Steroids 133 (2018) 38–43

Contents lists available at ScienceDirect

Steroids
journal homepage: www.elsevier.com/locate/steroids

Estrogens and female liver health T

a a,b,⁎
Karen L. Chen , Zeynep Madak-Erdogan
a
Division of Nutritional Sciences, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA
b
Department of Food Science and Human Nutrition, University of Illinois, Urbana-Champaign, Urbana, IL 61801, USA

A R T I C L E I N F O A B S T R A C T

Keywords: Due to declining estrogen levels during menopause, NAFLD prevalence is higher in postmenopausal women
Microbiome compared to in premenopausal women or in men. Postmenopausal women are more susceptible to weight gain,
Estrogens fat redistribution and dyslipidemia, all major hallmarks of metabolic syndrome associated with increased NAFLD
Botanical estrogens risk. Gut microbiota plays important roles in development of gastrointestinal tract, metabolism and immunity.
Dietary supplements
Host-microbe interactions allows regulation of a wide range of pathways that affect healthy and diseased
Estrogen receptor
physiology. Recent advances in – omics technologies, such as microbiome, transcriptome and metabolome
Metabolism
Menopause analysis, provided evidence that estrogens and intestinal microbiota (IM) can collectively influence obesity,
Non-alcoholic fatty liver disease inflammatory disease, diabetes, and cancers. By understanding underlying mechanisms of estrogens and mi-
crobiota crosstalk, we might design dietary and pharmacological interventions to alleviate the metabolic syn-
drome and NAFLD.

1. Metabolic health of postmenopausal women and hormone
replacement therapy
The prevalence of obesity among women is increasing, yet there is
no such significant trend for men. Currently, 70% of postmenopausal
women are overweight or obese. According to 2003–2012 National
Health and Nutrition Examination Survey (NHANES) data, metabolic
syndrome is present in about 34% of the population and the rates of
metabolic syndrome is increasing among postmenopausal women [1,2].
Metabolic syndrome is defined as a collection of metabolic pathologies
that increase an individual’s risk of heart disease, diabetes, cancer and
nonalcoholic fatty liver disease (NAFLD) [3,4]. National Heart, Lung,
and Blood Institute (NHLBI) and the American Heart Association (AHA)
identified risk factors for metabolic syndrome as a fasting glucose
≥100 mg/dL, blood pressure ≥130/85 mm Hg, triglycerides
≥150 mg/dL, HDL-C < 40 mg/dL, and waist circumference ≥102 cm
in men or ≥88 cm in women [5]. Metabolic syndrome is diagnosed if
an individual has 3 out of 5 of these risk factors. In addition, having
these symptoms is not associated with mortality in older men, yet
elevated glucose or low HDL levels are strongly associated with mor-
tality in older women [6].
Estrogens, which are necessary for the development and function of
reproductive tissues, have many beneficial effects in diverse, non-re-
productive target tissues, such as liver, fat pads, bone and vasculature.
The loss of these benefits and the development of obesity after meno-
pause highlights the estrogen receptor, especially the receptor subtype
ERα, as a relevant therapeutic target. These effects, including insulin
resistance and altered glucose homeostasis, can be reversed by estradiol
(E2) treatment [7,8]. The American Association of Clinical En-
docrinologist, the American College of Endocrinology [9], the North
American Menopause Society [10] and the Endocrine Society [11] re-
cognize the metabolic benefits of HRT in their guidelines but do not
recommend HRT use for prevention or treatment of these symptoms
due to insufficient data and potential risks. Currently, HRT is only
prescribed to women who display clinical symptoms, is given at the
lowest dose possible, and is continued only as long as the clinical
symptoms are present. Due to potential risks associated with these
products, they are not used long-term or for prevention. Moreover, the
patient needs to be constantly monitored by a general practitioner to
catch any problems that might arise due to HRT use. Hence, there re-
mains a critical need for safer alternatives that target the signaling
pathways of the estrogen receptor (ER) in ways that maintain the
postmenopausal health of metabolic tissues without stimulating re-
productive tissues.
Current HRT typically consists of an estrogen or estrogen in com-
bination with a progestin, and may be taken to relieve hot flashes or to
treat osteoporosis. Though the initial reason a woman would take HRT
are usually not metabolic, there are many metabolic benefits to HRT

Abbreviations: ER, estrogen receptor; IM, intestinal microbiota; LPL, lipoprotein lipase; LPS, lipopolysaccharide; ODMA, O-desmethylangolensin; NAFLD, non-alcoholic fatty liver
disease
⁎
Corresponding author at: Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, 905 S. Goodwin Ave, Urbana, IL 61801, USA.
E-mail address: zmadake2@illinois.edu (Z. Madak-Erdogan).

https://doi.org/10.1016/j.steroids.2017.10.015
Received 6 October 2017; Received in revised form 23 October 2017; Accepted 28 October 2017
Available online 01 November 2017
0039-128X/ © 2017 Elsevier Inc. All rights reserved.
K.L. Chen, Z. Madak-Erdogan
including diminishing insulin resistance and improving glucose home-
ostasis [7,8]. HRT has also been shown to favorably influence liver
enzymes and potentially lower liver fat accumulation in women with
type 2 diabetes [12]. However, though HRT has many metabolic ben-
efits, they have been shown to increase risks of certain cancers in-
cluding breast cancer and endometrial cancers [13–16]. Therefore, it is
essential to find safer alternatives to HRT such as novel and synthetic
estrogens that can maintain the health of non-reproductive tissues
without stimulating reproductive tissues.
Selective estrogen receptor modulators (SERMs) are compounds
that can bind to estrogen receptors and can exert agonistic or antag-
onistic activity. Bazedoxifene (BZA) is one such SERM that has estrogen
agonist activity in bone and reduces osteoporosis while possibly having
antagonistic activity in the breast and uterus [17,18]. In mice, the an-
tagonistic effects of BZA in the mammary gland can block E2 and in-
hibit the growth of tamoxifen sensitive and resistant tumors [19]. In cell
culture models conjugated estrogen (CE) was much less potent in in-
ducing breast cancer cell proliferation, and BZA entirely suppressed this
effect [20]. Although classic HRT uses an estrogen and progestin in
combination, replacing progestin with SERMs could more effectively
prevent side-effects. This new combination of estrogen and SERM has
been described as the tissue-selective estrogen complexes (TSECs). Most
notably, the TSEC comprised of CE and BZA has been shown to prevent
osteoporosis with minimal effects on reproductive organs [21–23]. This
combination was approved by the FDA for the prevention of post-
menopausal osteoporosis and the treatment of moderate-to-severe va-
somotor symptoms caused by menopause. Recently, the possibility of
this TSEC in preventing metabolic disorders is beginning to be explored.
It has been shown that the TSECs prevent visceral adiposity and had a
significant impact on body weight increase compared to control in
ovariectomized mice [24,25]. CE + BZA caused a significant decrease
in both uterine and mesenteric white adipose tissue (WAT), but did not
influence the uterine weight, which CE only and E2 treatments did
[25]. TSEC decreases serum leptin levels, leptin/adiponectin ratio, and
levels of thiobarbituric acid reactive substances (TBARS) compared to
control mice suggesting normalization of serum adipokines and sys-
temic inflammation [24]. Furthermore, the TSEC decreased hepatic
fatty acid synthase (FAS) enzymatic activity [24] and significant de-
creases in liver lipid deposition [25] suggesting benefits to liver health.
