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proteomic study revealed that the expressionof liver proteins is affected
sexual dimorphism affects both the level of individual gene expression
and the concerted activities of interconnected genes controlled by
observedboth in the secretionofGHand in theexpressionof its receptor
Biochimica et Biophysica Acta 1812 (2011) 964–973
Contents lists available at ScienceDirect
Biochimica et Bi
j ourna l homepage: www.e lsmore by gender than by nutritional status [2]. Despite 25 years of
intensive studies onNRs, the research in thisfield hasmainly focused on
one sex, primarily males; moreover, in some studies, the sex of the
subjects was not even mentioned.
In this review, first, we summarize the current knowledge on
hepatic, sex-associated roles of individual NRs. Second, we show that
(GHR). For instance, transcription of a liver-specificGHR (ghr1) is higher
in females than in male rats [5]. 17β-Estradiol (E2), by increasing or
feminizing the GH levels [6], may indirectly affect GHR expression: in
fact, E2 treatment induced ghr1 inmale rats; conversely, an ovariectomy
or treatmentwith the antiestrogen, tamoxifen, reduced ghr1 expression
in females [5]. Thus, sexual dimorphism in GH expression is controlled
by testosterone, and sexual dimorphism in the GHR appears to be
indirectly controlled by estrogen. This sets up a sex-dimorphic
Abbreviations:NRs, nuclear receptors; ER, estrogen receptor; AR, androgen receptor;
GR, glucocorticoid receptor; RXR, retinoic X receptor;
peroxisome proliferator activated receptor; TR, thyr
pregnane X receptor; CAR, constitutive androstane rece
☆ This article is part of a Special Issue entitled: Tran
health to disease.
⁎ Corresponding author. Center for Integrative Genom
Génopode, 1015 Lausanne, Switzerland. Tel.: +41 21 692
E-mail address: walter.wahli@unil.ch (W. Wahli).
0925-4439/$ – see front matter © 2011 Elsevier B.V. A
doi:10.1016/j.bbadis.2010.12.023ssion [1], most likely due
duction. Notably, a recent
[4]. This is a major factor in establishing and maintaining sexual
dimorphism in hepatic gene transcription. This dimorphism has beenconsiderable sexual dimorphism in gene expre
to differences in themetabolic needs for reprotract to the liver and ensures that x
processed in the liver before they reac
Thus, the liver is the major organ for
energy-providing metabolic substrat
products. In the liver,members of thenu
of transcription factors can sense fluct
molecules that reflect the body's me
promptly adapt the energy homeostas
changes by modulating the transcripti
range of metabolic response programtics present in food are
ntire circulatory system.
nating the circulation of
the disposal of toxic
eceptor (NR) superfamily
levels of small lipophilic
status; as a result, NRs
e body to environmental
enes involved in a broad
le and male livers show
“interactome” targets selected pathways in the liver, and deregulation
of these pathways may favor the development of sex-biased diseases.
2. Sexual dimorphism in nuclear receptor expression
In the liver, growth hormone (GH) regulates the expression of
different genes. GH is synthesized in the CNS pituitary glands. Its
secretion from the pituitary is subject to testosterone exposure, which
imprints pulsatile GH signaling inmales from neonatal life to adulthood
[3]; in contrast, pituitary secretion of GH is nearly continuous in femaleshormonal axis, w
GH secretion patt
the information
Another rodent,
GH secretion pa
differences in hep
GH axis elicits
LXR, liver X receptor; PPAR,
oid hormone receptor; PXR,
ptor
slating nuclear receptors from
ics, University of Lausanne, Le
41 10; fax: +41 21 692 41 15.
ll rights reserved.Thehepatic portal vein transportsnu fromthegastrointestinal NRs. Finally, we discuss the hypothesis that this sex-dimorphic NR1. IntroductionSex differences in nuclear receptor-regula
Gianpaolo Rando, Walter Wahli ⁎
Center for Integrative Genomics and National Research Center Frontiers in Genetics, Unive
a b s t r a c ta r t i c l e i n f o
Article history:
Received 23 November 2010
Received in revised form 23 December 2010
Accepted 24 December 2010
Available online 4 January 2011
Keywords:
Nuclear receptors
Liver sex dimorphism
Gender dimorphism
Sexual differences
Nuclear receptor crosstalk
Livermetabolism ismarkedl
sexes. The superfamily of nu
by sensing lipid-soluble ho
disease development is favo
actions in males and femal
sexes, andwe propose a first
in the female liver exhibited
provides empirical support
based on a more compensat
receptors from health to disd liver metabolic pathways☆
of Lausanne, Switzerland
x-dimorphic; accordingly, the prevalence of liver diseases is different between
r receptors (NRs) governs the proper expression of key livermetabolism genes
nes and dietary lipids. When the expression of those genes is deregulated,
. However, we lack a comprehensive picture of the differences between NR
Here, we reviewed explorative studies that assessed NR functions in both
p of sex-dimorphic NR expression in the liver. Our analysis suggested that NRs
ss-talk with more liver-protective potential than NRs in male liver. This study
he hypothesis that women are more resilient to some liver diseases than men,
NR network. This article is part of a Special Issue entitled: Translating nuclear
e.
