International Journal of Molecular Sciences

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14 pages, 1651 KiB

Open AccessArticle

Mouse Cardiac Pde1C Is a Direct Transcriptional Target of Pparα

by Varsha Shete, Ning Liu, Yuzhi Jia, Navin Viswakarma, Janardan K. Reddy and Bayar Thimmapaya

Int. J. Mol. Sci. 2018, 19(12), 3704; https://doi.org/10.3390/ijms19123704 - 22 Nov 2018

Cited by 4 | Viewed by 3580

Abstract

Phosphodiesterase 1C (PDE1C) is expressed in mammalian heart and regulates cardiac functions by controlling levels of second messenger cyclic AMP and cyclic GMP (cAMP and cGMP, respectively). However, molecular mechanisms of cardiac Pde1c regulation are currently unknown. In this study, we demonstrate that [...] Read more.

Phosphodiesterase 1C (PDE1C) is expressed in mammalian heart and regulates cardiac functions by controlling levels of second messenger cyclic AMP and cyclic GMP (cAMP and cGMP, respectively). However, molecular mechanisms of cardiac Pde1c regulation are currently unknown. In this study, we demonstrate that treatment of wild type mice and H9c2 myoblasts with Wy-14,643, a potent ligand of nuclear receptor peroxisome-proliferator activated receptor alpha (PPARα), leads to elevated cardiac Pde1C mRNA and cardiac PDE1C protein, which correlate with reduced levels of cAMP. Furthermore, using mice lacking either Pparα or cardiomyocyte-specific Med1, the major subunit of Mediator complex, we show that Wy-14,643-mediated Pde1C induction fails to occur in the absence of Pparα and Med1 in the heart. Finally, using chromatin immunoprecipitation assays we demonstrate that PPARα binds to the upstream Pde1C promoter sequence on two sites, one of which is a palindrome sequence (agcTAGGttatcttaacctagc) that shows a robust binding. Based on these observations, we conclude that cardiac Pde1C is a direct transcriptional target of PPARα and that Med1 may be required for the PPARα mediated transcriptional activation of cardiac Pde1C. Full article

(This article belongs to the Special Issue Molecular Biology of Nuclear Receptors)

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14 pages, 3553 KiB

Open AccessArticle

Altered Expression of Retinol Metabolism-Related Genes in an ANIT-Induced Cholestasis Rat Model

by Kimitaka Takitani, Kanta Kishi, Hiroshi Miyazaki, Maki Koh, Hirofumi Tamaki, Akiko Inoue and Hiroshi Tamai

Int. J. Mol. Sci. 2018, 19(11), 3337; https://doi.org/10.3390/ijms19113337 - 26 Oct 2018

Cited by 3 | Viewed by 3911

Abstract

Cholestasis is defined as a reduction of bile secretion caused by a dysfunction of bile formation. Insufficient bile secretion into the intestine undermines the formation of micelles, which may result in the reduced absorption of lipids and fat-soluble vitamins. Here, we investigated the [...] Read more.

Cholestasis is defined as a reduction of bile secretion caused by a dysfunction of bile formation. Insufficient bile secretion into the intestine undermines the formation of micelles, which may result in the reduced absorption of lipids and fat-soluble vitamins. Here, we investigated the retinol homeostasis and the alterations of retinol metabolism-related genes, including β-carotene 15,15′ monooxygenase (BCMO), lecithin:retinol acyltransferase (LRAT), aldehyde dehydrogenase (ALDH), cytochrome P450 26A1 (CYP26A1), and retinoic acid receptors (RAR) β, in a α-naphthyl isothiocyanate (ANIT)-induced cholestasis rat model. Moreover, we examined the expression of the farnesoid X receptor (FXR) target genes. Our results showed that plasma retinol levels were decreased in ANIT rats compared to control rats. On the contrary, hepatic retinol levels were not different between the two groups. The expression of FXR target genes in the liver and intestine of cholestasis model rats was repressed. The BCMO expression was decreased in the liver and increased in the intestine of ANIT rats compared to control rats. Finally, the hepatic expression of LRAT, RARβ, and ALDH1A1 in cholestatic rats was decreased compared to the control rats, while the CYP26A1 expression of the liver was not altered. The increased expression of intestinal BCMO in cholestasis model rats might compensate for decreased circulatory retinol levels. The BCMO expression might be regulated in a tissue-specific manner to maintain the homeostasis of retinol. Full article

(This article belongs to the Special Issue Molecular Biology of Nuclear Receptors)

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12 pages, 1754 KiB

Open AccessArticle

Efficient Lead Finding, Activity Enhancement and Preliminary Selectivity Control of Nuclear Receptor Ligands Bearing a Phenanthridinone Skeleton

by Yuko Nishiyama, Shinya Fujii, Makoto Makishima, Yuichi Hashimoto and Minoru Ishikawa

Int. J. Mol. Sci. 2018, 19(7), 2090; https://doi.org/10.3390/ijms19072090 - 18 Jul 2018

Cited by 3 | Viewed by 3816

Abstract

Background: Nuclear receptors (NRs) are considered as potential drug targets because they control diverse biological functions. However, steroidal ligands for NRs have the potential to cross-react with other nuclear receptors, so development of non-steroidal NR ligands is desirable to obtain safer agents for [...] Read more.

