6 mice
To achieve hepatic overexpression of Nur77 in mouse liver, we injected chow-
fed C57Bl/6 mice via the tail vein with control adenovirus (Ad.Mock) or with
adenovirus encoding human Nur77 (Ad.Nur77). Starting plasma cholesterol and
triglyceride levels, as well as liver weight (Wt), body Wt, and food intake did not
reveal significant changes between the two groups (Table 1). Mice were sacrificed
two days after adenoviral injection, after which livers were dissected and used for
immunohistochemistry, lipid analysis, and RNA expression analysis. We detected
Nur77 in hepatic lipid metabolism
hepatic mRNA expression of the Nur77 transgene in all mice injected with Ad.Nur77
virus (Figure 1A). Immunohistochemistry demonstrated enhanced expression
of Nur77 protein, predominantly in the nuclei of liver cells, in mice treated with
Ad.Nur77 virus as compared to Ad.Mock-treated animals (Figure 1B). In addition,
expression of enolase 3 (Eno3) and fructose-1,6-bisphosphatase 2 (Fbp2), two direct
target genes of Nur77 in mouse liver (Pei et al., 2006), was increased in livers of
mice with enhanced expression of Nur77 (7.3 and 18.0 fold induction, respectively;
Figure 1C), which confirmed expression of functional Nur77 protein.
expression of Nur77 in
C57BL/6 mice. (A) Hepatic
mRNA expression of the
in animals intravenously
injected with Ad.Nur77 or
Ad.Mock virus. (B) Nur77
protein in livers of mice
injected with Ad.Mock (left
panel) and Ad.Nur77 virus
(right panel). Insets in the
right upper corners show a
higher magnification. (C)
Hepatic mRNA expression
of Eno3 (left panel) and
Fbp2 (right panel) of mice
overexpressing Nur77 (Ad.
Nur77; white bars) and of
control animals (Ad.Mock;
black bars). Result represent
mean±SD, n=6; *statistically
23.6 ± 0.5
3.05 ± 0.34
0.87 ± 0.10
23.5 ± 0.4
3.1 ± 0.5
1.2 ± 0.1
5.3 ± 0.2
24.3 ± 0.5
3.18 ± 0.20
0.91 ± 0.11
24.2 ± 0.5
3.3 ± 0.4
1.4 ± 0.1
6.0 ± 0.6
Body Wt (g)
Total Plasma Cholesterol (mmol/L)
Total Plasma Triglycerides (mmol/L)
Body Wt (g)
Food intake, day -1 to 2 (g/day/mouse)
Liver Wt (g)
Liver Wt (% of body Wt)
Table 1. Physiological parameters of mice overexpressing hepatic Nur77 (Ad.Nur77) and of
control animals (Ad.Mock).
Results represent mean±SD, n=6. Wt Weight.
Nur77 modulates the plasma lipid profile
The plasma lipid profile analyzed two days after adenoviral treatment by HPGC
revealed that Nur77 induced a redistribution of plasma cholesterol and trigylceride.
Plasma HDL-cholesterol showed a moderate 12% reduction in response to Nur77
(2.15 ± 0.18 mmol/L vs. 2.52 ± 0.25 mmol/L in controls; Table 2). Concomitantly,
plasma LDL-cholesterol was 98% increased in animals with hepatic expression
of Nur77 as compared to control animals (0.79 ± 0.15 vs. 0.40 ± 0.03 mmol/L,
respectively; Table 2). In addition, plasma LDL-triglyceride was 67% increased in
mice overexpressing hepatic Nur77 as compared to control animals (0.55 ± 0.11
mmol/L vs. 0.33 ± 0.03 mmol/L, respectively; Table 2). Total plasma triglyceride
and cholesterol was found similar between the two groups.
Nur77 reduces hepatic triglyceride levels
We next analyzed cholesterol and triglyceride content of the liver. Hepatic cholesterol
level did not change in response to hepatic expression of Nur77 (Figure 2A). Hepatic
triglyceride levels, however, were reduced in response to expression of Nur77 (1.5 ±
0.3 vs. 1.9 ± 0.3 µmol/g, respectively; Figure 2B).
