Editorial

5 pages, 225 KiB

Open AccessEditorial

by Michael Schubert and Pierre Germain

Cells 2023, 12(6), 864; https://doi.org/10.3390/cells12060864 - 10 Mar 2023

Viewed by 1436

One of the most fundamental discoveries in human biology was that of the existence of essential micronutrients that the body cannot synthesize but nonetheless requires for proper functioning [...] Full article

(This article belongs to the Special Issue Retinoic Acid and Retinoid X Receptors)

Research

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20 pages, 3939 KiB

Open AccessArticle

Molluscan RXR Transcriptional Regulation by Retinoids in a Drosophila CNS Organ Culture System

by Eric de Hoog, Victoria Elda Saba Echezarreta, Anel Turgambayeva, Gregory Foran, Marvel Megaly, Aleksandar Necakov and Gaynor E. Spencer

Cells 2022, 11(16), 2493; https://doi.org/10.3390/cells11162493 - 11 Aug 2022

Cited by 1 | Viewed by 1469

Abstract

Retinoic acid, the active metabolite of Vitamin A, is important for the appropriate development of the nervous system (e.g., neurite outgrowth) as well as for cognition (e.g., memory formation) in the adult brain. We have shown that many of the effects of retinoids [...] Read more.

Retinoic acid, the active metabolite of Vitamin A, is important for the appropriate development of the nervous system (e.g., neurite outgrowth) as well as for cognition (e.g., memory formation) in the adult brain. We have shown that many of the effects of retinoids are conserved in the CNS of the mollusc, Lymnaea stagnalis. RXRs are predominantly nuclear receptors, but the Lymnaea RXR (LymRXR) exhibits a non-nuclear distribution in the adult CNS, where it is also implicated in non-genomic retinoid functions. As such, we developed a CNS Drosophila organ culture-based system to examine the transcriptional activity and ligand-binding properties of LymRXR, in the context of a live invertebrate nervous system. The novel ligand sensor system was capable of reporting both the expression and transcriptional activity of the sensor. Our results indicate that the LymRXR ligand sensor mediated transcription following activation by both 9-cis RA (the high affinity ligand for vertebrate RXRs) as well as the vertebrate RXR synthetic agonist, SR11237. The LymRXR ligand sensor was also activated by all-trans RA, and to a much lesser extent by the vertebrate RAR synthetic agonist, EC23. This sensor also detected endogenous retinoid-like activity in the CNS of developing Drosophila larvae, primarily during the 3^rd instar larval stage. These data indicate that the LymRXR sensor can be utilized not only for characterization of ligand activation for studies related to the Lymnaea CNS, but also for future studies of retinoids and their functions in Drosophila development. Full article

(This article belongs to the Special Issue Retinoic Acid and Retinoid X Receptors)

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24 pages, 9564 KiB

Open AccessArticle

Selective Ablation of BCL11A in Epidermal Keratinocytes Alters Skin Homeostasis and Accelerates Excisional Wound Healing In Vivo

by Nilika Bhattacharya, Arup K. Indra and Gitali Ganguli-Indra

Cells 2022, 11(13), 2106; https://doi.org/10.3390/cells11132106 - 03 Jul 2022

Cited by 3 | Viewed by 2722

Abstract

Transcriptional regulator BCL11A plays a crucial role in coordinating a suite of developmental processes including skin morphogenesis, barrier functions and lipid metabolism. There is little or no reports so far documenting the role of BCL11A in postnatal adult skin homeostasis and in the [...] Read more.

Transcriptional regulator BCL11A plays a crucial role in coordinating a suite of developmental processes including skin morphogenesis, barrier functions and lipid metabolism. There is little or no reports so far documenting the role of BCL11A in postnatal adult skin homeostasis and in the physiological process of tissue repair and regeneration. The current study establishes for the first time the In Vivo role of epidermal BCL11A in maintaining adult epidermal homeostasis and as a negative regulator of cutaneous wound healing. Conditional ablation of Bcl11a in skin epidermal keratinocytes (Bcl11a^ep−/−mice) enhances the keratinocyte proliferation and differentiation program, suggesting its critical role in epidermal homeostasis of adult murine skin. Further, loss of keratinocytic BCL11A promotes rapid closure of excisional wounds both in a cell autonomous manner likely via accelerating wound re-epithelialization and in a non-cell autonomous manner by enhancing angiogenesis. The epidermis specific Bcl11a knockout mouse serves as a prototype to gain mechanistic understanding of various downstream pathways converging towards the manifestation of an accelerated healing phenotype upon its deletion. Full article

(This article belongs to the Special Issue Retinoic Acid and Retinoid X Receptors)