2. NAFLD and estrogens
NAFLD is the most common form of chronic liver disease in the
United States and is characterized by histologic hepatitis in the absence
of alcohol abuse [26]. Though simple steatosis is considered benign,
steatosis of the liver can progress to the more serious conditions of
nonalcoholic steatohepatitis (NASH) and cirrhosis [27,28]. Population
studies have demonstrated that while premenopausal women have less
NAFLD compared to men, postmenopausal women have higher in-
cidences of NAFLD than men [29–36], which suggests a protective role
for estrogens. The decrease in estrogens due to the onset of menopause
makes postmenopausal women more susceptible to weight gain, fat
redistribution to abdominal areas, dyslipidemia, and insulin resistance,
all of which are major hallmarks of metabolic syndrome and are asso-
ciated with NAFLD [37–39]. Hormone replacement therapy (HRT) use
reduces NAFLD incidence in postmenopausal women [35,40]. Use of
Tamoxifen, a selective estrogen receptor modulator, increases NAFLD
incidence [41–43]. In addition, both the aromatase knock-out mice
[44], which are devoid of endogenous estrogens, and ERα knock-out
mice [45] had hepatic steatosis. All this evidence suggest a role for ERα
signaling and estrogen deficiency in NAFLD progression in both human
and mice.
The pathogenesis of NAFLD is complex, and there are significant
links between NAFLD and abnormal lipid metabolism as seen in obesity
and metabolic syndrome. The prevalence of NAFLD increases with in-
creasing body mass index (BMI), with the rates of steatosis and
39
Steroids 133 (2018) 38–43
steatohepatits at 65% and 20% respectively in obese individuals (BMI
30.0–39.9 kg/m2) and 85% and 40% respectively in extremely obese
patients (BMI ≥ 40 kg/m2) [46]. The prevalence of NAFLD is about
69% in patients with type 2 diabetes mellitus (T2DM) [47]. Risk factors
for NAFLD include dietary fat consumption, insulin resistance, elevated
serum free fatty acids, excess visceral adiposity, and pro-inflammatory
markers [48]. These factors contribute to the accumulation of excessive
hepatic fat and oxidative stress, that are components of the “two-hit
hypothesis” that explain disease etiology [49–51]. Therefore, targeting
one or both of these factors may be beneficial in treating NAFLD as
there are currently no FDA approved therapies for NAFLD.
The present Dietary Guidelines indicate that more than 35% of daily
energy consumed by Americans is from fat, particularly saturated fats,
and added sugar [52]. Excess consumption of saturated fat and sugar
contributes to increased body fatness and to the progression of chronic,
low-level inflammation, thus, adversely impacting hepatic health and
aggravating chronic diseases such as diabetes and hepatocellular car-
cinogenesis. Hepatic cancer risk increases with the progression into
NASH, which accounts for 20–25% of patients with NAFLD [53]. Since
saturated fatty acids are not a priority substrate for β-oxidation, they
are a poor source of energy, and are directed toward storage in the liver
[54]. Saturated fatty acids increase endoplasmic reticular stress and free
radical production in mitochondria, which promotes the cellular da-
mage and eventually, development of NASH [55]. Fructose, which is a
component of sucrose, is a highly lipogenic nutrient, enhancing hepatic
triglyceride accumulation through the de novo lipogenesis pathway
[56]. Therefore, the components of Westernized diet disrupts lipid
homeostasis and oxidative balance in the liver and enables the onset
and the progression of NAFLD.
3. Mechanisms of metabolic regulation by estrogens
In humans, there are three major estrogens endogenous to the
human body. These are estrone (E1), 17β-estradiol (E2), and estriol
(E3) with E2 being the most potent [57]. Estrogens are derived from
cholesterol by reactions catalyzed by the P450 aromatase [57]. E2 has
the greatest affinity for estrogen receptors and a higher bioactivity [58].
Several tissues are able to generate estrogens in humans including the
reproductive organs of both males and females, the liver, osteoblasts,
muscle cells, skin, and adipose tissue [59]. In premenopausal women,
the ovaries produce the majority of the estrogen released into circula-
tion [57]. However, after menopause, ovaries stop functioning, dra-
matically decreasing the concentrations of estrogen in the body. Es-
trogen synthesis continues in adipose tissue and adipose tissue-derived
estrogen accounts for most of the circulating estrogens in post-
menopausal women [60]. A longitudinal study showed that trends in
obesity and hormone levels in women differed by menopausal status
[61]. Obese and overweight women had significantly lower con-
centrations of estradiol than non-obese premenopausal women how-
ever, this trend was reversed after menopause where obese and over-
weight women have higher estradiol levels than non-obese women, due
aromatization of estrogens in adipose tissue.
The molecular mechanism of action of estrogens in each tissue is
determined (a) by the ER composition of the tissue; (b) by the com-
position of coregulators and partnering transcription factors, (c) and
notably, as we and others have shown, also by the activation of genomic
vs. non-genomic pathways by estrogens. Our previous studies showed that
reproductive tissues, including endometrium and the mammary gland,
which express dominantly ERα, are not stimulated by ligands that
preferentially activate non-genomic ER signaling [62–64]. These tissues
rely mostly on genomic signaling for the maintenance and proliferation
of these tissues and the cancers that arise in them [62,64]. Studies in-
volving mice expressing membrane-only ERα (MOER) showed defects
in uterus and mammary gland development [65]. Interestingly, liver
defects associated with lipid metabolism observed in ERα knockout
mice were not found in MOER mice [66,67], suggesting that membrane
K.L. Chen, Z. Madak-Erdogan
ERα signaling is sufficient to suppress lipid synthesis in the liver. In
addition, findings from mice with ERα that cannot bind estrogen re-
sponse elements, named KIKO mice, was protected from ovariectomy
and high-fat diet induced obesity upon estrogen supplementation,
suggesting that direct ERE binding is not required for metabolic effects
of ERα [68].
ERα is more associated with obesity and maintaining adipose tissue
function [57]. ERα knockout (ERαKO) mice are more prone to obesity
and have a reduced energy expenditure regardless of gender. These
results differ from ERβ knockout mice, which do not have significant
increase in visceral fat mass. Furthermore, ERαKO mice have increased
central adiposity. ERαKO mice have double the weight of fat pads
compared to wild type animals even though energy intake are about
equal. Studies in liver ERα knock-out mice (LERKO) showed that liver
ERα is required for preventing aberrant hepatic lipid deposition in both
males and females [69,70].
Even though ERα have more direct effects in metabolic regulation,
ERβ is also reported to have effects on the mechanism of fat accumu-
lation and distribution. In the absence of adipose ERα, ERβ prevents
inflammation and fibrosis [71]. Interestingly, ERβ was suggested to
influence microbiota maintenance in the gut [72]. The gastrointestinal
microbiota have hydrolytic capabilities, which may expand and reduce
the ability of the host to absorb and intake dietary components. In
addition to direct effects in the gut and microbiome, ERβ is expressed in
the dorsal raphe, a region of the brain where cell bodies of serotonin
neurons originate [73]. Serotonin neurons are critical in the regulation
of food intake. It has also been proposed that ERβ is important for the
maintenance of normal glucose and lipid metabolism in the body [74].
