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Nuclear Receptors in Health and Diseases

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 March 2023) | Viewed by 33858

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Dr. Pengfei Xu

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1. School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China
2. Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15261, USA
Interests: gut microbiota; intestinal and liver physiology; inflammatory bowel disease and colon cancer; liver diseases; metabolic diseases; nuclear receptors; lipid metabolism
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Dear Colleagues,

Nuclear receptors (NRs) are a superfamily of transcription factors, which consist of 48 NRs in the human genome, and 24 are ligand-dependent transcription factors. In general, NRs are crucial mediators of health and diseases. They can bind directly to DNA (sequence-specific promoter elements) to regulate the expression of target genes, thereby controlling the metabolism, homeostasis, development, and reproduction. Recently, accumulating evidence has emerged suggesting that NRs are ideal pharmacological targets for drug discovery. As a consequence, NRs play a key role in maintaining health and treating multiple diseases. This Special Issue provides an open-access forum that aims to bring together a collection of review and original research articles addressing the functions of NRs in physiological and pathological states. To this end, we welcome contributions that could cover the roles of NRs and their essential signaling pathways and metabolic mechanisms in the context of health maintenance and disease pathogenesis. We look forward to providing an exciting resource on the theme of NRs in health and diseases.

Dr. Pengfei Xu
Guest Editor

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Keywords

nuclear receptors
hormone receptors
orphan receptors
retinoid receptors
PPARs
PXR
CAR
LXRs
FXR
RORs
RXRs
ERs
HNF4s
health
metabolic diseases
cancers
drug metabolism
agonists and antagonists
coactivators and corepressors

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Nuclear Receptors in Health and Diseases 2.0 in International Journal of Molecular Sciences (1 article)

Published Papers (12 papers)

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Editorial

Jump to: Research, Review

6 pages, 813 KiB

Open AccessEditorial

Nuclear Receptors in Health and Diseases

by Pengfei Xu

Int. J. Mol. Sci. 2023, 24(11), 9153; https://doi.org/10.3390/ijms24119153 - 23 May 2023

Cited by 4 | Viewed by 2241

Abstract

Nuclear receptors (NRs) are a vital superfamily of transcription factors that play crucial roles in physiology and pharmacology [...] Full article

(This article belongs to the Special Issue Nuclear Receptors in Health and Diseases)

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Research

Jump to: Editorial, Review

13 pages, 8510 KiB

Open AccessArticle

Fibrates Affect Levels of Phosphorylated p38 in Intestinal Cells in a Differentiation-Dependent Manner

by Katerina Cizkova and Zdenek Tauber

Int. J. Mol. Sci. 2023, 24(9), 7695; https://doi.org/10.3390/ijms24097695 - 22 Apr 2023

Cited by 1 | Viewed by 1778

Abstract

Fibrates are widely used hypolipidaemic agents that act as ligands of the peroxisome proliferator-activated receptor α (PPARα). p38 is a protein kinase that is mainly activated by environmental and genotoxic stress. We investigated the effect of the PPARα activators fenofibrate and WY-14643 and the PPARα inhibitor GW6471 on the levels of activated p38 (p-p38) in the colorectal cancer cell lines HT-29 and Caco2 in relation to their differentiation status. Fibrates increased p-p38 in undifferentiated HT-29 cells, whereas in other cases p-p38 expression was decreased. HT-29 cells showed p-p38 predominantly in the cytoplasm, whereas Caco2 cells showed higher nuclear positivity. The effect of fibrates may depend on the differentiation status of the cell, as differentiated HT-29 and undifferentiated Caco2 cells share similar characteristics in terms of villin, CYP2J2, and soluble epoxide hydrolase (sEH) expression. In human colorectal carcinoma, higher levels of p-p38 were detected in the cytoplasm, whereas in normal colonic surface epithelium, p-p38 showed nuclear positivity. The decrease in p-p38 positivity was associated with a decrease in sEH, consistent with in vitro results. In conclusion, fibrates affect the level of p-p38, but its exact role in the process of carcinogenesis remains unclear and further research is needed in this area. Full article