Plasma Cholesterol (mmol/L)
0.12 ± 0.06
0.13 ± 0.02
0.40 ± 0.03
0.79 ± 0.15 *
2.52 ± 0.25
2.15 ± 0.18 *
3.02 ± 0.31
3.07 ± 0.17
Plasma Triglycerides (mmol/L)
0.64 ± 0.25
0.47 ± 0.06
0.33 ± 0.03
0.55 ± 0.11 *
0.05 ± 0.02
0.06 ± 0.02
1.02 ± 0.25
1.08 ± 0.16
Results represent mean±SD, n=6; *statistically significant, P<0.05.
Table 2. Plasma lipid profile of animals overexpressing hepatic Nur77 (Ad.Nur77) and of control
Cholesterol (μmol/g wet liver)
Triglycerides (μmol/g wet liver)
Figure 2. Nur77 reduces
hepatic triglyceride levels.
(A) Hepatic cholesterol
levels, and (B) hepatic
triglyceride levels of mice
Nur77 (Ad.Nur77; white
circles) and of control
animals (Ad.Mock; black
significant, P<0.05; NS not
Nur77 in hepatic lipid metabolism
Nur77 modulates hepatic gene expression
We next wished to understand the mechanism underlying the altered plasma lipid
profile and the reduced hepatic triglyceride content in response to hepatic expression
of Nur77. For this purpose, we performed mRNA expression analysis of a panel
of genes involved in hepatic lipid metabolism encoding transcription factors,
apolipoproteins, enzymes, and proteins involved in the uptake and transport of lipids
(see Supplementary Table 2). We visualized mRNA expression of individual mice in
a heat map, shown in Figure 3A. Even though we did not observe induction of genes
by Nur77 in our selection, a number of genes were found to be downregulated upon
expression of Nur77, suggesting activity of trans-repression mechanisms.
Nur77 downregulated genes encoding the transcription factors Sterol regulatory
element-binding binding protein-1 (SREBP-1), Retinoid X receptor-α (RXRα), and
the Farnesoid X receptor (FXR) (Figure 3B). Other genes observed downregulated
by expression of Nur77 are Stearoyl-coA desaturase-1 (Scd1), Hepatic lipase (Lipc),
Low density lipoprotein receptor (Ldlr), ATP-binding cassette subfamily G member 5
(Abcg5), Abcg8, Apolipoprotein-B (ApoB) and ApoE (Figure 3B).
In our initial selection of genes, SREBP-1 expression is most strongly suppressed
by Nur77. SREBP-1 directly controls transcription of multiple genes involved
in triglyceride synthesis, and is considered a major regulator of the latter process
(Horton et al., 2002). Our initial selection of genes comprised two direct target genes
of SREBP-1, Ldlr and Scd1, which are both downregulated upon expression of Nur77,
confirming decreased SREBP-1 activity in the livers of mice expressing Nur77.
Nur77 inhibits SREBP-1c and its downstream genes
To investigate whether the observed decrease in SREBP-1 expression involved
attenuated SREBP-1c expression, the major isoform of SREBP-1 in liver
(Shimomura et al., 1997), we analyzed expression of the two isoforms of SREBP-1.
SREBP-1a expression was not modulated by Nur77, but we did observe that Nur77
downregulated expression of SREBP-1c mRNA 6.3 fold (Figure 4A).
The expression of SREBP-1c target genes Scd1 and Ldlr (Figure 3B) decreased
in response to Nur77 and to validate the effect of reduced SREBP-1c expression,
we analyzed expression of three additional SREBP-1c downstream genes crucial in
triglyceride synthesis: mitochondrial glycerol-3-phosphate acyltransferase (Gpam),
fatty acid synthase (Fas), and acetyl-CoA carboxylase-α (Acaca). Although Acaca
was not significantly downregulated by Nur77 (P=0.06), we did observe that Nur77
downregulated expression of Gpam and Fas (Figure 4B), which further confirmed
decreased SREBP-1c activity in response to Nur77.
Using a gain-of-function-approach, we demonstrate that hepatic expression of Nur77
modulates the plasma lipid profile and decreases hepatic triglyceride content. Analysis
of mRNA expression of a panel of genes involved in hepatic lipid metabolism revealed
that Nur77 suppresses SREBP-1c gene expression, and provides an explanation for
the physiological changes observed.
The decrease in SREBP-1c activity and its downstream lipogenic enzymes Scd1,
Fas, and Gpam explains the reduced hepatic triglyceride levels observed in response
to Nur77. The increase in circulating LDL-triglycerides and LDL-cholesterol in
animals expressing Nur77 in the liver is explained by reduced expression of the Ldlr,
another SREBP-1c target gene.