Estrogens regulate adipocyte metabolism and induce remodeling of
particular adipose depots, which are different between premenopausal
women and men compared to post-menopausal women [59]. Estrogen
Receptors partner with other transcription factors including LXR,
SREBP and especially cHREBP to regulate metabolism and readers are
encouraged to read the detailed review on this topic (REF. Ellis Levin
review on “Membrane estrogen receptors signal to determine tran-
scription factor function”). Estrogens can decrease lipogenesis by in-
hibiting lipoprotein lipase (LPL) [75]. LPL is responsible for hydro-
lyzing triglycerides and facilitates adipose tissue storage. An in vitro
study using mouse adipocyte cell lines showed that fat accumulation
depended on the expression of this enzyme as E2 treatment decreased
LPL mRNA, which blocked lipid deposition in turn. This effect is
regulated by an estrogen-response suppressive element in the LPL
promoter gene. Increased levels of LPL have been shown in adipose
tissue of obese human patients [76]. In obese women, plasma estradiol
activity has a strong negative correlation with LPL activity in adipose
and postheparin plasma. These studies suggest that estrogen may di-
rectly influence fat storage and limit fat accumulation in adipocytes by
decreasing LPL action.
In ovariectomized mice fed a high fat diet, E2 administration im-
proved glucose tolerance and insulin sensitivity. When estrogen pro-
duction decreases, as in menopause or following ovariectomy, the body
weight increases. This increase can be prevented by estradiol treatment
[77–79]. In terms of glucose homeostasis, aromatase knockout mice
had hepatic insulin resistance because of decreased Akt phosphoryla-
tion in the liver [79]. Akt is a key mediator in the insulin signaling
pathways. With estrogen administration, Akt phosphorylation of ar-
omatase knockout mice was restored reversing these effects. Therefore,
estradiol treatment in estrogen deficient mice improved insulin sensi-
tivity by increasing the phosphorylation of the key mediators in insulin
signaling [79,80].
In addition to direct effects of estrogens on metabolic tissues, ERs
are also expressed in regions of central nervous system (CNS) that
regulates food intake and energy expenditure [81]. ERα is the main
mediator of estrogen action in CNS and play important roles in main-
taining function of specialized neuronal circuits such as pro-opiomela-
nocortin (POMC) neurons or ventral medial hypothalamus (VMH) and
40
Steroids 133 (2018) 38–43
regulating levels and activity of several adipokines including leptin,
adiponectin and NPY [82,83]. The levels of adipokines, such as adi-
ponectin and leptin may be affected by estrogen concentrations [84].
Aiponectin is prodced by adipocytes and are involved in fatty acid
metabolism and glucose regulation [85]. Levels of adiponectin are in-
versely correlated with the concentrations of plasma estrogen levels in
females even though females have higher overall concentrations of
plasma adiponectin than males do. However, this might be due to other
hormones such as testosterone that results in the dimorphic differences
in adiponectin levels. strogen increases leptin production as well as
leptin receptor expression in rats and humans [86]. Supplementation of
estrogen in postmenopausal women caused an increase in circulating
leptin levels. In ovariectomized female rats injected with exogenous
leptin, responsiveness to the anorexigenic effects of leptin were reduced
and these mice had much higher food intake and increase in body
weight than intact females. As leptin inhibits hunger and influences
satiety, estrogens can aid in energy regulation and food intake to con-
trol obesity through this mechanism. Other adipokines such as tumor
necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) were also shown
to be increased following estrogen treatment of aromatase knockout
mice [79]. These data show that estrogens control the levels of different
adipokines associated with glucose and lipid metabolism which may
lead to the higher instances of obesity after menopause when estrogen
levels decline.
Estrogens regulate expression levels of several genes that are im-
portant for lipid deposition. FASN is fatty acid synthase which syn-
thesizes fatty acids. Estradiol regulates FASN expression in liver and
adipocytes by modulating downstream signaling pathway cross-talk
[63,87,88]. In ovariectomized mice, FASN levels were increased, which
were reversed by the administration of an estrogen receptor ligand.
Estrogen also appears to upregulate α2A-adrenergic receptors in human
adipose tissue which lowers the lipolytic response in subcutaneous
adipose tissue of healthy women [89]. By upregulating these receptors
only in subcutaneous adipose tissue and not in abdominal adipose
tissue, fat accumulation is higher in subcutaneous areas. This may ex-
plain why females have higher deposits in these areas compared to the
higher abdominal fat accumulation in males. SREBP-1 is sterol reg-
ulatory element-binding protein 1 which is involved in glucose meta-
bolism, fatty acid production, and cholesterol production. After ovar-
iectomy, expression of SREBP-1c, one of the isoforms of the SREBP, was
much higher than in intact mice [90]. Like FASN, administration of
estrogens decreased expression of SREBP-1 to prevent fat accumulation
[63,88].
4. Interaction of microbiota and estrogens
Gut microbiota composition has a major impact on metabolic status
of the host. Insulin sensitivity of mice can be improved by small in-
testine infusion of gut microbiota samples from healthy donors in mice
[91]. In a healthy gut, microbiota digests resistant starch and fibers,
synthesize vitamins, provide immunity, and prevent pathogen coloni-
zation [92]. If gut microbiota is disrupted, bacterial metabolites and
bacterial cell components can reduce intestinal epithelial integrity and
access the liver through the portal vein. These microbial byproducts can
contribute to inflammation, liver steatosis, and hepatic injury ulti-
mately leading to NAFLD [93].
High fat diet changes gut microbiota composition and increases the
concentration of gram negative bacteria, which produces endotoxin,
lipopolysaccharide (LPS) [94,95]. As gram negative bacteria produces
endotoxins increase inflammation as associated diseases such as type 2
diabetes [96] and NAFLD [97–100]. NAFLD is strongly influenced by
obesity and insulin resistance [101]. In fact, gut microbiota composi-
tion is altered in NAFLD where certain bacterial overgrowths contribute
to disease development and progression [102]. Insulin sensitivity of
mice can be improved by small intestine infusion of gut microbiota
samples from healthy donors in mice [91]. Manipulating the gut
K.L. Chen, Z. Madak-Erdogan
microbiota composition with probiotics and prebiotics, such as Lacto-
bacillus and Bifidobacterium strains also improve weight and fat mass
development. Mice fed a high fat diet had improved glucose-insulin
homeostasis and attenuated weight gain when supplemented with
Lactobacillus and Bifidobacterium probiotics.
Gut microorganism composition can be altered with the addition of
various chemical substrates and dietary administration of estrogen-like
compounds were shown to promote the proliferation and growth of
certain types of bacteria [103]. Dietary consumption of soy isoflavones
such as daidzein, genistein, and glycitin can significantly alter fecal
bacterial community structure and composition in postmenopausal
women [104]. Specifically, soy phytoestrogen consumption increases
the concentration of Bifidobacterium, a bacteria beneficial to gut
health, and suppresses Clostridiaceae, an opportunistic pathogens
which cause of several human diseases [56]. As estrogens influence the
microbiota, some bacteria also metabolize estrogen-like compounds or
phytoestrogens, such as soy isoflavones to produce more biologically
active forms that have high affinity for human estrogen receptors [105].
Higher serum levels of gut microbial metabolites of phytoestrogen lig-
nans were associated with a lower weight in postmenopausal women
[106]. Some gut bacteria are known to metabolize phytoestrogens into
O-desmethylangolensin (ODMA) and equol, which are structurally si-
milar to mammalian estrogen [107]. ODMA producing individuals are
leaner [108,109]. Equol supplementation improves glycemic control
and lowers LDL levels [107,109]. Recently we showed that dietary li-
corice root supplementation, which contain isoliquiritegenin, a low-
affinity ER ligand, improved ovariectomy associated weight gain and
metabolic syndrome in mice [110]. Administration of this botanical
estrogen did not stimulate reproductive tissues. However, how iso-
liquiritegenin or any other low affinity estrogen supplementation would
alter gut microbiota and blood metabolites is not known.