Background: Nuclear receptors (NRs) are considered as potential drug targets because they control diverse biological functions. However, steroidal ligands for NRs have the potential to cross-react with other nuclear receptors, so development of non-steroidal NR ligands is desirable to obtain safer agents for clinical use. We anticipated that efficient lead finding and enhancement of activity toward nuclear receptors recognizing endogenous steroidal ligands might be achieved by exhaustive evaluation of a steroid surrogate library coupled with examination of structure-activity relationships (SAR). Method: We evaluated our library of RORs (retinoic acid receptor-related orphan receptors) inverse agonists and/or PR (progesterone receptor) antagonists based on the phenanthridinone skeleton for antagonistic activities toward liver X receptors (LXRs), androgen receptor (AR) and glucocorticoid receptor (GR) and examined their SAR. Results: Potent LXRβ, AR, and GR antagonists were identified. SAR studies led to a potent AR antagonist (IC₅₀: 0.059 μM). Conclusions: Our approach proved effective for efficient lead finding, activity enhancement and preliminary control of selectivity over other receptors. The phenanthridinone skeleton appears to be a promising steroid surrogate. Full article

(This article belongs to the Special Issue Molecular Biology of Nuclear Receptors)

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10 pages, 1198 KiB

Open AccessCommunication

Lithocholic Acid Is a Vitamin D Receptor Ligand That Acts Preferentially in the Ileum

by Michiyasu Ishizawa, Daisuke Akagi and Makoto Makishima

Int. J. Mol. Sci. 2018, 19(7), 1975; https://doi.org/10.3390/ijms19071975 - 6 Jul 2018

Cited by 46 | Viewed by 6411

Abstract

The vitamin D receptor (VDR) is a nuclear receptor that mediates the biological action of the active form of vitamin D, 1α,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], and regulates calcium and bone metabolism. Lithocholic acid (LCA), which is a secondary bile [...] Read more.

The vitamin D receptor (VDR) is a nuclear receptor that mediates the biological action of the active form of vitamin D, 1α,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃], and regulates calcium and bone metabolism. Lithocholic acid (LCA), which is a secondary bile acid produced by intestinal bacteria, acts as an additional physiological VDR ligand. Despite recent progress, however, the physiological function of the LCA−VDR axis remains unclear. In this study, in order to elucidate the differences in VDR action induced by 1,25(OH)₂D₃ and LCA, we compared their effect on the VDR target gene induction in the intestine of mice. While the oral administration of 1,25(OH)₂D₃ induced the Cyp24a1 expression effectively in the duodenum and jejunum, the LCA increased target gene expression in the ileum as effectively as 1,25(OH)₂D₃. 1,25(OH)₂D₃, but not LCA, increased the expression of the calcium transporter gene Trpv6 in the upper intestine, and increased the plasma calcium levels. Although LCA could induce an ileal Cyp24a1 expression as well as 1,25(OH)₂D₃, the oral LCA administration was not effective in the VDR target gene induction in the kidney. No effect of LCA on the ileal Cyp24a1 expression was observed in the VDR-null mice. Thus, the results indicate that LCA is a selective VDR ligand acting in the lower intestine, particularly the ileum. LCA may be a signaling molecule, which links intestinal bacteria and host VDR function. Full article

(This article belongs to the Special Issue Molecular Biology of Nuclear Receptors)

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9 pages, 3744 KiB

Open AccessArticle

Farnesoid X Receptor Activation Enhances Transforming Growth Factor β-Induced Epithelial-Mesenchymal Transition in Hepatocellular Carcinoma Cells

by Masahiko Kainuma, Ichiro Takada, Makoto Makishima and Keiji Sano

Int. J. Mol. Sci. 2018, 19(7), 1898; https://doi.org/10.3390/ijms19071898 - 28 Jun 2018

Cited by 29 | Viewed by 4949

Abstract

Farnesoid X receptor (FXR) is a receptor for bile acids and plays an important role in the regulation of bile acid metabolism in the liver. Although FXR has been shown to affect hepatocarcinogenesis through both direct and indirect mechanisms, potential roles of FXR [...] Read more.