(This article belongs to the Special Issue Nuclear Receptors in Health and Diseases)

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17 pages, 11166 KiB

Open AccessArticle

C-Terminal Truncated HBx Facilitates Oncogenesis by Modulating Cell Cycle and Glucose Metabolism in FXR-Deficient Hepatocellular Carcinoma

by Xuejun Wu, Zhengzhong Ni, Tiantian Song, Wenya Lv, Yan Chen, Danmei Huang, Yangmin Xie, Weiyi Huang and Yongdong Niu

Int. J. Mol. Sci. 2023, 24(6), 5174; https://doi.org/10.3390/ijms24065174 - 8 Mar 2023

Cited by 4 | Viewed by 2202

Abstract

Farnesoid X receptor (FXR) is a nuclear receptor known to play protective roles in anti-hepatocarcinogenesis and regulation of the basal metabolism of glucose, lipids, and bile acids. FXR expression is low or absent in HBV-associated hepatocarcinogenesis. Full-length HBx and HBx C-terminal truncation are frequently found in clinical HCC samples and play distinct roles in hepatocarcinogenesis by interacting with FXR or FXR signaling. However, the impact of C-terminal truncated HBx on the progression of hepatocarcinogenesis in the absence of FXR is unclear. In this study, we found that one known FXR binding protein, a C-terminal truncated X protein (HBx C40) enhanced obviously and promoted tumor cell proliferation and migration by altering cell cycle distribution and inducing apoptosis in the absence of FXR. HBx C40 enhanced the growth of FXR-deficient tumors in vivo. In addition, RNA-sequencing analysis showed that HBx C40 overexpression could affect energy metabolism. Overexpressed HSPB8 aggravated the metabolic reprogramming induced by down-regulating glucose metabolism-associated hexokinase 2 genes in HBx C40-induced hepatocarcinogenesis. Overall, our study suggests that C-terminal truncated HBx C40 synergizes with FXR deficiency by altering cell cycle distribution as well as disturbing glucose metabolism to promote HCC development. Full article

(This article belongs to the Special Issue Nuclear Receptors in Health and Diseases)

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19 pages, 5581 KiB

Open AccessArticle

Intestinal Farnesoid X Receptor Modulates Duodenal Surface Area but Does Not Control Glucose Absorption in Mice

by Jiufang Yang, Theo H. van Dijk, Martijn Koehorst, Rick Havinga, Jan Freark de Boer, Folkert Kuipers and Tim van Zutphen

Int. J. Mol. Sci. 2023, 24(4), 4132; https://doi.org/10.3390/ijms24044132 - 18 Feb 2023

Cited by 3 | Viewed by 3908

Abstract

Bile acids facilitate the intestinal absorption of dietary lipids and act as signalling molecules in the maintenance of metabolic homeostasis. Farnesoid X receptor (FXR) is a bile acid-responsive nuclear receptor involved in bile acid metabolism, as well as lipid and glucose homeostasis. Several studies have suggested a role of FXR in the control of genes regulating intestinal glucose handling. We applied a novel dual-label glucose kinetic approach in intestine-specific FXR^−/− mice (iFXR-KO) to directly assess the role of intestinal FXR in glucose absorption. Although iFXR-KO mice showed decreased duodenal expression of hexokinase 1 (Hk1) under obesogenic conditions, the assessment of glucose fluxes in these mice did not show a role for intestinal FXR in glucose absorption. FXR activation with the specific agonist GS3972 induced Hk1, yet the glucose absorption rate remained unaffected. FXR activation increased the duodenal villus length in mice treated with GS3972, while stem cell proliferation remained unaffected. Accordingly, iFXR-KO mice on either chow, short or long-term HFD feeding displayed a shorter villus length in the duodenum compared to wild-type mice. These findings indicate that delayed glucose absorption reported in whole-body FXR^−/− mice is not due to the absence of intestinal FXR. Yet, intestinal FXR does have a role in the small intestinal surface area. Full article