Figure 3. Nur77 modulates hepatic gene expression. (A) Heat map of mRNA expression of genes
involved in lipid metabolism in livers of mice overexpressing hepatic Nur77 (Ad.Nur77) and of
control animals (Ad.Mock) shown as fold change from the median. The average fold change in mRNA
expression is indicated at the right side of the heat map. (B) Bar graphs of mRNA expression of genes
involved in lipid metabolism in livers of mice overexpressing hepatic Nur77 (Ad.Nur77) and of control
animals (Ad.Mock). Only SREBP1 mRNA expression of control animals (Ad.Mock) is shown. Result
represent mean±SD, n=6; *statistically significant, P<0.05.
mRNA expression [AU]
0 50 100150200250
Fold change from median
Nur77 in hepatic lipid metabolism
We searched for consensus NBRE-, NurRE- and DR5 response elements within
the first 2 kilobase pairs promoter region of genes downregulated by Nur77, and found
that only the Lipc gene contains a consensus NBRE sequence (at -76bp). This may
indicate that Nur77 regulates most of the selected genes either through poorly defined
response elements, or by trans-repression of other transcription factors.
Nur77 inhibits expression of Abcg5 and Abcg8 (Figure 3B), well known target
genes of LXR, indicating that the activity of LXR may be reduced (Repa et al.,
2002). This may reflect trans-repression of LXR by Nur77, and could provide
an explanation for reduced expression of SREBP-1c, also a target gene of LXR,
in response to Nur77 (Repa et al., 2000). Further study, however, is required to
determine the precise mechanism by which Nur77 inhibits SREBP-1c expression.
Of note, hepatic mRNA levels of both LXRα and LXRβ were unaffected by
expression of Nur77 (Figure 3B), which demonstrates that Nur77 does not reduce
the transcriptional activity of LXR by inhibiting expression levels of these nuclear
receptors. Also Sterol 27-hydroxylase (Cyp27a1) and Cholesterol 25-hydroxylase
(Ch25h), enzymes involved in the production of oxysterols, physiological LXR
ligands, were not modified by Nur77 (Figure 3B), which eliminates reduced
LXR activity through changes in expression levels of these enzymes (Chen et al.,
It has been described that glucagon inhibits insulin-induced SREBP-1c expression,
although at present the exact regulatory pathways remain to be elucidated (Shimomura
et al., 2000). Since expression of Nur77 is, amongst others, regulated by cAMP
second messenger pathways in tissues such as pituitary, skeletal muscle and, as has
most recently been shown, in liver, our findings may indicate that Nur77 contributes
to glucagon-induced downregulation of SREBP-1c expression (Kovalovsky et al.,
2002; Maxwell et al., 2005; Pei et al., 2006).
Figure 4. Nur77 inhibits SREBP1c and its downstream genes. (A) Hepatic mRNA expression of
SREBP-1a and SREBP-1c, and (B) hepatic mRNA expression of SREBP-1c target genes Fas, Gpam,
and Acaca of mice overexpressing hepatic Nur77 (Ad.Nur77; white bars) and of control animals (Ad.
Mock; black bars). Result represent mean±SD, n=6; *statistically significant, P<0.05.
mRNA expression [AU]
mRNA expression [AU]
Recently, Pei et al. reported that Nur77 contributes to enhanced hepatic
gluconeogenesis observed in diabetic mice (Pei et al., 2006). If we extend our findings
to type II diabetes, Nur77 may also have beneficial properties in the latter disease.
High blood glucose levels and high insulin levels are observed in type II diabetes,
but insulin fails to properly stimulate glucose clearance from plasma by peripheral
tissue. Hepatic SREBP-1c-mediated lipogenesis, however, remains (over-)stimulated
by insulin in this pathology, promoting hepatic steatosis (Shimomura et al., 2000).
From this angle, we speculate that enhancing the expression and/or activity of Nur77
in the liver may be beneficial in type II diabetes with regard to its inhibitory effect on
SREBP-1c activity. Dedicated animal models are required to explore this hypothesis,
and potential unfavorable effects of Nur77, such as a potential increase in plasma
LDL and/or glucose levels, should be taken into consideration.
In summary, we demonstrate that Nur77 reduces hepatic triglyceride and
modulates the plasma lipid distribution. These physiological changes are explained
by decreased expression of SREBP-1c downstream genes, resulting from suppression
of SREBP-1c activity by Nur77.
Nur77 in hepatic lipid metabolism
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