Farnesoid X receptor (FXR) is a receptor for bile acids and plays an important role in the regulation of bile acid metabolism in the liver. Although FXR has been shown to affect hepatocarcinogenesis through both direct and indirect mechanisms, potential roles of FXR in epithelial–mesenchymal transition (EMT) in hepatocellular carcinoma (HCC) remain unclear. We examined the effect of several FXR ligands on EMT-related morphological changes in HCC cell lines, such as HuH-7 and Hep3B cells. FXR agonists (chenodeoxycholic acid, GW4064, and obeticholic acid)—but not an antagonist (guggulsterone)—induced actin polymerization and expression of N-cadherin and phosphorylated focal adhesion kinase, although they were less effective than transforming growth factor β (TGF-β). FXR agonist treatment enhanced TGF-β-induced EMT morphologic changes and FXR antagonist inhibited the effect of TGF-β. Thus, FXR activation enhances EMT in HCC and FXR antagonists may be EMT-suppressing drug candidates. Full article

(This article belongs to the Special Issue Molecular Biology of Nuclear Receptors)

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15 pages, 2027 KiB

Open AccessArticle

Ethanolic Extracts from Azadirachta indica Leaves Modulate Transcriptional Levels of Hormone Receptor Variant in Breast Cancer Cell Lines

by Deisi L. Braga, Sara T. S. Mota, Mariana A. P. Zóia, Paula M. A. P. Lima, Priscila C. Orsolin, Lara Vecchi, Júlio C. Nepomuceno, Cristina R. Fürstenau, Yara C. P. Maia, Luiz Ricardo Goulart and Thaise G. Araújo

Int. J. Mol. Sci. 2018, 19(7), 1879; https://doi.org/10.3390/ijms19071879 - 26 Jun 2018

Cited by 4 | Viewed by 5510

Abstract

Breast Cancer (BC) encompasses numerous entities with different biological and behavioral characteristics, favored by tumor molecular complexity. Azadirachta indica (neem) presents phenolic compounds, indicating its potential as an antineoplastic compound. The present study aimed to evaluate the cellular response of MCF10, MCF7, and [...] Read more.

Breast Cancer (BC) encompasses numerous entities with different biological and behavioral characteristics, favored by tumor molecular complexity. Azadirachta indica (neem) presents phenolic compounds, indicating its potential as an antineoplastic compound. The present study aimed to evaluate the cellular response of MCF10, MCF7, and MDA-MB-231 breast cell lines to ethanolic extracts of neem leaves (EENL) obtained by dichloromethane (DCM) and ethyl acetate (EA) solvent. Extracts’ antiproliferative activities were evaluated against MCF 10A, MCF7, and MDA-MB-231 for 24 and 48 h using MTT assay. ESR1, ESR2, AR, AR-V1, AR-V4, and AR-V7 transcripts were quantified through qPCR for 0.03125 μg/mL of DCM and 1.0 μg/mL for EA for 48 h. The EENL was tested on Drosophila melanogaster as a sole treatment and then also together with doxorubicin. Antiproliferative effect on tumor cell lines without affecting MCF 10A were 1.0 µg/mL (P < 0.001) for EA, and 0.03125 µg/mL (P < 0.0001) for DCM, both after 48 h. Transcriptional levels of AR-V7 increased after treatment. In vivo assays demonstrated that EENL induced fewer tumors at a higher concentration with doxorubicin (DXR). The behavior of AR-V7 in the MDA-MB-231 tumor lineage indicates new pathways involved in tumor biology and this may have therapeutic value for cancer. Full article

(This article belongs to the Special Issue Molecular Biology of Nuclear Receptors)

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16 pages, 26280 KiB

Open AccessArticle

Endocrine Disruption at the Androgen Receptor: Employing Molecular Dynamics and Docking for Improved Virtual Screening and Toxicity Prediction

by Joel Wahl and Martin Smieško

Int. J. Mol. Sci. 2018, 19(6), 1784; https://doi.org/10.3390/ijms19061784 - 15 Jun 2018

Cited by 31 | Viewed by 5953

Abstract

The androgen receptor (AR) is a key target for the development of drugs targeting hormone-dependent prostate cancer, but has also an important role in endocrine disruption. Reliable prediction of the binding of ligands towards the AR is therefore of great relevance. Molecular docking [...] Read more.

The androgen receptor (AR) is a key target for the development of drugs targeting hormone-dependent prostate cancer, but has also an important role in endocrine disruption. Reliable prediction of the binding of ligands towards the AR is therefore of great relevance. Molecular docking is a powerful computational method for exploring small-ligand binding to proteins. It can be applied for virtual screening experiments but also for predicting molecular initiating events in toxicology. However, in case of AR, there is no antagonist-bound crystal structure yet available. Our study demonstrates that molecular docking approaches are not able to satisfactorily screen for AR antagonists because of this reason. Therefore, we applied Molecular Dynamics simulations to generate antagonist AR structures and showed that this leads to a vast improvement for the docking of AR antagonists. We benchmarked the ability of these antagonist AR structures discriminate between AR antagonists and decoys using an ensemble docking approach and obtained promising results with good enrichment. However, distinguishing AR antagonists from agonists with high confidence is not possible with the current approach alone. Full article