As estrogens are metabolized by the liver through first-pass meta-
bolism and biotransformed through methylation, hydroxylation, and
conjugation. The estrobolome, collection of estrogen metabolizing en-
zymes associated with gut microbioata, could further alter these
transformed estrogens and generate novel ligands of varying potency
for estrogen receptors [111]. For example, some bacterial species with
β-glucosidase activity can deconjugate estrogens, producing estrogens
with higher biological activity [112]. Higher gut microbial diversity is
associated with more estrogen metabolites in urine [112]. Increased
parent estrogen concentrations compared to estrogen metabolites in
serum have been associated with a low gut microbial diversity and
increased breast cancer risk [113,114]. Estrogen metabolite to parent
estrogen ratio may also be an important indicator of metabolic dys-
function. These findings suggest gut microbiome as a potential bio-
marker for identifying metabolic disease risk and eventually preventing
these diseases using probiotic interventions.
5. Conclusions and future research
Estrogens are key in maintaining homeostasis in healthy pre-
menopausal individuals. When estrogen levels decrease with meno-
pause, metabolic rate decreases, causing increased weight and obesity.
However, we still do not know how certain estrogens may alter the
microbiome to resemble normal weight phenotypes or how gut estro-
genic byproducts produced by gut bacteria may act as ER ligands to
mediate metabolic functions. It may be possible that the microbiota
metabolize endogenous or dietary estrogens to produce novel ER li-
gands that can also be used to mitigate symptoms associated with
menopause and obesity. Alternatively, the microbiota may be ma-
nipulated to produce less potent estrogens that could maintain meta-
bolic function but reduce the risk of other diseases such as cancer. By
identifying and analyzing other forms of estrogen that may be less
potent and bind loosely to receptors, it may be possible to find more
effective forms of estrogen replacement therapies. Treatment may also
involve using microbiota therapies in combination with estrogen
41
Steroids 133 (2018) 38–43
therapies that work independently or synergistically to provide a more
holistic treatment approach to prevent metabolic disease.
Funding
This work was supported by grants from the University of Illinois,
Office of the Vice Chancellor for Research, Arnold O. Beckman award
RB15150 (to ZME), National Institute of Food and Agriculture, U.S.
Department of Agriculture, award ILLU-698-909 (to ZME), and in-
vestigator initiated grant-WI196180 from Pfizer (to ZME).
References
[1] K.M. Flegal, D. Kruszon-Moran, M.D. Carroll, C.D. Fryar, C.L. Ogden, Trends in
obesity among adults in the United States, 2005 to 2014, JAMA 315 (21) (2016)
2284–2291.
[2] M. Aguilar, T. Bhuket, S. Torres, B. Liu, R.J. Wong, Prevalence of the metabolic
syndrome in the United States, 2003–2012, JAMA 313 (19) (2015) 1973–1974.
[3] M. Rodriguez-Monforte, E. Sanchez, F. Barrio, B. Costa, G. Flores-Mateo, Metabolic
syndrome and dietary patterns: a systemic review and meta-analysis of observa-
tional studies, Eur. J. Nutr. 56 (3) (2016) 925–947.
[4] G.A. Bray, The Metabolic Syndrome and Obesity, Humana Press, 2007.
[5] S.M. Grundy, H.B. Brewer, J.I. Cleeman, S.C. Smith, C. Lenfant, Definition of
metabolic syndrome: report of the national heart, lung, and blood institute/
american heart association conference on scientific issues related to definition,
Arterioscler Thromb. Vasc. Biol. 24 (2004) e13–e18.
[6] J.L. Kulk, C.I. Ardem, Age and sex differences in the clustering of metabolic syn-
drome factors: association with mortality risk, Diabetes Care 33 (11) (2010)
2457–2461.
[7] S. Kumagai, A. Holmang, P. Bjorntorp, The effects of oestrogen and progesterone
on insulin sensitivity in female rats, Acta Physiol. Scand. 149 (1993) 91–97.
[8] J.D. Wagner, M.K. Thomas, J.K. Williams, L. Zhang, K.A. Greaves, W.T. Cefalu,
Insulin sensitivity and cardiovascular risk factors in ovariectomized monkeys with
estradiol alone or combined with nomegestrol acetate, J. Clin. Endocrinol. Metab.
83 (1998) 896–901.
[9] N.F. Goodman, R.H. Cobin, S.B. Ginzburg, I.A. Katz, D.E. Woode, E. American
Association of Clinical, American Association of Clinical Endocrinologists Medical
Guidelines for Clinical Practice for the diagnosis and treatment of menopause,
Endocr. Pract. 17 (Suppl 6) (2011) 1–25.
[10] The 2017 hormone therapy position statement of The North American Menopause
Society, Menopause 24(7) (2017) 728–753.
[11] C.A. Stuenkel, S.R. Davis, A. Gompel, M.A. Lumsden, M.H. Murad, J.V. Pinkerton,
R.J. Santen, Treatment of symptoms of the menopause: an endocrine society
clinical practice guideline, J. Clin. Endocrinol. Metab. 100 (11) (2015)
3975–4011.
[12] J. MacKenzie, B.M. Fisher, A.J. Jaap, A. Stanley, K. Paterson, N. Sattar, Effects of
HRT on liver enzyme levels in women with type 2 diabetes: a randomized placebo-
controlled trial, Clin. Endocrinol. 65 (1) (2006) 40–44.
[13] Z. Bai, R. Gust, Breast cancer, estrogen receptor and ligands, Arch. Pharm. 342
(2009) 133–149.
[14] B.J. Deroo, K.S. Korach, Estrogen receptors and human disease, J. Clin. Invest. 116
(2006) 561–570.
[15] E.M. Fox, J. Davis, M.A. Shupnik, ERB in breast cancer–onlooker, passive player,
or active protector? Steroids 73 (2008) 1039–1051.
[16] C. Osipo, H. Liu, K. Meeke, V.C. Jordan, The consequences of exhaustive anti-
estrogen therapy in breast cancer: estrogen-induced tumor cell death, Exp. Biol.
Med. 229 (2004) 722–731.
[17] J.V. Pinkerton, J.A. Harvey, R. Lindsay, K. Pan, A.A. Chines, S. Mirkin,
D.F. Archer, Effects of bazedoxifene/conjugated estrogens on the endometrium
and bone: a randomized trial, J. Clin. Endocrinol. Metab. 99 (2) (2014)
E189–E198.
[18] A. Itabashi, K. Yoh, A.A. Chines, T. Miki, M. Takada, H. Sato, I. Goria, T. Sugimoto,
H. Mizunuma, H. Ochi, G.D. Constantine, H. Ohta, Effects of bazedoxifene on bone
mineral density. bone turnover, and safety in postmenopausal japanese women
with osteoporosis, J. Bone Miner. Res. 26 (3) (2011) 519–529.
[19] S.E. Wardell, E.R. Nelson, C.A. Chao, D.P. McDonnell, Bazedoxifene exhibits an-
tiestrogenic activity in animal models of tamoxifen resistant breast cancer; im-
plications for treatment of advanced disease, Clin. Cancer Res. 19 (9) (2013)
2420–2431.
[20] Z. Madak-Erdogan, P. Gong, B.S. Katzenellenbogen, Differential utilization of
nuclear and extranuclear receptor signaling pathways in the actions of estrogens,
SERMs, and a tissue-selective estrogen complex (TSEC), J. Steroid Biochem. Mol.
Biol. 158 (2016) 198–206.
[21] R. Lindsey, Preventing osteoporosis with a tissue selective estrogen complex
(TSEC) containing bazedoxifene/conjugated estrogens (BZA/CE), Osteoporos Int.