(This article belongs to the Special Issue Nuclear Receptors in Health and Diseases)

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19 pages, 6056 KiB

Open AccessArticle

Constitutive Androstane Receptor Agonist, TCPOBOP: Maternal Exposure Impairs the Growth and Development of Female Offspring in Mice

by Shijia Pan, Yuan Guo, Wen Yu, Jia Zhang, Xiaoxiao Qiao, Letong Li, Pengfei Xu and Yonggong Zhai

Int. J. Mol. Sci. 2023, 24(3), 2602; https://doi.org/10.3390/ijms24032602 - 30 Jan 2023

Cited by 2 | Viewed by 2023

Abstract

Environmental chemicals, which are known to impact offspring health, have become a public concern. Constitutive activated receptor (CAR) is activated by various environmental chemicals and participates in xenobiotic metabolism. Here, we described the effects of maternal exposure to the CAR-specific ligand 1,4-bis[2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP, TC) on offspring health outcomes. Maternal TC exposure exhibited a stronger inhibition of body weight in 3-week-old and 8-week-old first-generation (F1) offspring female mice compared to controls. Further, maternal TC exposure obtained a strong increase in hepatic drug-metabolizing enzyme expression in 3-week-old female mice that persisted into 8-week-old adulthood. Interestingly, we observed distorted intestinal morphological features in 8-week-old F1 female mice in the TC-exposed group. Moreover, maternal TC exposure triggered a loss of intestinal barrier integrity by reducing the expression of intestinal tight junction proteins. Accordingly, maternal exposure to TC down-regulated serum triglyceride levels as well as decreased the expression of intestinal lipid uptake and transport marker genes. Mechanistically, maternal TC exposure activated the intestinal inflammatory response and disrupted the antioxidant system in the offspring female mice, thereby impeding the intestinal absorption of nutrients and seriously threatening offspring health. Altogether, these findings highlight that the effects of maternal TC exposure on offspring toxicity could not be ignored. Full article

(This article belongs to the Special Issue Nuclear Receptors in Health and Diseases)

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16 pages, 4272 KiB

Open AccessArticle

An Inverse Agonist GSK5182 Increases Protein Stability of the Orphan Nuclear Receptor ERRγ via Inhibition of Ubiquitination

by Soon-Young Na, Ki-Sun Kim, Yoon Seok Jung, Don-Kyu Kim, Jina Kim, Sung Jin Cho, In-Kyu Lee, Jongkyeong Chung, Jeong-Sun Kim and Hueng-Sik Choi

Int. J. Mol. Sci. 2023, 24(1), 96; https://doi.org/10.3390/ijms24010096 - 21 Dec 2022

Cited by 2 | Viewed by 2297

Abstract

The orphan nuclear receptor, estrogen-related receptor γ (ERRγ) is a constitutively active transcription factor involved in mitochondrial metabolism and energy homeostasis. GSK5182, a specific inverse agonist of ERRγ that inhibits transcriptional activity, induces a conformational change in ERRγ, resulting in a loss of coactivator binding. However, the molecular mechanism underlying the stabilization of the ERRγ protein by its inverse agonist remains largely unknown. In this study, we found that GSK5182 inhibited ubiquitination of ERRγ, thereby stabilizing the ERRγ protein, using cell-based assays and confocal image analysis. Y326 of ERRγ was essential for stabilization by GSK5182, as ligand-induced stabilization of ERRγ was not observed with the ERRγ-Y326A mutant. GSK5182 suppressed ubiquitination of ERRγ by the E3 ligase Parkin and subsequent degradation. The inhibitory activity of GSK5182 was strong even when the ERRγ protein level was elevated, as ERRγ bound to GSK5182 recruited a corepressor, small heterodimer partner-interacting leucine zipper (SMILE), through the activation function 2 (AF-2) domain, without alteration of the nuclear localization or DNA-binding ability of ERRγ. In addition, the AF-2 domain of ERRγ was critical for the regulation of protein stability. Mutants in the AF-2 domain were present at higher levels than the wild type in the absence of GSK5182. Furthermore, the ERRγ-L449A/L451A mutant was no longer susceptible to GSK5182. Thus, the AF-2 domain of ERRγ is responsible for the regulation of transcriptional activity and protein stability by GSK5182. These findings suggest that GSK5182 regulates ERRγ by a unique molecular mechanism, increasing the inactive form of ERRγ via inhibition of ubiquitination. Full article

