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.
- SourceAvailable from: Hervé Guillou[show abstract] [hide abstract]
ABSTRACT: Since it is associated to the obesity epidemic, Non Alcoholic Fatty Liver Disease (NAFLD) has become a major public health issue. NAFLD ranges from benign hepatic steatosis, ie abnormally elevated triglyceride accumulation, to Non Alcoholic Steatohepatitis (NASH) that can lead to irreversible liver damages. The search for pharmacological and dietary approaches to treat or prevent NAFLD has pointed at nuclear receptors as sensible targets. Indeed, nuclear receptors are ligand-sensitive transcription factors that play a central role in hepatic lipid metabolism. Among nuclear receptors, the Liver X Receptor has been identified as an oxysterol receptor. It is involved in the control of various aspects of lipid metabolism that are reviewed in this manuscript. We highlight the role of LXR in the gut-liver axis and the studies that have provided a rationale for strategies specifically targeting the hepatic activity of LXR in NAFLD.Biochemical pharmacology 03/2013; · 4.25 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: It is clear that lipid disorder and inflammation are associated with cardiovascular diseases and underlying atherosclerosis. Nur77 has been shown to be involved in inflammatory response and lipid metabolism. Here, we explored the role of Nur77 in atherosclerotic plaque progression in apoE(-/-) mice fed a high-fat/high cholesterol diet. The Nur77 gene, a nuclear hormone receptor, was highly induced by treatment with Cytosporone B (Csn-B, specific Nur77 agonist), recombinant plasmid over-expressing Nur77 (pcDNA-Nur77), while inhibited by treatment with siRNAs against Nur77 (si-Nur77) in THP-1 macrophage-derived foam cells, HepG2 cells and Caco-2 cells, respectively. In addition, the expression of Nur77 was highly induced by Nur77 agonist Csn-B, lentivirus encoding Nur77 (LV-Nur77), while silenced by lentivirus encoding siRNA against Nur77 (si-Nur77) in apoE(-/-) mice fed a high-fat/high cholesterol diet, respectively. We found that increased expression of Nur77 reduced macrophage-derived foam cells formation and hepatic lipid deposition, downregulated gene levels of inflammatory molecules, adhesion molecules and intestinal lipid absorption, and decreases atherosclerotic plaque formation. These observations provide direct evidence that Nur77 is an important nuclear hormone receptor in regulation of atherosclerotic plaque formation and thus represents a promising target for the treatment of atherosclerosis.PLoS ONE 01/2014; 9(1):e87313. · 3.73 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Type 2 diabetes mellitus is a disorder characterized by insulin resistance and a relative deficit in insulin secretion, both of which result in elevated blood glucose. Understanding the molecular mechanisms underlying the pathophysiology of diabetes could lead to the development of new therapeutic approaches. An ever-growing body of evidence suggests that members of the NR4A family of nuclear receptors could play a pivotal role in glucose homoeostasis. This review aims to present and discuss advances so far in the evaluation of the potential role of NR4A in the regulation of glucose homoeostasis and the development of type 2 diabetes.Diabetes & Metabolism 09/2013; · 2.39 Impact Factor
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Chapter 2: Nur77 modulates hepatic lipid metabolism through suppression of SREBP-1c
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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
Aerts JM, Ottenhoff R, Powlson AS, Grefhorst A, van Eijk M, Dubbelhuis PF, Aten J, Kuipers F,
Serlie MJ, Wennekes T, Sethi JK, O’Rahilly S, and Overkleeft HS. Pharmacological inhibition of
glucosylceramide synthase enhances insulin sensitivity. Diabetes (2007); 56: 1341-1349.
Arkenbout EK, de Waard V, van Bragt M, van Achterberg TA, Grimbergen JM, Pichon B, Pannekoek
H, and de Vries CJ. Protective function of transcription factor TR3 orphan receptor in atherogenesis:
decreased lesion formation in carotid artery ligation model in TR3 transgenic mice. Circulation (2002);
Chao LC, Zhang Z, Pei L, Saito T, Tontonoz P, and Pilch PF. Nur77 coordinately regulates expression of
genes linked to glucose metabolism in skeletal muscle. Mol. Endocrinol. (2007); 21: 2152-2163.
Chen W, Chen G, Head DL, Mangelsdorf DJ, and Russell DW. Enzymatic reduction of oxysterols
impairs LXR signaling in cultured cells and the livers of mice. Cell Metab (2007); 5: 73-79.
Fu Y, Luo L, Luo N, Zhu X, and Garvey WT. NR4A orphan nuclear receptors modulate insulin action
and the glucose transport system: potential role in insulin resistance. J. Biol. Chem. (2007); 282: 31525-
Hong CY, Park JH, Ahn RS, Im SY, Choi HS, Soh J, Mellon SH, and Lee K. Molecular mechanism
of suppression of testicular steroidogenesis by proinflammatory cytokine tumor necrosis factor alpha.
Mol. Cell Biol. (2004); 24: 2593-2604.
Horton JD, Goldstein JL, and Brown MS. SREBPs: activators of the complete program of cholesterol
and fatty acid synthesis in the liver. J. Clin. Invest (2002); 109: 1125-1131.