22 (2011) 447–451.
[22] R.A. Lobo J.V. Pinkerton M.L. Gass M.H. Dorin S. Ronkin J.H. Pickar G.
Constantine Evaluation of bazedoxifene/conjugated estrogens for the treatment of
menopausal symptoms and effects on metabolic parameters and overal safety
profile Fetil. Steril. 92(3) (2009) 1025-1038.
[23] R.J. Santen, Y. Song, W. Yue, J.P. Wang, D.F. Heitjan, Effects of menopausal
hormonal therapy on occult breast tumors, J. Steroid Biochem. Mol. Biol. 137
K.L. Chen, Z. Madak-Erdogan
(2013) 150–156.
[24] J.H. Kim, M.S. Meyers, S.S. Khuder, S.L. Abdallah, H.T. Muturi, L. Russo, C.R. Tate,
A.L. Hevener, S.M. Najjar, C. Leloup, F. Mauvais-Jarvis, Tissue-selective estrogen
complexes with bazedoxifene prevent metabolic dysfunction in female mice, Mol.
Metab. 3 (2014) 177–190.
[25] J. Barrera, K.L. Chambliss, M. Ahmed, K. Tanigaki, B. Thompson, J.G. McDonald,
C. Mineo, P.W. Shaul, Bazedoxifene and conjugated estrogen prevent diet-induced
obesity, hepatic steatosis, and type 2 diabetes in mice without impacting the re-
productive tract, Am. J. Physiol. Endocrinol. Metab. 307 (2014) E345–E354.
[26] J. Henao-Mejia, E. Elinav, C. Kin, L. Hao, W.Z. Mehal, T. Strowig, C.A. Thaiss,
A.L. Kau, S.C. Eisenbarth, M.J. Jurczak, J.-P. Camporez, G.I. Shulmanm,
J.I. Gordon, H.M. Hoffman, R.A. Flavell, Inflammasome-mediated dysbiosi reg-
ulates progression of NAFLD and obesity, Nature 482 (2012) 179–185.
[27] E. Scorletti, P.C. Calder, C.D. Byrne, Non-alcoholic fatty liver disease and cardi-
ovascular risk: metabolic aspects and novel treatments, Endocrine 40 (3) (2011)
332–343.
[28] C. Loguercio, T. De Simone, M.V. D'Auria, I. de Sio, A. Federico, C. Tuccillo,
A.M. Abbatecola, C. Del Vecchio Blnco, Non-alcoholic fatty liver disease: a mul-
ticentre clinical study by the Italian Association for the Study of the Liver, Dig.
Liver Dis. 36 (6) (2004) 398–405.
[29] S.-I. Kojima, N. Watanabe, M. Numata, T. Ogawa, S. Matsuzaki, Increase in the
prevalence of fatty liver in Japan over the past 12 years: analysis of clinical
background, J. Gastroenterol. 38 (10) (2003) 954–961.
[30] S.H. Park, W.K. Jeon, S.H. Kim, H.J. Kim, D.I. Park, Y.K. Cho, I.K. Sung, C.I. Sohn,
D.K. Keum, B.I. Kim, Prevalence and risk factors of non-alcoholic fatty liver disease
among Korean adults, J. Gastroenterol. Hepatol. 21 (1) (2006) 138–143.
[31] Y.-J. Zhou, Y.-Y. Li, Y.-Q. Nie, J.-X. Ma, L.-G. Lu, S.-L. Shi, M.-H. Chen, P.-J. Hu,
Prevalence of fatty liver disease and its risk factors in the population of South
China, World J. Gastroenterol. 13 (47) (2007) 6419–6424.
[32] H. Nomura, S. Kashiwagi, J. Hayashi, W. Kajiyama, S. Tani, M. Goto, Prevalence of
fatty liver in a general population of Okinawa, Japan, Jpn. J. Med. 27 (2) (1988)
142–149.
[33] Y. Gutierrez-Grobe, G. Ponciano-Rodriguez, M.H. Ramos, M. Uribe, N. Mendez-
Sanchez, Prevalence of non alcoholic fatty liver disease in premenopausal, post-
menopausal and polycystic ovary syndrome women. The role of estrogens, Ann.
Heptaology 9 (4) (2010) 402–409.
[34] Z.X. Wang, M. Xu, Z. Hu, U.K. Shrestha, Prevalence of nonalcoholic fatty liver
disease and its metabollic risk factors in women of different ages and body mass
index, Menopause 22 (6) (2014) 667–673.
[35] G.S.d.A. Florentino, H.P. Cotrim, C.P. Vilar, A.V.d.A. Florentino,
G.M.A. Guimaraes, V.S.T. Barreto, Nonalcoholic fatty liver disease in menopausal
women, Arquivos de Gastroenterologia 50 (2013) 180–185.
[36] C.W. Brady, Liver disease in menopause, World J. Gastroenterol. 21 (25) (2015)
7613–7620.
[37] F. Mauvais-Jarvis, D.J. Clegg, A.L. Hevener, The role of estrogens in control of
energy balance and glucose homeostasis, Endocr. Rev. 34 (3) (2013) 309–338.
[38] G. Pagano, G. Pacini, G. Musso, R. Gambino, F. Mecca, N. Depetris, M. Cassader,
E. David, P. Cavallo-Perin, M. Rizzetto, Nonalcoholic steatohepatitis, insulin re-
sistance, and metabolic syndrome: Further evidence for an etiologic association,
Hepatology 35 (2) (2002) 367–372.
[39] G. Marchesini, E. Bugianesi, G. Forlani, F. Cerrelli, M. Lenzi, R. Manini, S. Natale,
E. Vanni, N. Villanova, N. Melchionda, M. Rizzetto, Nonalcoholic fatty liver,
steatohepatitis, and the metabolic syndrome, Hepatology 37 (4) (2003) 917–923.
[40] J. McKenzie, B.M. Fisher, A.J. Jaap, A. Stanley, K. Paterson, N. Sattar, Effects of
HRT on liver enzyme levels in women with type 2 diabetes: a randomized placebo-
controlled trial, Clin. Endocrinol. 65 (1) (2006) 40–44.
[41] K.A. Oien, D. Moffat, G.W. Curry, J. Dickson, T. Habeshaw, P.R. Mills,
R.N.M. MacSween, Cirrhosis with steatohepatitis after adjuvant tamoxifen, The
Lancet 353 (9146) (1999) 36–37.
[42] D.S. Pratt, T.A. Knox, J. Erban, TAmoxifen-induced steatohepatitis, Ann. Intern.
Med. 123 (3) (1995) 236–236.
[43] S. Bruno, P. Maisonneuve, P. Castellana, N. Rotmensz, S. Rossi, M. Maggioni,
M. Persico, A. Colombo, F. Monasterolo, D. Casadei-Giunchi, F. Desiderio,
T. Stroffolini, V. Sacchini, A. Decensi, U. Veronesi, Incidence and risk factors for
non-alcoholic steatohepatitis: prospective study of 5408 women enrolled in Italian
tamoxifen chemoprevention trial, BMJ 330 (7497) (2005) 932.
[44] J.D.Y. Chow, M.E.E. Jones, K. Prelle, E.R. Simpson, W.C. Boon, A selective es-
trogen receptor α agonist ameliorates hepatic steatosis in the male aromatase
knockout mouse, J. Endocrinol. 210 (3) (2011) 323–334.
[45] G. Rando, W. Wahli, Sex differences in nuclear receptor-regulated liver metabolic
pathways, Biochimica et Biophysica Acta (BBA) – Molecular Basis Disease 1812
(8) (2011) 964–973.