(This article belongs to the Special Issue Nuclear Receptors in Health and Diseases)

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14 pages, 2060 KiB

Open AccessArticle

All-trans Retinoic Acids Synergistically and Beneficially Affect In Vitro Glaucomatous Trabecular Meshwork (TM) Models Using 2D and 3D Cell Cultures of Human TM Cells

by Megumi Watanabe, Tatsuya Sato, Yuri Tsugeno, Megumi Higashide, Masato Furuhashi, Araya Umetsu, Soma Suzuki, Yosuke Ida, Fumihito Hikage and Hiroshi Ohguro

Int. J. Mol. Sci. 2022, 23(17), 9912; https://doi.org/10.3390/ijms23179912 - 31 Aug 2022

Cited by 2 | Viewed by 1733

Abstract

We report herein on the effects of all-trans retinoic acid (ATRA) on two-dimensional (2D) and three-dimensional (3D) cultures of human trabecular meshwork (HTM) cells that were treated with transforming growth factor β2 (TGF-β2). In the presence of 5 ng/mL TGF-β2, the effects of ATRA on the following were observed: (1) the barrier function of the 2D HTM monolayers, as determined by trans-endothelial electrical resistance (TEER) and fluorescein isothiocyanate (FITC) dextran permeability measurements; (2) a Seahorse cellular bio-metabolism analysis; (3) physical properties, including the size and stiffness, of 3D spheroids; (4) the gene expression of extracellular matrix (ECM) molecules, ECM modulators including tissue inhibitor of metalloproteinases (TIMPs), matrix metalloproteinases (MMPs), tight junction (TJ)-related molecules, and endoplasmic reticulum (ER)-stress-related factors. ATRA significantly inhibited the TGF-β2-induced increase in the TEER values and FITC dextran permeability of the 2D monolayers, while an ATRA monotreatment induced similar effects as TGF-β2. A real-time metabolic analysis revealed that ATRA significantly inhibited the TGF-β2-induced shift in metabolic reserve from mitochondrial oxidative phosphorylation to glycolysis in 2D HTM cells, whereas ATRA alone did not induce significant metabolic changes. In contrast, ATRA induced the formation of substantially downsized and softer 3D spheroids in the absence and presence of TGF-β2. The different effects induced by ATRA toward 2D and 3D HTM cells were also supported by the qPCR analysis of several proteins as above. The findings reported here indicate that ATRA may induce synergistic and beneficial effects on TGF-β2-treated 2D- and 3D-cultured HTM cells; those effects varied significantly between the 2D and 3D cultures. Full article

(This article belongs to the Special Issue Nuclear Receptors in Health and Diseases)

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18 pages, 3409 KiB

Open AccessArticle

Transcriptional Control of Trpm6 by the Nuclear Receptor FXR

by Eun Young Kim and Jae Man Lee

Int. J. Mol. Sci. 2022, 23(4), 1980; https://doi.org/10.3390/ijms23041980 - 10 Feb 2022