(This article belongs to the Special Issue Molecular Biology of Nuclear Receptors)

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16 pages, 3911 KiB

Open AccessArticle

Involvement of MAFB and MAFF in Retinoid-Mediated Suppression of Hepatocellular Carcinoma Invasion

by Hiroyuki Tsuchiya and Seiya Oura

Int. J. Mol. Sci. 2018, 19(5), 1450; https://doi.org/10.3390/ijms19051450 - 13 May 2018

Cited by 11 | Viewed by 4495

Abstract

Retinoids exert antitumor effects through the retinoic acid receptor α (RARα). In the present study, we sought to identify the factors involved in the RARα-mediated transcriptional regulation of the tumor suppressor gene and the tissue factor pathway inhibitor 2 (TFPI2) in hepatocellular carcinoma [...] Read more.

Retinoids exert antitumor effects through the retinoic acid receptor α (RARα). In the present study, we sought to identify the factors involved in the RARα-mediated transcriptional regulation of the tumor suppressor gene and the tissue factor pathway inhibitor 2 (TFPI2) in hepatocellular carcinoma (HCC). All-trans-retinoic acid (ATRA) was used in the in vitro experiments. Cell invasiveness was measured using trans-well invasion assay. ATRA significantly increased TFPI2 expression through RARα in a human HCC cell line known as HuH7. TFPI2 was vital in the ATRA-mediated suppression of HuH7 cell invasion. The musculo-aponeurotic fibrosarcoma oncogene homolog B (MAFB) significantly enhanced the activation of the TFPI2 promoter via RARα while MAFF inhibited it. The knockdown of RARα or MAFB counteracted the ATRA-mediated suppression of HuH7 cell invasion while the knockdown of MAFF inhibited the invasion. TFPI2 expression in HCC tissues was significantly downregulated possibly due to the decreased expression of RARβ and MAFB. Patients with HCC expressing low MAFB and high MAFF levels showed the shortest disease-free survival time. These results suggest that MAFB and MAFF play critical roles in the antitumor effects of retinoids by regulating the expression of retinoid target genes such as TFPI2 and can be promising for developing therapies to combat HCC invasion. Full article

(This article belongs to the Special Issue Molecular Biology of Nuclear Receptors)

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13 pages, 1376 KiB

Open AccessArticle

Endogenous Purification of NR4A2 (Nurr1) Identified Poly(ADP-Ribose) Polymerase 1 as a Prime Coregulator in Human Adrenocortical H295R Cells

by Erika Noro, Atsushi Yokoyama, Makoto Kobayashi, Hiroki Shimada, Susumu Suzuki, Mari Hosokawa, Tomohiro Takehara, Rehana Parvin, Hiroki Shima, Kazuhiko Igarashi and Akira Sugawara

Int. J. Mol. Sci. 2018, 19(5), 1406; https://doi.org/10.3390/ijms19051406 - 8 May 2018

Cited by 6 | Viewed by 5839

Abstract

Aldosterone is synthesized in zona glomerulosa of adrenal cortex in response to angiotensin II. This stimulation transcriptionally induces expression of a series of steroidogenic genes such as HSD3B and CYP11B2 via NR4A (nuclear receptor subfamily 4 group A) nuclear receptors and ATF (activating [...] Read more.

Aldosterone is synthesized in zona glomerulosa of adrenal cortex in response to angiotensin II. This stimulation transcriptionally induces expression of a series of steroidogenic genes such as HSD3B and CYP11B2 via NR4A (nuclear receptor subfamily 4 group A) nuclear receptors and ATF (activating transcription factor) family transcription factors. Nurr1 belongs to the NR4A family and is regarded as an orphan nuclear receptor. The physiological significance of Nurr1 in aldosterone production in adrenal cortex has been well studied. However, coregulators supporting the Nurr1 function still remain elusive. In this study, we performed RIME (rapid immunoprecipitation mass spectrometry of endogenous proteins), a recently developed endogenous coregulator purification method, in human adrenocortical H295R cells and identified PARP1 as one of the top Nurr1-interacting proteins. Nurr1-PARP1 interaction was verified by co-immunoprecipitation. In addition, both siRNA knockdown of PARP1 and treatment of AG14361, a specific PARP1 inhibitor suppressed the angiotensin II-mediated target gene induction in H295R cells. Furthermore, PARP1 inhibitor also suppressed the aldosterone secretion in response to the angiotensin II. Together, these results suggest PARP1 is a prime coregulator for Nurr1. Full article

(This article belongs to the Special Issue Molecular Biology of Nuclear Receptors)

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Review

Jump to: Research

24 pages, 1911 KiB

Open AccessReview

Nuclear Receptor Metabolism of Bile Acids and Xenobiotics: A Coordinated Detoxification System with Impact on Health and Diseases

by Manon Garcia, Laura Thirouard, Lauriane Sedès, Mélusine Monrose, Hélène Holota, Françoise Caira, David H. Volle and Claude Beaudoin

Int. J. Mol. Sci. 2018, 19(11), 3630; https://doi.org/10.3390/ijms19113630 - 17 Nov 2018

Cited by 40 | Viewed by 7574

Abstract

Structural and functional studies have provided numerous insights over the past years on how members of the nuclear hormone receptor superfamily tightly regulate the expression of drug-metabolizing enzymes and transporters. Besides the role of the farnesoid X receptor (FXR) in the transcriptional control [...] Read more.

