Margaret Warner

• PhD
• Professor at University of Houston

Microglia, the largest population of brain immune cells, play an essential role in regulating neuroinflammation by removing foreign materials and debris and in cognition by pruning synapses. Since liver X receptor β (LXRβ) has been identified as a regulator of microglial homeostasis, this study examined whether its removal from microglia affects ne...

The role of thyroid hormone (TH) in the development and function of the central nervous system (CNS) has been known for many years. However, the role of liver X receptors (LXRs) in TH function and protection against neuronal degeneration was not recognized until recently. The relationship between thyroid hormone receptors (TRs) and LXRs became appa...

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with aggressive behavior and poor prognosis. Current therapeutic options available for TNBC patients are primarily chemotherapy. With our evolving understanding of this disease, novel targeted therapies, including poly ADP-ribose polymerase (PARP) inhibitors, antibody–drug conjugate...

Liver X receptors (LXRα and LXRβ) are oxysterol-activated nuclear receptors that play key roles in cholesterol homeostasis, the central nervous system, and the immune system. We have previously reported that LXRαβ-deficient mice are more susceptible to dextran sodium sulfate (DSS)-induced colitis than their WT littermates, and that an LXR agonist p...

Valproic acid (VPA) exposure during pregnancy leads to a higher risk of autism spectrum disorder (ASD) susceptibility in offspring. Human dorsal forebrain organoids were used to recapitulate course of cortical neurogenesis in the developing human brain. Combining morphological characterization with massive parallel RNA sequencing (RNA-seq) on organ...

In this review, we discuss the role of liver X receptors (LXRs) in glial cells (microglia, oligodendrocytes and astrocytes) in the central nervous system (CNS). LXRs are oxysterol-activated nuclear receptors that, in adults, regulate genes involved in cholesterol homeostasis, the modulation of inflammatory responses and glutamate homeostasis. The s...

Age-related hearing loss is the most common type of hearing impairment, and is typically characterized by the loss of spiral ganglion neurons (SGNs). The two liver X receptors (LXRs) are oxysterol-activatednuclear receptors which in adults, regulate genes involved in cholesterol homeostasis and modulation of macrophage activity. LXRβ plays a key ro...

Astrocytes are integral components of synaptic transmission, and their dysfunction leads to neuropsychiatric disorders such as anxiety and depression. Liver X receptor β (LXRβ) is expressed in astrocytes, and LXRβ global knockout mice shows impaired synaptic formation. In order to define the role of LXRβ in astrocytes, we used a conditional Cre-lox...

After the discovery of ERβ, a novel role for DHT in estrogen signaling was revealed. Instead of just being a better androgen, DHT was found to be a precursor of the ERβ agonist 5α-androstane-3β, 17β-diol (3βAdiol), the second estrogen in the body which did not require aromatase for its synthesis. ERβ was found to oppose androgen signaling and thus...

Significance Although PCa depends on AR signaling, the effect of androgen deprivation therapy is temporary and eventually leads to lethal castration-resistant prostate cancer (CRPC). The present study revealed that finasteride, abiraterone, and enzalutamide all increased EGFR nuclear translocation and increased proliferation. In men with BPH, treat...

Disagreements about the phenotype of estrogen receptor β (ERβ) knockout mouse, created by removing the DNA-binding domain of the ERβ gene or interruption of the gene with a neocassette (Oliver Smithies ERβ knockout mice [ERβ OS−/− ]), prompted us to create an ERβ knockout mouse by deleting the ERβ gene with the use of CRISPR/Cas9 technology. We con...

Significance Optic neuritis, an inflammatory disease of the optic nerve, leads to death of retinal ganglion cells (RGC) and impaired vision. Both LXRα and LXRβ are expressed in the retina and optic nerve. The present study reveals that deletion of LXRβ from the mouse genome leads to loss of RGC. Immunostaining of LXRβ knockout mouse eyes showed tha...