[46] E. Fabbrini, S. Sullivan, S. Klein, Obesity and nonalcoholic fatty liver disease:
biochemical, metabolic and clinical implications, Heptaology 51 (2) (2010)
679–689.
[47] N.C. Leite, G.F. Salles, A.L. Araujo, C.A. Villeda-Nogueira, C.R. Cardoso,
Prevalence and assocaited factors of non-alcoholic fatty liver disease in patients
with type-2 diabetes mellitus, Liver Int. 29 (2009) 113–119.
[48] M.E. Rinella, Nonalcoholic fatty liver disease: a systematic review, J. Am. Med.
Assoc. 313 (22) (2015) 2263–2273.
[49] A.E. Feldstein, N.W. Werneburg, A. Canbay, M.E. Guicciardi, S.F. Bronk,
R. Rydzewski, L.J. Burgart, G.J. Gores, Free fatty acids promote hepatic lipotoxi-
city by stimulating TNF-alpha expression via ysosomal pathway, Hepatology 40
(2004) 184–194.
[50] C.P. Day, Steatohepatitis: a tale of two ‘hits’? Gastroenterology 114 (1998)
1349–1354.
42
Steroids 133 (2018) 38–43
[51] K. Yamaguchi, L. Yang, S. McCall, J. Huang, X.X. Yu, S.K. Pandey, S. Bhanot,
B.P. Monia, Y.X. Li, A.M. Diehl, Inhibiting triglyceride synthesis improves hepatic
steatosis but exacerbates liver damage and fibrosis in obese mice with nonalco-
holic steatohepatitis, Hepatology 45 (6) (2007) 1366–1374.
[52] U.S.D.o.H.a.H.S. U.S. Department of Agriculture, Dietary Guidelines for
Americans, 7 ed., U.S. Government Printing Office, Washington, DC, 2010.
[53] P. Angulo, L.M. Alba, L.A. Adams, K.D. Lindor, M.D. Jensen, Leptin, insulin re-
sistance, and liver fibrosis in human nonalcoholic fatty liver disease, J. Hepatol. 41
(2004) 943–949.
[54] L.H. Storlien, X.F. Huang, S. Lin, X. Xin, H.Q. Wang, P.L. Else, Dietary fat subtypes
and obesity, World Rev. Nutr. Dietetics 88 (2001) 148–154.
[55] A.K. Leamy, R.A. Egnatchik, J.D. Young, Molecular mechanisms and the role of
saturated fatty acids in the progression of non-alcoholic fatty liver disease, Prog.
Lipid Res. 52 (1) (2013) 165–174.
[56] M.J. Dekker, Q.Z. Su, C. Baker, A.C. Rutledge, K. Adeli, Fructose: a highly lipo-
genic nutrient implicated in insulin resistance, hepatic steatosis, and the metabolic
syndrome, Am. J. Physiol.-Endoc. M 299 (5) (2010) E685–E694.
[57] C.J. Park, Z. Zhao, C. Glidewell-Kenney, M. Lazic, P. Chambon, A. Krust, J. Weiss,
D.J. Clegg, A. Dunaif, J.L. Jameson, J.E. Levine, Genetic rescue of nonclassical
ERalpha signaling normalizes energy balance in obese Eralpha-null mutant mice,
J. Clin. Invest. 121 (2) (2011) 604–612.
[58] A. Foryst-Ludwig, U. Kintscher, Metabolic impact of estrogen signalling through
ERalpha and ERbeta, J. Steroid Biochem. Mol. Biol. 122 (1–3) (2010) 74–81.
[59] C.J. Gruber, W. Tschugguel, C. Schneeberger, J.C. Huber, Production and actions
of estrogens, N. Engl. J. Med. 346 (5) (2002) 340–352.
[60] C. Stocco, Tissue physiology and pathology of aromatase, Steroids 77 (1–2) (2012)
27–35.
[61] E.R. Simpson, Y. Zhao, V.R. Agarwal, M.D. Michael, S.E. Bulun,
M.M. Hinshelwood, S. Graham-Lorence, T. Sun, C.R. Fisher, K. Qin,
C.R. Mendelson, Aromatase expression in health and disease, Recent Prog. Horm.
Res. 52 (1997) 185–213 discussion 213-4.
[62] K.L. Chambliss, Q. Wu, S. Oltmann, E.S. Konaniah, M. Umetani, K.S. Korach,
G.D. Thomas, C. Mineo, I.S. Yuhanna, S.H. Kim, Z. Madak-Erdogan, A. Maggi,
S.P. Dineen, C.L. Roland, D.Y. Hui, R.A. Brekken, J.A. Katzenellenbogen,
B.S. Katzenellenbogen, P.W. Shaul, Non-nuclear estrogen receptor alpha signaling
promotes cardiovascular protection but not uterine or breast cancer growth in
mice, J. Clin. Invest. 120 (7) (2010) 2319–2330.
[63] Z. Madak-Erdogan, S.H. Kim, P. Gong, Y.C. Zhao, K.L. Chambliss, K.E. Carlson,
C.G. Mayne, P.W. Shaul, K.S. Korach, J.A. Katzenellenbogen,
B.S. Katzenellenbogen, Design of pathway preferential estrogens that provide
beneficial metabolic and vascular effects without stimulating reproductive tissues,
Sci. Signal 9 (429) (2016) ra53.
[64] Z. Madak-Erdogan, K.J. Kieser, S.H. Kim, B. Komm, J.A. Katzenellenbogen,
B.S. Katzenellenbogen, Nuclear and extranuclear pathway inputs in the regulation
of global gene expression by estrogen receptors, Mol. Endocrinol. 22 (9) (2008)
2116–2127.
[65] A. Pedram, M. Razandi, J.K. Kim, F. O'Mahony, E.Y. Lee, U. Luderer, E.R. Levin,
Developmental phenotype of a membrane only estrogen receptor alpha (MOER)
mouse, J. Biol. Chem. 284 (6) (2009) 3488–3495.
[66] K.J. Hamilton, Y. Arao, K.S. Korach, Estrogen hormone physiology: reproductive
findings from estrogen receptor mutant mice, Reprod. Biol. 14 (1) (2014) 3–8.
[67] A. Pedram, M. Razandi, F. O'Mahony, H. Harvey, B.J. Harvey, E.R. Levin, Estrogen
reduces lipid content in the liver exclusively from membrane receptor signaling,
Sci. Signal 6 (276) (2013) ra36.
[68] A. Yasrebi, J.A. Rivera, E.A. Krumm, J.A. Yang, T.A. Roepke, Activation of es-
trogen response element-independent ERα signaling protects female mice from
diet-induced obesity, Endocrinology 158 (2) (2017) 319–334.
[69] S. Della Torre, N. Mitro, R. Fontana, M. Gomaraschi, E. Favari, C. Recordati,
F. Lolli, F. Quagliarini, C. Meda, C. Ohlsson, M. Crestani, Nina H. Uhlenhaut,
L. Calabresi, A. Maggi, An essential role for liver ERα in coupling hepatic meta-
bolism to the reproductive cycle, Cell Rep. 15 (2) (2016) 360–371.
[70] S. Qiu, J.T. Vazquez, E. Boulger, H. Liu, P. Xue, M.A. Hussain, A. Wolfe, Hepatic
estrogen receptor α is critical for regulation of gluconeogenesis and lipid meta-
bolism in males, Sci. Rep. 7 (1) (2017) 1661.