Structural and functional studies have provided numerous insights over the past years on how members of the nuclear hormone receptor superfamily tightly regulate the expression of drug-metabolizing enzymes and transporters. Besides the role of the farnesoid X receptor (FXR) in the transcriptional control of bile acid transport and metabolism, this review provides an overview on how this metabolic sensor prevents the accumulation of toxic byproducts derived from endogenous metabolites, as well as of exogenous chemicals, in coordination with the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR). Decrypting this network should provide cues to better understand how these metabolic nuclear receptors participate in physiologic and pathologic processes with potential validation as therapeutic targets in human disabilities and cancers. Full article

(This article belongs to the Special Issue Molecular Biology of Nuclear Receptors)

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14 pages, 863 KiB

Open AccessReview

Novel Transcriptional Mechanisms for Regulating Metabolism by Thyroid Hormone

by Brijesh Kumar Singh, Rohit Anthony Sinha and Paul Michael Yen

Int. J. Mol. Sci. 2018, 19(10), 3284; https://doi.org/10.3390/ijms19103284 - 22 Oct 2018

Cited by 36 | Viewed by 6828

Abstract

The thyroid hormone plays a key role in energy and nutrient metabolisms in many tissues and regulates the transcription of key genes in metabolic pathways. It has long been believed that thyroid hormones (THs) exerted their effects primarily by binding to nuclear TH [...] Read more.

The thyroid hormone plays a key role in energy and nutrient metabolisms in many tissues and regulates the transcription of key genes in metabolic pathways. It has long been believed that thyroid hormones (THs) exerted their effects primarily by binding to nuclear TH receptors (THRs) that are associated with conserved thyroid hormone response elements (TREs) located on the promoters of target genes. However, recent transcriptome and ChIP-Seq studies have challenged this conventional view as discordance was observed between TH-responsive genes and THR binding to DNA. While THR association with other transcription factors bound to DNA, TH activation of THRs to mediate effects that do not involve DNA-binding, or TH binding to proteins other than THRs have been invoked as potential mechanisms to explain this discrepancy, it appears that additional novel mechanisms may enable TH to regulate the mRNA expression. These include activation of transcription factors by SIRT1 via metabolic actions by TH, the post-translational modification of THR, the THR co-regulation of transcription with other nuclear receptors and transcription factors, and the microRNA (miR) control of RNA transcript expression to encode proteins involved in the cellular metabolism. Together, these novel mechanisms enlarge and diversify the panoply of metabolic genes that can be regulated by TH. Full article

(This article belongs to the Special Issue Molecular Biology of Nuclear Receptors)

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20 pages, 1237 KiB

Open AccessReview

New Insights in Prostate Cancer Development and Tumor Therapy: Modulation of Nuclear Receptors and the Specific Role of Liver X Receptors

by Laura Bousset, Amandine Rambur, Allan Fouache, Julio Bunay, Laurent Morel, Jean-Marc A. Lobaccaro, Silvère Baron, Amalia Trousson and Cyrille De Joussineau

Int. J. Mol. Sci. 2018, 19(9), 2545; https://doi.org/10.3390/ijms19092545 - 28 Aug 2018

Cited by 12 | Viewed by 5043

Abstract

Prostate cancer (PCa) incidence has been dramatically increasing these last years in westernized countries. Though localized PCa is usually treated by radical prostatectomy, androgen deprivation therapy is preferred in locally advanced disease in combination with chemotherapy. Unfortunately, PCa goes into a castration-resistant state [...] Read more.