Significance Defects in the neurogenesis of the dentate gyrus (DG) seem to be involved in the genesis of autism spectrum disorders (ASD)-like behaviors. Our study reveals that deletion of the Liver X receptor β (LXRβ) in mice causes hypoplasia in the DG, including abnormalities in the formation of progenitor cells and reduced neurogenesis. Behavior...

Significance Prostate cancer is an androgen receptor (AR)-dependent disease. Goals in treatment of prostate cancer include keeping low Gleason grades low and preventing development of the lethal disease castration-resistant metastatic prostate cancer. The present study revealed that ERβ modulates AR signaling by repressing AR driver RORc and increa...

Significance Nonalcoholic fatty liver disease (NAFLD) is a common chronic hepatic disease, eventually leading to liver fibrosis and cirrhosis. Currently, no effective treatment is available. This study reports the role of cytochrome P450 omega-hydroxylase 4A14 (CYP4A14) in the development and progression of NAFLD. Overexpression of CYP4A14 promotes...

Increasing evidence indicates that the liver X receptor(LXR) β modulates inflammatory pain. However, the molecular mechanisms through which LXRβ modulates pain are unclear. Here, we found that LXRβ-null mice responded more strongly to acute noxious stimuli than wild-type (WT) littermates (in the hot plate and Hargreaves tests) and had augmented ton...

Estrogen, via estrogen receptor alpha (ERα), exerts several beneficial effects on metabolism and energy homeostasis by controlling size, enzymatic activity and hormonal content of adipose tissue. The actions of estrogen on sympathetic ganglia, which are key players in the browning process, are less well known. In the present study we show that ERβ...

A major issue in clinical endocrinology today is how to use hormones to achieve the health benefits that they clearly can provide but avoid the negative side effects, that is, how to develop more precise medicines. This problem of how to use hormones is pervasive in clinical endocrinology. It is true for estrogen, progesterone, androgen, vitamin D,...

Significance The aryl hydrocarbon receptor (AhR), in addition to its well-known role in repressing ER signaling, has now been shown to have a physiological function in regulating Notch signaling. Thus, in AhR −/− male mice, there is growth of mammary ducts and degenerative changes in the testes. There is germ cell apoptosis, reduction of expression...

Significance Lung cancer is the leading cause of cancer death worldwide. Lung squamous cell carcinoma (SCCa) is classified as central or peripheral, according to the location of the primary tumor. Peripheral SCCa (PSCCa) is becoming as common as central SCCa, but the reasons for this increase are unclear. Smoking and chronic lung inflammation are r...

The recent discovery of browning of white adipose tissue (WAT) has raised great research interest because of its significant potential in counteracting obesity and type II diabetes. However, the mechanisms underlying browning are still poorly understood. Liver X receptors (LXRs) are one class of nuclear receptors, which play a vital role in regulat...

Significance Liver X receptors (LXRs) are nuclear receptors vital in controlling lipid and glucose metabolism through direct or indirect mechanisms. Here, we demonstrate for the first time, to our knowledge, that, in addition to changing the activity of classic brown adipose tissue, LXRs, especially LXRβ, are able to regulate the browning of white...

Of the two isoforms of Liver X receptor (LXR), LXRβ has been shown to have major effects in the central nervous system (CNS) and on the regulation of aquaporins while LXRα has its most marked effects on cholesterol homeostasis. Both receptors have immunomodulatory functions. In LXRαβ knockout (ko) mice, the CNS phenotype is much more severe than in...

Significance Estrogen receptor β (ERβ) is thought to be the predominant nuclear receptor that regulates estrogen signaling in a wide variety of tissues. In several circumstances, it can oppose the effects of ERα. Here, we generated a novel ERβ exon 3-deleted mouse model (ERβ-Δex3) in which the first zinc finger of the DNA binding domain is missing...

Excessive exposure to estrogen has long been associated with an increased risk for developing breast cancer and anti-estrogen therapy is the gold standard of care in the treatment of estrogen receptor (ER) α-positive breast cancers. However, there are several mysteries concerning both anti-estrogen, tamoxifen, and estrogen. The most important of th...