[71] K.E. Davis, M.D. Neinast, K. Sun, W.M. Skiles, J.D. Bills, J.A. Zehr, D. Zeve,
L.D. Hahner, D.W. Cox, L.M. Gent, Y. Xu, Z.V. Wang, S.A. Khan, D.J. Clegg, The
sexually dimorphic role of adipose and adipocyte estrogen receptors in modulating
adipose tissue expansion, inflammation, and fibrosis, Mol. Metab. 2 (3) (2013)
227–242.
[72] A. Pedram, M. Razandi, E.R. Levin, Nature of functional estrogen receptors at the
plasma membrane, Mol. Endocrinol. 20 (9) (2006) 1996–2009.
[73] P.A. Heine, J.A. Taylor, G.A. Iwamoto, D.B. Lubahn, P.S. Cooke, Increased adipose
tissue in male and female estrogen receptor-alpha knockout mice, Proc. Natl.
Acad. Sci. USA 97 (23) (2000) 12729–12734.
[74] P.J. Shughrue, M.V. Lane, I. Merchenthaler, Comparative distribution of estrogen
receptor-alpha and -beta mRNA in the rat central nervous system, J. Comp.
Neurol. 388 (4) (1997) 507–525.
[75] H. Homma, H. Kurachi, Y. Nishio, T. Takeda, T. Yamamoto, K. Adachi,
K. Morishige, M. Ohmichi, Y. Matsuzawa, Y. Murata, Estrogen suppresses tran-
scription of lipoprotein lipase gene. Existence of a unique estrogen response ele-
ment on the lipoprotein lipase promoter, J. Biol. Chem. 275 (15) (2000)
11404–11411.
[76] J.M. Ong, P.A. Kern, Effect of feeding and obesity on lipoprotein lipase activity,
immunoreactive protein, and messenger RNA levels in human adipose tissue, J.
Clin. Invest. 84 (1) (1989) 305–311.
[77] C. Tagliaferri, J. Salles, J.F. Landrier, C. Giraudet, V. Patrac, P. Lebecque,
K.L. Chen, Z. Madak-Erdogan
M.J. Davicco, A. Chanet, C. Pouyet, A. Dhaussy, A. Huertas, Y. Boirie, Y. Wittrant,
V. Coxam, S. Walrand, Increased body fat mass and tissue lipotoxicity associated
with ovariectomy or high-fat diet differentially affects bone and skeletal muscle
metabolism in rats, Eur. J. Nutr. 54 (7) (2015) 1139–1149.
[78] R.E. Stubbins, V.B. Holcomb, J. Hong, N.P. Nunez, Estrogen modulates abdominal
adiposity and protects female mice from obesity and impaired glucose tolerance,
Eur. J. Nutr. 51 (7) (2012) 861–870.
[79] M.L. Van Sinderen, G.R. Steinberg, S.B. Jorgensen, J. Honeyman, J.D. Chow,
K.A. Herridge, A.L. Winship, E. Dimitriadis, M.E. Jones, E.R. Simpson, W.C. Boon,
Effects of estrogens on adipokines and glucose homeostasis in female aromatase
knockout mice, PLoS One 10 (8) (2015) e0136143.
[80] M.L. Van Sinderen, G.R. Steinberg, S.B. Jorgensen, J. Honeyman, J.D. Chow,
K.A. Herridge, A.L. Winship, E. Dimitriadis, M.E.E. Jones, E.R. Simpson,
W.C. Boon, Effects of estrogens on adipokines and glucose homeostasis in female
aromatase knockout mice, PLoS One 10 (8) (2015) e0136143.
[81] A.L. Hevener, D.J. Clegg, F. Mauvais-Jarvis, Impaired estrogen receptor action in
the pathogenesis of the metabolic syndrome, Mol. Cell. Endocrinol. 418 (Part 3)
(2015) 306–321.
[82] A. Frank, L.M. Brown, D.J. Clegg, The role of hypothalamic estrogen receptors in
metabolic regulation, Front. Neuroendocrinol. 35 (4) (2014) 550–557.
[83] M. López, M. Tena-Sempere, Estrogens and the control of energy homeostasis: a
brain perspective, Trends Endocrinol. Metab. 26 (8) (2015) 411–421.
[84] P.H. Iverius, J.D. Brunzell, Relationship between lipoprotein lipase activity and
plasma sex steroid level in obese women, J. Clin. Invest. 82 (3) (1988) 1106–1112.
[85] T.P. Combs, A.H. Berg, M.W. Rajala, S. Klebanov, P. Iyengar, J.C. Jimenez-
Chillaron, M.E. Patti, S.L. Klein, R.S. Weinstein, P.E. Scherer, Sexual differentia-
tion, pregnancy, calorie restriction, and aging affect the adipocyte-specific secre-
tory protein adiponectin, Diabetes 52 (2) (2003) 268–276.
[86] H. Shimizu, Y. Shimomura, Y. Nakanishi, T. Futawatari, K. Ohtani, N. Sato,
M. Mori, Estrogen increases in vivo leptin production in rats and human subjects,
J. Endocrinol. 154 (2) (1997) 285–292.
[87] M.F. Santolla, R. Lappano, P. De Marco, M. Pupo, A. Vivacqua, D. Sisci,
S. Abonante, D. Iacopetta, A.R. Cappello, V. Dolce, M. Maggiolini, G protein-
coupled estrogen receptor mediates the up-regulation of fatty acid synthase in-
duced by 17beta-estradiol in cancer cells and cancer-associated fibroblasts, J. Biol.
Chem. 287 (52) (2012) 43234–43245.
[88] Z. Madak-Erdogan, P. Gong, Y. Chen Zhao, L. Xu, K.U. Wrobel, J.A. Hartman,
M. Wang, A. Cam, U.T. Iwaniec, R.T. Turner, N.C. Twaddle, D.R. Doerge,
I.A. Khan, J.A. Katzenellenbogen, B.S. Katzenellenbogen, W.G. Helferich, Dietary
licorice root supplementation reduces diet-induced weight gain, lipid deeposition,
and heptaic steatosis in ovariectomized mice without stimulating reproductive
tissues and mammary gland, Mol. Nutr. Food Res. 60 (2) (2015) 369–380.
[89] S.B. Pedersen, K. Kristensen, P.A. Hermann, J.A. Katzenellenbogen, B. Richelsen,
Estrogen controls lipolysis by up-regulating alpha2A-adrenergic receptors directly
in human adipose tissue through the estrogen receptor alpha. Implications for the
female fat distribution, J. Clin. Endocrinol. Metab. 89 (4) (2004) 1869–1878.
[90] A. Paquette, D. Wang, M. Jankowski, J. Gutkowska, J.M. Lavoie, Effects of ovar-
iectomy on PPAR alpha, SREBP-1c, and SCD-1 gene expression in the rat liver,
Menopause 15 (6) (2008) 1169–1175.
[91] A. Vrieze, E. Van Nood, F. Holleman, J. Salojarvi, R.S. Kootte, J.F. Bartelsman,
G.M. Dallinga-Thie, M.T. Ackermans, M.J. Serlie, R. Oozeer, M. Derrien,
A. Druesne, J.E. Van Hylckama Vlieg, V.W. Bloks, A.K. Groen, H.G. Heilig,
E.G. Zoetendal, E.S. Stroes, W.M. de Vos, J.B. Hoekstra, M. Nieuwdorp, Transfer of
intestinal microbiota from lean donors increases insulin sensitivity in individuals
with metabolic syndrome, Gastroenterology 143 (4) (2012) 913-6 e7.
[92] H.J. Flint, K.P. Scott, P. Louis, S.H. Duncan, The role of the gut microbiota in
nutrition and health, Nat. Rev. Gastroenterol. Hepatol. 9 (2012) 577–589.