Prostate cancer (PCa) incidence has been dramatically increasing these last years in westernized countries. Though localized PCa is usually treated by radical prostatectomy, androgen deprivation therapy is preferred in locally advanced disease in combination with chemotherapy. Unfortunately, PCa goes into a castration-resistant state in the vast majority of the cases, leading to questions about the molecular mechanisms involving the steroids and their respective nuclear receptors in this relapse. Interestingly, liver X receptors (LXRα/NR1H3 and LXRβ/NR1H2) have emerged as new actors in prostate physiology, beyond their historical roles of cholesterol sensors. More importantly LXRs have been proposed to be good pharmacological targets in PCa. This rational has been based on numerous experiments performed in PCa cell lines and genetic animal models pointing out that using selective liver X receptor modulators (SLiMs) could actually be a good complementary therapy in patients with a castration resistant PCa. Hence, this review is focused on the interaction among the androgen receptors (AR/NR3C4), estrogen receptors (ERα/NR3A1 and ERβ/NR3A2), and LXRs in prostate homeostasis and their putative pharmacological modulations in parallel to the patients’ support. Full article

(This article belongs to the Special Issue Molecular Biology of Nuclear Receptors)

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20 pages, 6006 KiB

Open AccessReview

Retinoid X Receptor Antagonists

by Masaki Watanabe and Hiroki Kakuta

Int. J. Mol. Sci. 2018, 19(8), 2354; https://doi.org/10.3390/ijms19082354 - 10 Aug 2018

Cited by 29 | Viewed by 6452

Abstract

Retinoid X receptor (RXR) antagonists are not only useful as chemical tools for biological research, but are also candidate drugs for the treatment of various diseases, including diabetes and allergies, although no RXR antagonist has yet been approved for clinical use. In this [...] Read more.

Retinoid X receptor (RXR) antagonists are not only useful as chemical tools for biological research, but are also candidate drugs for the treatment of various diseases, including diabetes and allergies, although no RXR antagonist has yet been approved for clinical use. In this review, we present a brief overview of RXR structure, function, and target genes, and describe currently available RXR antagonists, their structural classification, and their evaluation, focusing on the latest research. Full article

(This article belongs to the Special Issue Molecular Biology of Nuclear Receptors)

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20 pages, 467 KiB

Open AccessReview

Beyond the Foam Cell: The Role of LXRs in Preventing Atherogenesis

by Adil Rasheed and Carolyn L. Cummins

Int. J. Mol. Sci. 2018, 19(8), 2307; https://doi.org/10.3390/ijms19082307 - 7 Aug 2018

Cited by 32 | Viewed by 5929

Abstract

Atherosclerosis is a chronic condition associated with cardiovascular disease. While largely identified by the accumulation of lipid-laden foam cells within the aorta later on in life, atherosclerosis develops over several stages and decades. During atherogenesis, various cell types of the aorta acquire a [...] Read more.

Atherosclerosis is a chronic condition associated with cardiovascular disease. While largely identified by the accumulation of lipid-laden foam cells within the aorta later on in life, atherosclerosis develops over several stages and decades. During atherogenesis, various cell types of the aorta acquire a pro-inflammatory phenotype that initiates the cascade of signaling events facilitating the formation of these foam cells. The liver X receptors (LXRs) are nuclear receptors that upon activation induce the expression of transporters responsible for promoting cholesterol efflux. In addition to promoting cholesterol removal from the arterial wall, LXRs have potent anti-inflammatory actions via the transcriptional repression of key pro-inflammatory cytokines. These beneficial functions sparked an interest in the potential to target LXRs and the development of agonists as anti-atherogenic agents. These early studies focused on mediating the contributions of macrophages to the underlying pathogenesis. However, further evidence has since demonstrated that LXRs reduce atherosclerosis through their actions in multiple cell types apart from those monocytes/macrophages that infiltrate the lesion. LXRs and their target genes have profound effects on multiple other cells types of the hematopoietic system. Furthermore, LXRs can also mediate dysfunction within vascular cell types of the aorta including endothelial and smooth muscle cells. Taken together, these studies demonstrate the whole-body benefits of LXR activation with respect to anti-atherogenesis, and that LXRs remain a viable target for the treatment of atherosclerosis, with a reach which extends beyond plaque macrophages. Full article

(This article belongs to the Special Issue Molecular Biology of Nuclear Receptors)

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15 pages, 1935 KiB

Open AccessReview

Liver X Receptors: A Possible Link between Lipid Disorders and Female Infertility

by Sarah Dallel, Igor Tauveron, Florence Brugnon, Silvère Baron, Jean Marc A. Lobaccaro and Salwan Maqdasy

Int. J. Mol. Sci. 2018, 19(8), 2177; https://doi.org/10.3390/ijms19082177 - 25 Jul 2018

Cited by 16 | Viewed by 7068

Abstract

A close relationship exists between cholesterol and female reproductive physiology. Indeed, cholesterol is crucial for steroid synthesis by ovary and placenta, and primordial for cell structure during folliculogenesis. Furthermore, oxysterols, cholesterol-derived ligands, play a potential role in oocyte maturation. Anomalies of cholesterol metabolism [...] Read more.