The anti-proliferative properties of estrogen receptor β (ERβ) and its ability to regulate growth and differentiation of the prostate epithelium make it interesting as a therapeutic target in prostate cancer. In 1998, the first ERβ knockout (ERβ-/-) mouse was created by inserting a neocassette into the ERβ gene to interrupt the gene at the DNA bind...

What is DHEA and why is there so much public interest in this steroid which has been touted as the fountain of youth and is supposed have all kinds of health benefits? Endocrinologists have been fascinated with DHEA for a long time because of its high production in the fetal adrenals and its continued high levels until the 7th decade of life. Yet t...

Several psychiatric disorders are associated with aberrant white matter development, suggesting oligodendrocyte and myelin dysfunction in these diseases. There are indications that radial glial cells (RGCs) are involved in initiating myelination, and may contribute to the production of oligodendrocyte progenitor cells (OPCs) in the dorsal cortex. L...

Several psychiatric disorders are associated with aberrant white matter development, suggesting oligodendrocyte and myelin dysfunction in these diseases. There are indications that radial glial cells (RGCs) are involved in initiating myelination, and may contribute to the production of oligodendrocyte progenitor cells (OPCs) in the dorsal cortex. L...

In the last decade of the twentieth century, two nuclear receptors were discovered in our laboratory and, very surprisingly, were found to have key roles in the central nervous system. These receptors have provided some novel insights into the etiology and progression of neurodegenerative diseases and anxiety disorders. The two receptors are estrog...

Estrogen analogue 27-hydroxycholesterol, which binds to and modulates the estrogen receptor and the liver X receptor, has recently been implicated in the risk of breast cancer and liver cancer in mouse models.

Significance Whether breast cancer will respond to the antiestrogen tamoxifen is determined by whether cellular proliferation is estrogen receptor (ER) α-mediated. As opposed to early ductal cancer, which is an ERα-rich, proliferating disease, in early lobular cancer both ERα and ERβ are abundantly expressed and proliferation is rare. In advanced l...

Estrogen and its receptors (ERs) influence many biological processes involved in physiology and pathology in men and women. ERs are involved in the etiology and/or progression of cancers of the prostate, breast, uterus, ovary, colon, lung, stomach, and malignancies of the immune system. In estrogen-sensitive malignancy, estrogen receptor β (ERβ) us...

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC The aryl hydrocarbon receptor (AhR) is a sensor of environmental toxins such as TCDD and its activation by these ligands can lead to immune system impairment, endocrine disruption and cancer. However, the normal physiological functions of AhR are still under investigation....

Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Excessive exposure to Estrogen has long been indicated to increase breast cancer risk. Although the anti-estrogen endocrine therapy by selective estrogen receptor modulator (SERM) is widely used to treat the ERα-positive breast cancers, there are several mysteries in the f...

This study evaluated the effect of a selective estrogen receptor beta (ERβ) agonist in the prostate of the aging Mongolian gerbil. The gerbil is a rodent known for spontaneous development of prostatic lesions such as prostatic intraepithelial neoplasias (PIN), adenocarcinomas and micro invasive carcinomas as they become old. This representative fea...

The aim of this study was to evaluate among postmenopausal women the effects of a 3-month treatment with estradiol (E2) alone or in combination with norethindrone acetate (NA) on expression of hormone receptors and proliferation in the breast as well as on lipids and climacteric symptoms. Sixty healthy postmenopausal women were computer-randomized...

A therapeutic goal in the treatment of certain CNS diseases, including multiple sclerosis, amyotrophic lateral sclerosis, and Parkinson disease, is to down-regulate inflammatory pathways. Inflammatory molecules produced by microglia are responsible for removal of damaged neurons, but can cause collateral damage to normal neurons located close to de...

The Mongolian gerbil is useful for prostate studies since both males and females spontaneously develop prostatic disorders with age. Estrogens regulate prostate homeostasis via two estrogen receptors, ER alpha (ESR1) and ER beta (ESR2) but the cellular distribution and regulation of these receptors in the gerbil prostate has not been described. Bot...