[93] M.R. Charlton, J.M. Burns, R.A. Pedersen, K.D. Watt, J.K. Heimbach,
R.A. Dierkhising, Frequency and outcomes of liver transplantation for nonalco-
holic steatohepatitis in the United States, Gastroenterology 141 (2011)
1249–1253.
[94] P.J. Turnbaugh, F. Backhed, L. Fulton, J.I. Gordon, Diet-induced obesity is linked
to marked but reversible alterations in the mouse distal gut microbiome, Cell Host
Microbe. 3 (4) (2008) 213–223.
[95] P.J. Turnbaugh, V.K. Ridaura, J.J. Faith, F.E. Rey, R. Knight, J.I. Gordon, The
effect of diet on the human gut microbiome: a metagenomic analysis in humanized
gnotobiotic mice, Sci. Transl. Med. 1 (6) (2009) 6ra14.
[96] V. Blasco-Baque, M. Serino, J.N. Vergnes, E. Riant, P. Loubieres, J.F. Arnal,
P. Gourdy, M. Sixou, R. Burcelin, P. Kemoun, High-fat diet induces periodontitis in
43
Steroids 133 (2018) 38–43
mice through lipopolysaccharides (LPS) receptor signaling: protective action of
estrogens, PLoS One 7 (11) (2012) e48220.
[97] G. Paolella, C. Mandato, L. Pierri, M. Poeta, M. Di Stasi, P. Vajro, Gut-liver axis and
probiotics: their role in non-alcoholic fatty liver disease, World J.
Gastroenterology: WJG 20 (42) (2014) 15518–15531.
[98] J. Henao-Mejia, E. Elinav, C. Jin, L. Hao, W.Z. Mehal, T. Strowig, C.A. Thaiss,
A.L. Kau, S.C. Eisenbarth, M.J. Jurczak, J.P. Camporez, G.I. Shulman, J.I. Gordon,
H.M. Hoffman, R.A. Flavell, Inflammasome-mediated dysbiosis regulates pro-
gression of NAFLD and obesity, Nature 482 (7384) (2012) 179–185.
[99] W. Jiang, N. Wu, X. Wang, Y. Chi, Y. Zhang, X. Qiu, Y. Hu, J. Li, Y. Liu, Dysbiosis
gut microbiota associated with inflammation and impaired mucosal immune
function in intestine of humans with non-alcoholic fatty liver disease, Sci. Rep. 5
(2015) 8096.
[100] L.C. Kong, B.A. Holmes, A. Cotillard, F. Habi-Rachedi, R. Brazeilles, S. Gougis,
N. Gausseres, P.D. Cani, S. Fellahi, J.P. Bastard, S.P. Kennedy, J. Dore,
S.D. Ehrlich, J.D. Zucker, S.W. Rizkalla, K. Clement, Dietary patterns differently
associate with inflammation and gut microbiota in overweight and obese subjects,
PLoS One 9 (10) (2014) e109434.
[101] B.W. Smith, L.A. Adams, Nonalcoholic fatty liver disease and diabetes mellitus:
pathogenesis and treatment, Nat. Rev. Endocrinol. 7 (8) (2011) 456–465.
[102] S.M. Ferolla, G.N. Armiliato, C.A. Couto, T.C. Ferrari, The role of intestinal bac-
teria overgrowth in obesity-related nonalcoholic fatty liver disease, Nutrients 6
(12) (2014) 5583–5599.
[103] C.L. Frankenfeld, Relationship of obesity and high urinary enterolignan con-
centrations in 6806 children and adults: analysis of National Health and Nutrition
Examination Survey data, Eur. J. Clin. Nutr. 67 (8) (2013) 887–889.
[104] S. Possemiers, S. Bolca, W. Verstraete, A. Heyerick, The intestinal microbiome: a
separate organ inside the body with the metabolic potential to influence the
bioactivity of botanicals, Fitoterapia 82 (1) (2011) 53–66.
[105] C.L. Frankenfeld, C. Atkinson, K. Wahala, J.W. Lampe, Obesity prevalence in re-
lation to gut microbial environments capable of producing equol or O-desmethy-
langolensin from the isoflavone daidzein, Eur. J. Clin. Nutr. 68 (4) (2014)
526–530.
[106] T. Usui, M. Tochiya, Y. Sasaki, K. Muranaka, H. Yamakage, A. Himeno,
A. Shimatsu, A. Inaguma, T. Ueno, S. Uchiyama, N. Satoh-Asahara, Effects of
natural S-equol supplements on overweight or obesity and metabolic syndrome in
the Japanese, based on sex and equol status, Clin. Endocrinol. (Oxf) 78 (3) (2013)
365–372.
[107] V.C. Antharam, E.C. Li, A. Ishmael, A. Sharma, V. Mai, K.H. Rand, G.P. Wang,
Intestinal dysbiosis and depletion of butyrogenic bacteria in Clostridium difficile
infection and nosocomial diarrhea, J. Clin. Microbiol. 51 (9) (2013) 2884–2892.
[108] R. Menon, S.E. Watson, L.N. Thomas, C.D. Allred, A. Dabney, M.A. Azcarate-Peril,
J.M. Sturino, Diet complexity and estrogen receptor beta status affect the com-
position of the murine intestinal microbiota, Appl. Environ. Microbiol. 79 (18)
(2013) 5763–5773.
[109] C.H. Nakatsu, A. Armstrong, A.P. Clavijo, B.R. Martin, S. Barnes, C.M. Weaver,
Fecal bacterial community changes associated with isoflavone metabolites in
postmenopausal women after soy bar consumption, PLoS One 9 (10) (2014)
e108924.
[110] Z. Madak-Erdogan, P. Gong, Y.C. Zhao, L. Xu, K.U. Wrobel, J.A. Hartman,
M. Wang, A. Cam, U.T. Iwaniec, R.T. Turner, N.C. Twaddle, D.R. Doerge,
I.A. Khan, J.A. Katzenellenbogen, B.S. Katzenellenbogen, W.G. Helferich, Dietary
licorice root supplementation reduces diet-induced weight gain, lipid deposition,
and hepatic steatosis in ovariectomized mice without stimulating reproductive
tissues and mammary gland, Mol. Nutr. Food Res. 60 (2) (2016) 369–380.
[111] M. Kwa, C.S. Plottel, M.J. Blaser, S. Adams, The intestinal microbiome and es-
trogen receptor-positive female breast cancer, J. Natl. Cancer Inst. 108 (8) (2016)
djw029.
[112] R. Flores, J. Shi, B. Fuhrman, X. Xu, T.D. Veenstra, M.H. Gail, P. Gajer, J. Ravel,
J.J. Goedert, Fecal microbial determinants of fecal and systemic estrogens and
estrogen metabolites: a cross sectional study, J. Transl. Med. 10 (2012) 253.
[113] R.T. Falk, L.A. Brinton, J.F. Dorgan, B.J. Fuhrman, T.D. Veenstra, X. Xu,
G.L. Gierach, Relationship of serum estrogens and estrogen metabolites to post-
menopausal breast cancer risk: a nested case-control study, Breast Cancer Res. 15
(2) (2015) R34.
[114] B.J. Fuhrman, H.S. Feigelson, R. Flores, M.H. Gail, X. Xu, J. Ravel, J.J. Goedert,
Associations of the Fecal Microbiome With Urinary Estrogens and Estrogen
Metabolites in Postmenopausal Women, The J. Clin. Endocrinol. Metab. 99 (12)
(2014) 4632–4640.