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16 pages, 7146 KiB

Open AccessArticle

Evolutionary Transition in the Regulation of Vertebrate Pronephros Development: A New Role for Retinoic Acid

by Pascal Schmidt, Eva Leman, Ronan Lagadec, Michael Schubert, Sylvie Mazan and Ram Reshef

Cells 2022, 11(8), 1304; https://doi.org/10.3390/cells11081304 - 12 Apr 2022

Cited by 3 | Viewed by 2172

Abstract

The anterior-posterior (AP) axis in chordates is regulated by a conserved set of genes and signaling pathways, including Hox genes and retinoic acid (RA), which play well-characterized roles in the organization of the chordate body plan. The intermediate mesoderm (IM), which gives rise [...] Read more.

The anterior-posterior (AP) axis in chordates is regulated by a conserved set of genes and signaling pathways, including Hox genes and retinoic acid (RA), which play well-characterized roles in the organization of the chordate body plan. The intermediate mesoderm (IM), which gives rise to all vertebrate kidneys, is an example of a tissue that differentiates sequentially along this axis. Yet, the conservation of the spatiotemporal regulation of the IM across vertebrates remains poorly understood. In this study, we used a comparative developmental approach focusing on non-conventional model organisms, a chondrichthyan (catshark), a cyclostome (lamprey), and a cephalochordate (amphioxus), to assess the involvement of RA in the regulation of chordate and vertebrate pronephros formation. We report that the anterior expression boundary of early pronephric markers (Pax2 and Lim1), positioned at the level of somite 6 in amniotes, is conserved in the catshark and the lamprey. Furthermore, RA, driving the expression of Hox4 genes like in amniotes, regulates the anterior pronephros boundary in the catshark. We find no evidence for the involvement of this regulatory hierarchy in the AP positioning of the lamprey pronephros and the amphioxus pronephros homolog, Hatschek’s nephridium. This suggests that despite the conservation of Pax2 and Lim1 expressions in chordate pronephros homologs, the responsiveness of the IM, and hence of pronephric genes, to RA- and Hox-dependent regulation is a gnathostome novelty. Full article

(This article belongs to the Special Issue Retinoic Acid and Retinoid X Receptors)

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12 pages, 1542 KiB

Open AccessArticle

Cytoplasmic Colocalization of RXRα and PPARγ as an Independent Negative Prognosticator for Breast Cancer Patients

by Wanting Shao, Melitta B. Köpke, Theresa Vilsmaier, Alaleh Zati Zehni, Mirjana Kessler, Sophie Sixou, Mariella Schneider, Nina Ditsch, Vincent Cavaillès and Udo Jeschke

Cells 2022, 11(7), 1244; https://doi.org/10.3390/cells11071244 - 06 Apr 2022

Cited by 4 | Viewed by 1635

Abstract

Retinoid X receptor α (RXRα) is a nuclear receptor (NR) which functions as the primary heterodimeric partner of other NRs including the peroxisome proliferator-activated receptor γ (PPARγ). We previously reported that, in breast cancers (BC), the subcellular localization of these two receptors was [...] Read more.

Retinoid X receptor α (RXRα) is a nuclear receptor (NR) which functions as the primary heterodimeric partner of other NRs including the peroxisome proliferator-activated receptor γ (PPARγ). We previously reported that, in breast cancers (BC), the subcellular localization of these two receptors was strongly associated with patient prognosis. In the present work, we investigated the prognosis value of the combined cytoplasmic expression of RXRα and PPARγ using a retrospective cohort of 250 BC samples. Patients with tumors expressing both NRs in tumor cell cytoplasm exhibited a significant shorter overall (OS) and disease-free survival (DFS). This was also observed for patients with stage 1 tumors. Cox univariate analysis indicated that patients with tumors coexpressing RXRα and PPARγ in the cytoplasm of tumor cells have a decreased 5 y OS rate. Cytoplasmic co-expression of the two NRs significantly correlated with HER2 positivity and with NCAD and CD133, two markers of tumor aggressiveness. Finally, in Cox multivariate analysis, the co-expression of RXRα and PPARγ in the cytoplasm appeared as an independent OS prognosticator. Altogether, this study demonstrates that the cytoplasmic co-expression of RXRα and PPARγ could be of relevance for clinicians by identifying high-risk BC patients, especially amongst those with early and node-negative disease. Full article

(This article belongs to the Special Issue Retinoic Acid and Retinoid X Receptors)