There are some diseases like autoimmune diseases, osteoporosis, and lymphangioleiomyomatosis where estrogen, the predominant female hormone, could play an important role. Despite major advances in medicine and pharmacology, there are a large number of serious diseases which remain untreatable. In recent years, there has been a growing appreciation...

Parkinson disease (PD) is a progressive neurodegenerative disease whose progression may be slowed, but at present there is no pharmacological intervention that would stop or reverse the disease. Liver X receptor β (LXRβ) is a member of the nuclear receptor super gene family expressed in the central nervous system, where it is important for cortical...

The serotonergic neurons of the dorsal raphe (DR) nucleus in the CNS are involved in fear, anxiety and depression. Depression and anxiety occur quite frequently in postmenopausal women, but estrogen replacement to correct these CNS disorders is at present not favored because estrogen carries with it an increased risk for breast cancer. Serotonin sy...

Anxiety disorders are the most prevalent mental disorders in adolescents in the United States. Female adolescents are more likely than males to be affected with anxiety disorders, but less likely to have behavioral and substance abuse disorders. The prefrontal cortex (PFC), amygdala, and dorsal raphe are known to be involved in anxiety disorders. I...

The present study demonstrates a key role for the oxysterol receptor liver X receptor β (LXRβ) in the etiology of diabetes insipidus (DI). Given free access to water, LXRβ(-/-) but not LXRα(-/-) mice exhibited polyuria (abnormal daily excretion of highly diluted urine) and polydipsia (increased water intake), both features of diabetes insipidus. LX...

An estrogen receptor (ER) β ligand (LY3201) with a preference for ERβ over ERα was administered in s.c. pellets releasing 0.04 mg/d. The brains of these mice were examined 3 d after treatment had begun. Although estradiol-17β is known to increase spine density and glutaminergic signaling, as measured by Golgi staining, a clear reduction in spines w...

The aryl hydrocarbon receptor (AhR) knockout mice raised in the laboratory of Fujii-Kuriyama have been under investigation for several years because of the presence in their urinary bladder of large, yellowish stones. The stones are composed of uric acid and become apparent in the bladders as tiny stones when mice are 10 wk of age. By the time the...

In 2008, the number of poisoning deaths exceeded the number of motor vehicle traffic deaths and was the leading cause of injury death for the fi rst time since at least 1980. During the past three decades, the poisoning death rate nearly tripled, while the motor vehicle traffic death rate decreased by one-half. During this period, the percentage of...

The estrogen receptors alpha (ERα) and beta (ERβ) have been demonstrated in mouse models to be important for immune system regulation, and are differentially expressed in lymphoid organs. One ERβ splice variant, ERβ2, inhibits the ERα-mediated estrogen effect, and expression might predict response to selective estrogen receptor modulators. We studi...

Estrogen acting through two estrogen receptors (ERs), ERalpha and ERbeta, regulates multiple functions in the central nervous system. Studies in rodent brains have revealed that ERalpha is the predominant ER in the hypothalamus and controls reproduction. ERbeta influences on non-reproductive processes and appears to be the main ER subtype expressed...

The discovery of a second estrogen receptor, ERbeta, and the finding that 5alpha-androstane-3beta,17beta-diol (3betaAdiol) strongly binds to ERbeta, have opened up a new aspect of estrogen signaling. Some of the major shifts in our understanding come from finding ERbeta in tissues which do not express ERalpha but are estrogen-responsive; these were...

Gallbladder cancer is a highly aggressive disease with poor prognosis that is two to six times more frequent in women than men. The development of gallbladder cancer occurs over a long time (more than 15 y) and evolves from chronic inflammation to dysplasia/metaplasia, carcinoma in situ, and invasive carcinoma. In the present study we found that, i...

In the past year, two members of the nuclear receptor family, liver X receptor beta (LXRbeta) and thyroid hormone receptor alpha (TRalpha), have been found to be essential for correct migration of neurons in the developing cortex in mouse embryos. TRalpha and LXRbeta bind to identical response elements on DNA and sometimes regulate the same genes....