A close relationship exists between cholesterol and female reproductive physiology. Indeed, cholesterol is crucial for steroid synthesis by ovary and placenta, and primordial for cell structure during folliculogenesis. Furthermore, oxysterols, cholesterol-derived ligands, play a potential role in oocyte maturation. Anomalies of cholesterol metabolism are frequently linked to infertility. However, little is known about the molecular mechanisms. In parallel, increasing evidence describing the biological roles of liver X receptors (LXRs) in the regulation of steroid synthesis and inflammation, two processes necessary for follicle maturation and ovulation. Both of the isoforms of LXRs and their bona fide ligands are present in the ovary. LXR-deficient mice develop late sterility due to abnormal oocyte maturation and increased oocyte atresia. These mice also have an ovarian hyper stimulation syndrome in response to gonadotropin stimulation. Hence, further studies are necessary to explore their specific roles in oocyte, granulosa, and theca cells. LXRs also modulate estrogen signaling and this could explain the putative protective role of the LXRs in breast cancer growth. Altogether, clinical studies would be important for determining the physiological relevance of LXRs in reproductive disorders in women. Full article

(This article belongs to the Special Issue Molecular Biology of Nuclear Receptors)

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25 pages, 1786 KiB

Open AccessReview

Update on FXR Biology: Promising Therapeutic Target?

by Chang Yeob Han

Int. J. Mol. Sci. 2018, 19(7), 2069; https://doi.org/10.3390/ijms19072069 - 16 Jul 2018

Cited by 149 | Viewed by 12144

Abstract

Farnesoid X receptor (FXR), a metabolic nuclear receptor, plays critical roles in the maintenance of systemic energy homeostasis and the integrity of many organs, including liver and intestine. It regulates bile acid, lipid, and glucose metabolism, and contributes to inter-organ communication, in particular [...] Read more.

Farnesoid X receptor (FXR), a metabolic nuclear receptor, plays critical roles in the maintenance of systemic energy homeostasis and the integrity of many organs, including liver and intestine. It regulates bile acid, lipid, and glucose metabolism, and contributes to inter-organ communication, in particular the enterohepatic signaling pathway, through bile acids and fibroblast growth factor-15/19 (FGF-15/19). The metabolic effects of FXR are also involved in gut microbiota. In addition, FXR has various functions in the kidney, adipose tissue, pancreas, cardiovascular system, and tumorigenesis. Consequently, the deregulation of FXR may lead to abnormalities of specific organs and metabolic dysfunction, allowing the protein as an attractive therapeutic target for the management of liver and/or metabolic diseases. Indeed, many FXR agonists have been being developed and are under pre-clinical and clinical investigations. Although obeticholic acid (OCA) is one of the promising candidates, significant safety issues have remained. The effects of FXR modulation might be multifaceted according to tissue specificity, disease type, and/or energy status, suggesting the careful use of FXR agonists. This review summarizes the current knowledge of systemic FXR biology in various organs and the gut–liver axis, particularly regarding the recent advancement in these fields, and also provides pharmacological aspects of FXR modulation for rational therapeutic strategies and novel drug development. Full article

(This article belongs to the Special Issue Molecular Biology of Nuclear Receptors)

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20 pages, 776 KiB

Open AccessReview

Integrating Thyroid Hormone Signaling in Hypothalamic Control of Metabolism: Crosstalk Between Nuclear Receptors

by Soumaya Kouidhi and Marie-Stéphanie Clerget-Froidevaux

Int. J. Mol. Sci. 2018, 19(7), 2017; https://doi.org/10.3390/ijms19072017 - 11 Jul 2018

Cited by 27 | Viewed by 11954

Abstract

The obesity epidemic is well recognized as a significant global health issue. A better understanding of the energy homeostasis mechanisms could help to identify promising anti-obesity therapeutic strategies. It is well established that the hypothalamus plays a pivotal role governing energy balance. The [...] Read more.

The obesity epidemic is well recognized as a significant global health issue. A better understanding of the energy homeostasis mechanisms could help to identify promising anti-obesity therapeutic strategies. It is well established that the hypothalamus plays a pivotal role governing energy balance. The hypothalamus consists of tightly interconnected and specialized neurons that permit the sensing and integration of several peripheral inputs, including metabolic and hormonal signals for an appropriate physiological response. Current evidence shows that thyroid hormones (THs) constitute one of the key endocrine factors governing the regulation and the integration of metabolic homeostasis at the hypothalamic level. THs modulate numerous genes involved in the central control of metabolism, as TRH (Thyrotropin-Releasing Hormone) and MC4R (Melanocortin 4 Receptor). THs act through their interaction with thyroid hormone receptors (TRs). Interestingly, TH signaling, especially regarding metabolic regulations, involves TRs crosstalk with other metabolically linked nuclear receptors (NRs) including PPAR (Peroxisome proliferator-activated receptor) and LXR (Liver X receptor). In this review, we will summarize current knowledge on the important role of THs integration of metabolic pathways in the central regulation of metabolism. Particularly, we will shed light on the crosstalk between TRs and other NRs in controlling energy homeostasis. This could be an important track for the development of attractive therapeutic compounds. Full article