Cited by 7 | Viewed by 2650

Abstract

Farnesoid x receptor (FXR) is a nuclear bile acid receptor that belongs to the nuclear receptor superfamily. It plays an essential role in bile acid biosynthesis, lipid and glucose metabolism, liver regeneration, and vertical sleeve gastrectomy. A loss of the FXR gene or dysregulations of FXR-mediated gene expression are associated with the development of progressive familial intrahepatic cholestasis, tumorigenesis, inflammation, and diabetes mellitus. Magnesium ion (Mg²⁺) is essential for mammalian physiology. Over 600 enzymes are dependent on Mg²⁺ for their activity. Here, we show that the Trpm6 gene encoding a Mg²⁺ channel is a direct FXR target gene in the intestinal epithelial cells of mice. FXR expressed in the intestinal epithelial cells is absolutely required for sustaining a basal expression of intestinal Trpm6 that can be robustly induced by the treatment of GW4064, a synthetic FXR agonist. Analysis of FXR ChIP-seq data revealed that intron regions of Trpm6 contain two prominent FXR binding peaks. Among them, the proximal peak from the transcription start site contains a functional inverted repeat 1 (IR1) response element that directly binds to the FXR-RXRα heterodimer. Based on these results, we proposed that an intestinal FXR-TRPM6 axis may link a bile acid signaling to Mg²⁺ homeostasis. Full article

(This article belongs to the Special Issue Nuclear Receptors in Health and Diseases)

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21 pages, 15419 KiB

Open AccessArticle

Nonsteroidal Anti-Inflammatory Drugs as PPARγ Agonists Can Induce PRODH/POX-Dependent Apoptosis in Breast Cancer Cells: New Alternative Pathway in NSAID-Induced Apoptosis

by Adam Kazberuk, Magda Chalecka, Jerzy Palka and Arkadiusz Surazynski

Int. J. Mol. Sci. 2022, 23(3), 1510; https://doi.org/10.3390/ijms23031510 - 28 Jan 2022

Cited by 11 | Viewed by 3096

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) are considered to be therapeutics in cancer prevention because of their inhibitory effect on cyclooxygenases (COX), which are frequently overexpressed in many types of cancer. However, it was also demonstrated that NSAIDs provoked a proapoptotic effect in COX knocked-out cancer cells. Here, we suggest that this group of drugs may provoke antineoplastic activity through the activation of PPARγ, which induces proline dehydrogenase/proline oxidase (PRODH/POX)-dependent apoptosis. PRODH/POX is a mitochondrial enzyme that catalyzes proline degradation, during which ATP or reactive oxygen species (ROS) are generated. We have found that NSAIDs induced PRODH/POX and PPARγ expressions (as demonstrated by Western Blot or immunofluorescence analysis) and cytotoxicity (as demonstrated by MTT, cytometric assay, and DNA biosynthesis assay) in breast cancer MCF7 cells. Simultaneously, the NSAIDs inhibited collagen biosynthesis, supporting proline for PRODH/POX-induced ROS-dependent apoptosis (as demonstrated by an increase in the expression of apoptosis markers). The data suggest that targeting proline metabolism and the PRODH/POX–PPARγ axis can be considered a novel approach for breast cancer treatment. Full article

(This article belongs to the Special Issue Nuclear Receptors in Health and Diseases)

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Review

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18 pages, 1283 KiB

Open AccessReview

PPARs and Their Neuroprotective Effects in Parkinson’s Disease: A Novel Therapeutic Approach in α-Synucleinopathy?

by Isaac Pérez-Segura, Alberto Santiago-Balmaseda, Luis Daniel Rodríguez-Hernández, Adriana Morales-Martínez, Hilda Angélica Martínez-Becerril, Paola A. Martínez-Gómez, Karen M. Delgado-Minjares, Citlaltepetl Salinas-Lara, Irma A. Martínez-Dávila, Magdalena Guerra-Crespo, Francisca Pérez-Severiano and Luis O. Soto-Rojas

Int. J. Mol. Sci. 2023, 24(4), 3264; https://doi.org/10.3390/ijms24043264 - 7 Feb 2023