The discovery of ERbeta in the middle of the 1990s represents a paradigm shift in our understanding of estrogen signaling. It has turned out that estrogen action is not mediated by one receptor, ERalpha, but by two balancing factors, ERalpha and ERbeta, which are often antagonistic to one another. Excitingly, ERbeta has been shown to be widespread...

At 2 years of age, 100% (23/23) of ERbeta(-/-) female mice have developed large pituitary and ovarian tumors. The pituitary tumors are gonadotropin-positive and the ovarian tumors are sex cord (less differentiated) and granulosa cell tumors (differentiated and estrogen secreting). No male mice had pituitary tumors and no pituitary or ovarian tumors...

Estrogen acting through two estrogen receptors (ERs), ERα and ERβ, regulates multiple functions in the central nervous system. Studies in rodent brains have revealed that ERα is the predominant ER in the hypothalamus and controls reproduction. ERβ influences on non-reproductive processes and appears to be the main ER subtype expressed in the cerebr...

Estradiol-17 β influences a wide variety of brain functions in mammals, including development, plasticity, feedback regulation of hypothalamic and pituitary hormone secretion, motor behavior, mood, and mental state, by the control of central aminergic and peptidergic neurotransmission, preservation of cognitive brain function, and perhaps neuroprot...

We examined nociceptive responses to mechanical stimulation in mice of both sexes lacking the estrogen receptor alpha or beta and in respective wild types under normal conditions, after inflammation of a hindpaw or peripheral nerve injury. In normal wild-type mice, females had significantly lower paw withdrawal threshold than males. There was no si...

Glucose uptake and homeostasis are regulated mainly by skeletal muscle (SM), white adipose tissue (WAT), pancreas, and the liver. Participation of estradiol in this regulation is still under intense investigation. We have demonstrated that, in SM of male mice, expression of the insulin-regulated glucose transporter (GLUT)4 is reduced by estrogen re...

Benign prostatic hyperplasia (BPH) is usually described as a pathological proliferation of prostatic fibroblasts/myofibroblasts and epithelial cells. In the present study of BPH samples, we have made a morphological and immunohistochemical study of BPH prostatic sections using markers of proliferation, apoptosis, hormone receptors, and TGF-beta sig...

Liver X receptors, LXRalpha and LXRbeta, are nuclear receptors belonging to the large family of transcription factors. After activation by oxysterols, LXRs play a central role in the control of lipid and carbohydrate metabolism as well as inflammation. The role of LXRalpha has been extensively studied, particularly in the liver and macrophages. In...

With specific liver X receptor alpha and beta (LXRalpha and LXRbeta) antibodies, we found that LXRalpha is strongly expressed in the luminal and basal cells of prostatic epithelium. The ventral prostates (VP) of LXRalpha(-/-) mice are characterized by the presence of smooth-muscle actin-positive stromal overgrowth around the prostatic ducts and by...

This study reports on the spatiotemporal dynamics of the expression of estrogen receptors (ERs) in the mouse central nervous system (CNS) during the early postnatal and the peripubertal period. At postnatal day 7 (P7), neurons with strong nuclear immunostaining for both ERalpha and ERbeta1 were widely distributed throughout the brain. Sucrose densi...

Liver X receptor (LXR) β regulates cholesterol levels in the brain and is essential for maintenance of motor neurons in the spinal cord and dopaminergic neurons in the substantia nigra. Here, we have examined the expression pattern of LXRβ protein in the cerebral cortex and looked for defects in cortical development in LXRβ knockout (LXRβ−/−) mice....

Liver X receptors (LXRs) α and β are nuclear oxysterol receptors with a key role in cholesterol, triglyceride, and glucose metabolism. In LXRβ−/− mice on a normal diet, there is a reduction in size of perigonadal fat pad and, on high-fat diet there is resistance to obesity. In the present study, we investigated the reason for the resistance of LXRβ...

For the past 10 years it is known that oestrogen functions through the activation of two oestrogen receptors (ERalpha and ERbeta). To the great surprise of endocrinologists, ERbeta was found to be widely distributed in tissues throughout the body including tissues previously considered as 'oestrogen insensitive'. The epithelium of the ventral prost...