Kanzleiter T, Schneider T, Walter I, Bolze F, Eickhorst C, Heldmaier G, Klaus S, and Klingenspor M. Evidence
for Nr4a1 as a cold-induced effector of brown fat thermogenesis. Physiol Genomics (2005); 24: 37-44.
Kovalovsky D, Refojo D, Liberman AC, Hochbaum D, Pereda MP, Coso OA, Stalla GK, Holsboer F,
and Arzt E. Activation and induction of NUR77/NURR1 in corticotrophs by CRH/cAMP: involvement
of calcium, protein kinase A, and MAPK pathways. Mol. Endocrinol. (2002); 16: 1638-1651.
Lammi J, Rajalin AM, Huppunen J, and Aarnisalo P. Cross-talk between the NR3B and NR4A families
of orphan nuclear receptors. Biochem. Biophys. Res. Commun. (2007); 359: 391-397.
Levels JH, Lemaire LC, van den Ende AE, van Deventer SJ, and van Lanschot JJ. Lipid composition
and lipopolysaccharide binding capacity of lipoproteins in plasma and lymph of patients with systemic
inflammatory response syndrome and multiple organ failure. Crit Care Med. (2003); 31: 1647-1653.
Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, Blumberg B, Kastner
P, Mark M, Chambon P, and Evans RM. The nuclear receptor superfamily: the second decade. Cell
(1995); 83: 835-839.
Maxwell MA, Cleasby ME, Harding A, Stark A, Cooney GJ, and Muscat GE. Nur77 regulates lipolysis
in skeletal muscle cells. Evidence for cross-talk between the beta-adrenergic and an orphan nuclear
hormone receptor pathway. J. Biol. Chem. (2005); 280: 12573-12584.
Mix KS, Attur MG, Al-Mussawir H, Abramson SB, Brinckerhoff CE, and Murphy EP. Transcriptional
repression of matrix metalloproteinase gene expression by the orphan nuclear receptor NURR1 in
cartilage. J. Biol. Chem. (2007); 282: 9492-9504.
Nakai A, Kartha S, Sakurai A, Toback FG, and DeGroot LJ. A human early response gene homologous
to murine nur77 and rat NGFI-B, and related to the nuclear receptor superfamily. Mol. Endocrinol.
(1990); 4: 1438-1443.
Pei L, Waki H, Vaitheesvaran B, Wilpitz DC, Kurland IJ, and Tontonoz P. NR4A orphan nuclear receptors
are transcriptional regulators of hepatic glucose metabolism. Nat. Med. (2006); 12: 1048-1055.
Perlmann T and Jansson L. A novel pathway for vitamin A signaling mediated by RXR heterodimerization
with NGFI-B and NURR1. Genes Dev. (1995); 9: 769-782.
Philips A, Lesage S, Gingras R, Maira MH, Gauthier Y, Hugo P, and Drouin J. Novel dimeric Nur77
signaling mechanism in endocrine and lymphoid cells. Mol. Cell Biol. (1997); 17: 5946-5951.
Pols TW, Bonta PI, and de Vries CJ. NR4A nuclear orphan receptors: protective in vascular disease?
Curr. Opin. Lipidol. (2007); 18: 515-520.
Repa JJ, Berge KE, Pomajzl C, Richardson JA, Hobbs H, and Mangelsdorf DJ. Regulation of ATP-
binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors alpha and beta. J. Biol.
Chem. (2002); 277: 18793-18800.
Repa JJ, Liang G, Ou J, Bashmakov Y, Lobaccaro JM, Shimomura I, Shan B, Brown MS, Goldstein JL,
and Mangelsdorf DJ. Regulation of mouse sterol regulatory element-binding protein-1c gene (SREBP-
1c) by oxysterol receptors, LXRalpha and LXRbeta. Genes Dev. (2000); 14: 2819-2830.
Schaap FG, Rensen PC, Voshol PJ, Vrins C, van der Vliet HN, Chamuleau RA, Havekes LM, Groen
AK, and van Dijk KW. ApoAV reduces plasma triglycerides by inhibiting very low density lipoprotein-
triglyceride (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis.
J. Biol. Chem. (2004); 279: 27941-27947.
Shimomura I, Matsuda M, Hammer RE, Bashmakov Y, Brown MS, and Goldstein JL. Decreased IRS-2
and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and
ob/ob mice. Mol. Cell (2000); 6: 77-86.
Shimomura I, Shimano H, Horton JD, Goldstein JL, and Brown MS. Differential expression of exons
1a and 1c in mRNAs for sterol regulatory element binding protein-1 in human and mouse organs and
cultured cells. J. Clin. Invest (1997); 99: 838-845.
Wang Z, Benoit G, Liu J, Prasad S, Aarnisalo P, Liu X, Xu H, Walker NP, and Perlmann T. Structure and
function of Nurr1 identifies a class of ligand-independent nuclear receptors. Nature (2003); 423: 555-560.
Wilson TE, Fahrner TJ, Johnston M, and Milbrandt J. Identification of the DNA binding site for NGFI-
B by genetic selection in yeast. Science (1991); 252: 1296-1300.