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15 pages, 2588 KiB

Open AccessArticle

The Sin3A/MAD1 Complex, through Its PAH2 Domain, Acts as a Second Repressor of Retinoic Acid Receptor Beta Expression in Breast Cancer Cells

by Nisha Rani Dahiya, Boris A. Leibovitch, Rama Kadamb, Nidhi Bansal and Samuel Waxman

Cells 2022, 11(7), 1179; https://doi.org/10.3390/cells11071179 - 31 Mar 2022

Cited by 1 | Viewed by 2227

Abstract

Retinoids are essential in balancing proliferation, differentiation and apoptosis, and they exert their effects through retinoic acid receptors (RARs) and retinoid X receptors (RXRs). RARβ is a tumor-suppressor gene silenced by epigenetic mechanisms such as DNA methylation in breast, cervical and non-small cell [...] Read more.

Retinoids are essential in balancing proliferation, differentiation and apoptosis, and they exert their effects through retinoic acid receptors (RARs) and retinoid X receptors (RXRs). RARβ is a tumor-suppressor gene silenced by epigenetic mechanisms such as DNA methylation in breast, cervical and non-small cell lung cancers. An increased expression of RARβ has been associated with improved breast cancer-specific survival. The PAH2 domain of the scaffold protein SIN3A interacts with the specific Sin3 Interaction Domain (SID) of several transcription factors, such as MAD1, bringing chromatin-modifying proteins such as histone deacetylases, and it targets chromatin for specific modifications. Previously, we have established that blocking the PAH2-mediated Sin3A interaction with SID-containing proteins using SID peptides or small molecule inhibitors (SMI) increased RARβ expression and induced retinoic acid metabolism in breast cancer cells, both in in vitro and in vivo models. Here, we report studies designed to understand the mechanistic basis of RARβ induction and function. Using human breast cancer cells transfected with MAD1 SID or treated with the MAD SID peptide, we observed a dissociation of MAD1, RARα and RARβ from Sin3A in a coimmunoprecipitation assay. This was associated with increased RARα and RARβ expression and function by a luciferase assay, which was enhanced by the addition of AM580, a specific RARα agonist; EMSA showed that MAD1 binds to E-Box, similar to MYC, on the RARβ promoter, which showed a reduced enrichment of Sin3A and HDAC1 by ChIP and was required for the AM580-enhanced RARβ activation in MAD1/SID cells. These data suggest that the Sin3A/HDAC1/2 complex co-operates with the classical repressors in regulating RARβ expression. These data suggest that SIN3A/MAD1 acts as a second RARβ repressor and may be involved in fine-tuning retinoid sensitivity. Full article

(This article belongs to the Special Issue Retinoic Acid and Retinoid X Receptors)

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16 pages, 6365 KiB

Open AccessArticle

Retinoic Acid Receptor Alpha Is Essential in Postnatal Sertoli Cells but Not in Germ Cells

by Diana Condrea, Sirine Souali-Crespo, Betty Féret, Muriel Klopfenstein, Sylvain Faisan, Manuel Mark, Norbert B. Ghyselinck and Nadège Vernet

Cells 2022, 11(5), 891; https://doi.org/10.3390/cells11050891 - 04 Mar 2022

Cited by 1 | Viewed by 2776

Abstract

Retinoic acid signaling is indispensable for the completion of spermatogenesis. It is known that loss of retinoic acid nuclear receptor alpha (RARA) induces male sterility due to seminiferous epithelium degeneration. Initial genetic studies established that RARA acts in Sertoli cells, but a recent [...] Read more.

Retinoic acid signaling is indispensable for the completion of spermatogenesis. It is known that loss of retinoic acid nuclear receptor alpha (RARA) induces male sterility due to seminiferous epithelium degeneration. Initial genetic studies established that RARA acts in Sertoli cells, but a recent paper proposed that RARA is also instrumental in germ cells. In the present study, we have re-assessed the function of RARA in germ cells by genetically ablating the Rara gene in spermatogonia and their progenies using a cell-specific conditional mutagenesis approach. We show that loss of Rara in postnatal male germ cells does not alter the histology of the seminiferous epithelium. Furthermore, RARA-deficient germ cells differentiate normally and give rise to normal, living pups. This establishes that RARA plays no crucial role in germ cells. We also tested whether RARA is required in Sertoli cells during the fetal period or after birth. For this purpose, we deleted the Rara gene in Sertoli cells at postnatal day 15 (PN15), i.e., after the onset of the first spermatogenic wave. To do so, we used temporally controlled cell-specific mutagenesis. By comparing the testis phenotypes generated when Rara is lost either at PN15 or at embryonic day 13, we show that RARA exerts all of its functions in Sertoli cells not at the fetal stage but from puberty. Full article