Epidemiological research has indicated that the anti-oestrogen tamoxifen, used in breast cancer therapy, may increase the risk of gastric adenocarcinoma of the intestinal but not of the diffuse type. To test this hypothesis, and evaluate possible involvement of oestrogen receptors (ERs), we conducted a study amongst tamoxifen users and non-users. T...

Administration of β-sitosterol (42 mg/kg per day) for 3 weeks to 8-month-old male LXRβ−/− mice resulted in the death of motor neurons in the lumbar region of the spinal cord and loss of tyrosine hydroxylase-positive dopaminergic neurons in the substantia nigra. In mice at 5 months of age, β-sitosterol had no observed toxicity but at 16 months of ag...

Estrogen might protect women against gastric adenocarcinoma of the intestinal histological type. We addressed this hypothesis and proposed that gastric estrogen receptors (ERs) are involved. A population-based cohort of patients with gastric adenocarcinoma diagnosed in 1958-2004 in the county of Stockholm was identified through the Swedish Cancer R...

Estrogen is known to influence pain, but the specific roles of the two estrogen receptors (ERs) in the spinal cord are unknown. In the present study, we have examined the expression of ERα and ERβ in the spinal cord and have looked for defects in pain pathways in ERβ knockout (ERβ−/−) mice. In the spinal cords of 10-month-old WT mice, ERβ-positive...

During the past decade there has been a substantial advance in our understanding of estrogen signaling both from a clinical as well as a preclinical perspective. Estrogen signaling is a balance between two opposing forces in the form of two distinct receptors (ER alpha and ER beta) and their splice variants. The prospect that these two pathways can...

Interstitial cystitis/painful bladder syndrome is a disease seen mostly in women, and symptoms tend to be worse premenopausally or during ovulation. The four cardinal symptoms of interstitial cystitis/painful bladder syndrome are bladder pain, urgency, frequency, and nocturia. Estrogen has been implicated in the etiology of this disease, but the ro...

The onset of climacteric symptoms (hot flashes and night sweats) is the primary reason for perimenopausal women to start hormone therapy. The association of a lower incidence of postmenopausal symptoms with high intake of soybeans in Asian women suggests that phytoestrogens are an alternative to estrogen therapy. The main effective compounds in soy...

Ovulation rarely occurs in mice in which the estrogen receptor β (ERβ) gene has been inactivated (ERβ−/− mice). Here, we investigated whether this subfertility is due to a defect in the ovary itself or to more general endocrine changes in ERβ−/− mice. We transplanted ERβ−/− ovaries into WT mice and WT ovaries into ERβ−/− mice. Upon mating with ERβ−...

Our previous studies with estrogen receptor beta knockout (ERbeta(-/-)) mice demonstrated that ERbeta is necessary for embryonic development of the brain as early as embryonic day 14.5 (E14.5) and is involved in neuronal migration. Such early effects of ER were unexpected because estradiol synthesis and action in the brain occur at E18.5. In the pr...

Epidemiological studies show that oestrogen reduces the risk of colorectal cancer in postmenopausal women and ERbeta (oestrogen receptor beta)-selective ligands have been reported to be very effective treatment in animal models of inflammatory bowel disease. Several studies have shown that ERbeta is the predominant ER in the colonic epithelium, but...

In this study, we compared the uterine tissue of estrogen receptor (ER)β−/− mice and their WT littermates for differences in morphology, proliferation [the percentage of labeled cells 2 h after BrdUrd injection and EGF receptor (EGFR) expression], and differentiation (expression of progesterone receptor, E-cadherin, and cytokeratins). In ovariectom...

Estrogen receptor β (ERβ) is highly expressed in both type I and II pneumocytes as well as bronchiolar epithelial cells. ERα is not detectable in the adult lung. Lungs of adult female ERβ knockout (ERβ−/−) mice have already been reported to have fewer alveoli and reduced elastic recoil. In this article, we report that, by 5 months of age, there are...