© 2011 Elsevier B.V. All rights reserved.
ophysica Acta
ev ie r.com/ locate /bbad isith species-specific characteristics. For instance, the
ern is particularlymarked in rats [7], wherefore a lot of
regarding sex differences comes from these animals.
the mouse, has a less pronounced sex-dependent
ttern [8] and the human even less [9], despite sex
atic geneexpression are evident also formice [10]. The
several intracellular signaling pathways, including

the activation of a family of transcription factors called STATs (signal
transducer and activators of transcription), which are largely respon-
sible for the sex-dimorphic gene expression in the male liver [11].
Although Stat5b is a major player, it is not by itself responsible for all
the observed sex differences in hepatic gene expression. Furthermore,
the mechanisms of female predominant hepatic gene expression are so
far less clear. Interestingly, some GH-responsive transcription factors
enriched in female liver have been recently described [12].
The surgical disruption of the GH axis (e.g., with a hypophysec-
tomy) caused impaired hepatic expression of some nuclear receptors
in rats, including the estrogen receptor alpha (ERα, NR3A1) [13] and
the glucocorticoid receptor (GR, NR3C1) [14]; this suggested potential
GH-dependent sex-dimorphic expression of these receptors. In
mice, the influence of pituitary hormones on liver gene expression
was recently investigated in both sexes by microarray analysis
following hypophysectomy [15]; 10 pituitary-responsive nuclear
receptors were found in this dataset (Fig. 1). However, only three
receptor genes (namely, errα (NR3B1), errγ (NR3B3), and rxrγ
(NR2B3)) showed differential response to hypophysectomy in the
two sexes, suggesting that, if the pituitary hormones play a regulatory
role in NR expression, other factors might determinate their sex-
dimorphic expression. Those results gave rise to the question of
whether the expression of NRs is really different in male and female
livers. We found that this was indeed the case with a simple cross-
sectional profiling of NR expression in livers of male and female mice
[16]; 17 of the 38 NRs expressed in the liver were sex-dimorphic
(Fig. 1). For instance, rarγ (NR1B3), errβ (NR3B2), and trβ (NR1A2)
were predominantly expressed in male liver, and errγ, rxrγ, and pparγ
(NR1C3) were predominantly expressed in female liver. Interestingly,
for most hepatic sex-dimorphic NR functions, which are discussed
in the following sections, we found no evidence of differential gene
expression in ourmicroarray analysis (Fig. 1 and Section 3). This led to
two non-mutually exclusive conclusions; first, the data in Fig. 1 may
underestimate the global NR sex dimorphism, because it did not take
into account the effects that circadian rhythms, fasting-to-feeding
transitions, or estrous cycles might have on NR expression; second,
sex-dimorphic NR functions might be governed by mechanisms other
than mRNA expression levels (i.e., post-translational modifications).
For instance, we previously found that a fraction of the hepatic
peroxisome proliferator-activated receptor-α (PPARα, NR1C1) pro-
tein was sumoylated preferentially in females [16]. Structural
modeling of the PPARα ligand-binding domain (LBD) revealed that
the agonist-induced change in the LBD conformation caused the
sumoylation-targeted Lys358 residue to move to the surface of the
molecule, making it available for this modification. In fact, sumoyla-
tion of the PPARα LBD triggered the interaction between PPARα and
the LXXLL peptide motif of the GA binding protein-alpha (GABPα),
which was bound to the steroid oxysterol 7α-hydroxylase cyto-
chrome P450 7b1 (cyp7b1) promoter used in the model. Furthermore,
despite the “agonist-like” conformation required for sumoylation,
the thus-modified PPARα recruits the NR corepressor (NCoR [16,17]).
DNA and histone methyltransferases are also recruited, and these
methylate a Sp1-binding site near the GABP sites and histones. These
events resulted in the loss of Sp1-stimulated expression and, thus, the
6
Sex-dimorphic NR expression
Pituitary
response Sex-dimorphic NR functionsM F
prevalence
in males
-de
gnal
The
f hy
965G. Rando, W. Wahli / Biochimica et Biophysica Acta 1812 (2011) 964–973mRNA (log2 M/F)
-8 -6 -4 -2 2 40
N
uc
le
ar
R
ec
ep
to
r
prevalence
in females
Fig. 1. Sexual dimorphism in nuclear receptor expression and function. This microarray
study [16]. Sex differences are expressed as the log2 of the ratio between the absolute si
color is proportional to the prevalence of expression in females (pink) or males (blue).
negative response: arrow down) was observed in a gene expression study on the effect o
indicated (green dots). The text in the right column indicates the appropriate section in wh8
rived data show nuclear receptor mRNA expression levels in the liver from a previous
s obtained in male vs. female livers harvested 2 h after dark (ZT14). The intensity of the
impact of pituitary hormones on NR expression in liver (positive response: arrow up,
pophysectomy in both sexes [15]. Known sex-dimorphic nuclear receptor functions are
ich they are discussed.