Cited by 13 | Viewed by 3301

Abstract

Parkinson’s disease (PD) is the most common α-synucleinopathy worldwide. The pathognomonic hallmark of PD is the misfolding and propagation of the α-synuclein (α-syn) protein, observed in post-mortem histopathology. It has been hypothesized that α-synucleinopathy triggers oxidative stress, mitochondrial dysfunction, neuroinflammation, and synaptic dysfunction, leading to neurodegeneration. To this date, there are no disease-modifying drugs that generate neuroprotection against these neuropathological events and especially against α-synucleinopathy. Growing evidence suggests that peroxisome proliferator-activated receptor (PPAR) agonists confer neuroprotective effects in PD, however, whether they also confer an anti-α-synucleinopathy effect is unknown. Here we analyze the reported therapeutic effects of PPARs, specifically the gamma isoform (PPARγ), in preclinical PD animal models and clinical trials for PD, and we suggest possible anti-α-synucleinopathy mechanisms acting downstream from these receptors. Elucidating the neuroprotective mechanisms of PPARs through preclinical models that mimic PD as closely as possible will facilitate the execution of better clinical trials for disease-modifying drugs in PD. Full article

(This article belongs to the Special Issue Nuclear Receptors in Health and Diseases)

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16 pages, 1940 KiB

Open AccessReview

Role of FXR in Renal Physiology and Kidney Diseases

by Yanlin Guo, Guixiang Xie and Xiaoyan Zhang

Int. J. Mol. Sci. 2023, 24(3), 2408; https://doi.org/10.3390/ijms24032408 - 26 Jan 2023

Cited by 13 | Viewed by 3584

Abstract

Farnesoid X receptor, also known as the bile acid receptor, belongs to the nuclear receptor (NR) superfamily of ligand-regulated transcription factors, which performs its functions by regulating the transcription of target genes. FXR is highly expressed in the liver, small intestine, kidney and adrenal gland, maintaining homeostasis of bile acid, glucose and lipids by regulating a diverse array of target genes. It also participates in several pathophysiological processes, such as inflammation, immune responses and fibrosis. The kidney is a key organ that manages water and solute homeostasis for the whole body, and kidney injury or dysfunction is associated with high morbidity and mortality. In the kidney, FXR plays an important role in renal water reabsorption and is thought to perform protective functions in acute kidney disease and chronic kidney disease, especially diabetic kidney disease. In this review, we summarize the recent advances in the understanding of the physiological and pathophysiological function of FXR in the kidney. Full article

(This article belongs to the Special Issue Nuclear Receptors in Health and Diseases)

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15 pages, 716 KiB

Open AccessReview

Role of Nuclear Receptors in Controlling Erythropoiesis

by Valentina Pastori, Serena Pozzi, Agata Labedz, Sajeela Ahmed and Antonella Ellena Ronchi

Int. J. Mol. Sci. 2022, 23(5), 2800; https://doi.org/10.3390/ijms23052800 - 3 Mar 2022

Cited by 9 | Viewed by 3202

Abstract

Nuclear receptors (NRs), are a wide family of ligand-regulated transcription factors sharing a common modular structure composed by an N-terminal domain and a ligand-binding domain connected by a short hinge linker to a DNA-binding domain. NRs are involved in many physiological processes, including metabolism, reproduction and development. Most of them respond to small lipophilic ligands, such as steroids, retinoids, and phospholipids, which act as conformational switches. Some NRs are still “orphan” and the search for their ligands is still ongoing. Upon DNA binding, NRs can act both as transcriptional activators or repressors of their target genes. Theoretically, the possibility to modulate NRs activity with small molecules makes them ideal therapeutic targets, although the complexity of their signaling makes drug design challenging. In this review, we discuss the role of NRs in erythropoiesis, in both homeostatic and stress conditions. This knowledge is important in view of modulating red blood cells production in disease conditions, such as anemias, and for the expansion of erythroid cells in culture for research purposes and for reaching the long-term goal of cultured blood for transfusion. Full article

(This article belongs to the Special Issue Nuclear Receptors in Health and Diseases)

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