(This article belongs to the Special Issue Molecular Biology of Nuclear Receptors)

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19 pages, 324 KiB

Open AccessReview

Roles of the Glucocorticoid and Mineralocorticoid Receptors in Skin Pathophysiology

by Lisa M. Sevilla and Paloma Pérez

Int. J. Mol. Sci. 2018, 19(7), 1906; https://doi.org/10.3390/ijms19071906 - 29 Jun 2018

Cited by 45 | Viewed by 8231

Abstract

The nuclear hormone receptor (NR) superfamily comprises approximately 50 evolutionarily conserved proteins that play major roles in gene regulation by prototypically acting as ligand-dependent transcription factors. Besides their central role in physiology, NRs have been largely used as therapeutic drug targets in many [...] Read more.

The nuclear hormone receptor (NR) superfamily comprises approximately 50 evolutionarily conserved proteins that play major roles in gene regulation by prototypically acting as ligand-dependent transcription factors. Besides their central role in physiology, NRs have been largely used as therapeutic drug targets in many chronic inflammatory conditions and derivatives of their specific ligands, alone or in combination, are frequently prescribed for the treatment of skin diseases. In particular, glucocorticoids (GCs) are the most commonly used compounds for treating prevalent skin diseases such as psoriasis due to their anti-proliferative and anti-inflammatory actions. However, and despite their therapeutic efficacy, the long-term use of GCs is limited because of the cutaneous adverse effects including atrophy, delayed wound healing, and increased susceptibility to stress and infections. The GC receptor (GR/NR3C1) and the mineralocorticoid receptor (MR/NR3C2) are members of the NR subclass NR3C that are highly related, both structurally and functionally. While the GR is ubiquitously expressed and is almost exclusively activated by GCs; an MR has a more restricted tissue expression pattern and can bind GCs and the mineralocorticoid aldosterone with similar high affinity. As these receptors share 95% identity in their DNA binding domains; both can recognize the same hormone response elements; theoretically resulting in transcriptional regulation of the same target genes. However, a major mechanism for specific activation of GRs and/or MRs is at the pre-receptor level by modulating the local availability of active GCs. Furthermore, the selective interactions of each receptor with spatio-temporally regulated transcription factors and co-regulators are crucial for the final transcriptional outcome. While there are abundant genome wide studies identifying GR transcriptional targets in a variety of tissue and cell types; including keratinocytes; the data for MR is more limited thus far. Our group and others have studied the role of GRs and MRs in skin development and disease by generating and characterizing mouse and cellular models with gain- and loss-of-function for each receptor. Both NRs are required for skin barrier competence during mouse development and also play a role in adult skin homeostasis. Moreover, the combined loss of epidermal GRs and MRs caused a more severe skin phenotype relative to single knock-outs (KOs) in developing skin and in acute inflammation and psoriasis, indicating that these corticosteroid receptors play cooperative roles. Understanding GR- and MR-mediated signaling in skin should contribute to deciphering their tissue-specific relative roles and ultimately help to improve GC-based therapies. Full article

(This article belongs to the Special Issue Molecular Biology of Nuclear Receptors)

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13 pages, 575 KiB

Open AccessReview

Nuclear Receptor Regulation of Aquaglyceroporins in Metabolic Organs

by Matteo Tardelli, Thierry Claudel, Francesca Virginia Bruschi and Michael Trauner

Int. J. Mol. Sci. 2018, 19(6), 1777; https://doi.org/10.3390/ijms19061777 - 15 Jun 2018

Cited by 12 | Viewed by 4790

Abstract

Nuclear receptors, such as the farnesoid X receptor (FXR) and the peroxisome proliferator-activated receptors gamma and alpha (PPAR-γ, -α), are major metabolic regulators in adipose tissue and the liver, where they govern lipid, glucose, and bile acid homeostasis, as well as inflammatory cascades. [...] Read more.

Nuclear receptors, such as the farnesoid X receptor (FXR) and the peroxisome proliferator-activated receptors gamma and alpha (PPAR-γ, -α), are major metabolic regulators in adipose tissue and the liver, where they govern lipid, glucose, and bile acid homeostasis, as well as inflammatory cascades. Glycerol and free fatty acids are the end products of lipid droplet catabolism driven by PPARs. Aquaporins (AQPs), a family of 13 small transmembrane proteins, facilitate the shuttling of water, urea, and/or glycerol. The peculiar role of AQPs in glycerol transport makes them pivotal targets in lipid metabolism, especially considering their tissue-specific regulation by the nuclear receptors PPARγ and PPARα. Here, we review the role of nuclear receptors in the regulation of glycerol shuttling in liver and adipose tissue through the function and expression of AQPs. Full article

(This article belongs to the Special Issue Molecular Biology of Nuclear Receptors)

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