(This article belongs to the Special Issue Retinoic Acid and Retinoid X Receptors)

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24 pages, 6404 KiB

Open AccessFeature PaperArticle

Altered RBP1 Gene Expression Impacts Epithelial Cell Retinoic Acid, Proliferation, and Microenvironment

by Jianshi Yu, Mariarita Perri, Jace W. Jones, Keely Pierzchalski, Natalia Ceaicovscaia, Erika Cione and Maureen A. Kane

Cells 2022, 11(5), 792; https://doi.org/10.3390/cells11050792 - 24 Feb 2022

Cited by 7 | Viewed by 2615

Abstract

Vitamin A is an essential diet-derived nutrient that has biological activity affected through an active metabolite, all-trans retinoic acid (atRA). Retinol-binding protein type 1 (RBP1) is an intracellular chaperone that binds retinol and retinal with high affinity, protects retinoids from non-specific oxidation, and [...] Read more.

Vitamin A is an essential diet-derived nutrient that has biological activity affected through an active metabolite, all-trans retinoic acid (atRA). Retinol-binding protein type 1 (RBP1) is an intracellular chaperone that binds retinol and retinal with high affinity, protects retinoids from non-specific oxidation, and delivers retinoids to specific enzymes to facilitate biosynthesis of RA. RBP1 expression is reduced in many of the most prevalent cancers, including breast cancer. Here, we sought to understand the relationship between RBP1 expression and atRA biosynthesis in mammary epithelial cells, as well as RBP1 expression and atRA levels in human mammary tissue. We additionally aimed to investigate the impact of RBP1 expression and atRA on the microenvironment as well as the potential for therapeutic restoration of RBP1 expression and endogenous atRA production. Using human mammary ductal carcinoma samples and a series of mammary epithelial cell lines representing different stages of tumorigenesis, we investigated the relationship between RBP1 expression as determined by QPCR and atRA via direct liquid chromatography-multistage-tandem mass spectrometry-based quantification. The functional effect of RBP1 expression and atRA in epithelial cells was investigated via the expression of direct atRA targets using QPCR, proliferation using Ki-67 staining, and collagen deposition via picrosirius red staining. We also investigated the atRA content of stromal cells co-cultured with normal and tumorigenic epithelial cells. Results show that RBP1 and atRA are reduced in mammary tumor tissue and tumorigenic epithelial cell lines. Knock down of RBP1 expression using shRNA or overexpression of RBP1 supported a direct relationship between RBP1 expression with atRA. Increases in cellular atRA were able to activate atRA direct targets, inhibit proliferation and inhibit collagen deposition in epithelial cell lines. Conditions encountered in tumor microenvironments, including low glucose and hypoxia, were able to reduce RBP1 expression and atRA. Treatment with either RARα agonist AM580 or demethylating agent Decitabine were able to increase RBP1 expression and atRA. Cellular content of neighboring fibroblasts correlated with the RA producing capacity of epithelial cells in co-culture. This work establishes a direct relationship between RBP1 expression and atRA, which is maintained when RBP1 expression is restored therapeutically. The results demonstrate diseases with reduced RBP1 could potentially benefit from therapeutics that restore RBP1 expression and endogenous atRA. Full article

(This article belongs to the Special Issue Retinoic Acid and Retinoid X Receptors)

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23 pages, 2948 KiB

Open AccessArticle

Enhanced Loss of Retinoic Acid Network Genes in Xenopus laevis Achieves a Tighter Signal Regulation

by Tali Abbou, Liat Bendelac-Kapon, Audeliah Sebag and Abraham Fainsod

Cells 2022, 11(3), 327; https://doi.org/10.3390/cells11030327 - 19 Jan 2022

Cited by 2 | Viewed by 1923

Abstract

Retinoic acid (RA) is a major regulatory signal during embryogenesis produced from vitamin A (retinol) by an extensive, autoregulating metabolic and signaling network to prevent fluctuations that result in developmental malformations. Xenopus laevis is an allotetraploid hybrid frog species whose genome includes L [...] Read more.

Retinoic acid (RA) is a major regulatory signal during embryogenesis produced from vitamin A (retinol) by an extensive, autoregulating metabolic and signaling network to prevent fluctuations that result in developmental malformations. Xenopus laevis is an allotetraploid hybrid frog species whose genome includes L (long) and S (short) chromosomes from the originating species. Evolutionarily, the X. laevis subgenomes have been losing either L or S homoeologs in about 43% of genes to generate singletons. In the RA network, out of the 47 genes, about 47% have lost one of the homoeologs, like the genome average. Interestingly, RA metabolism genes from storage (retinyl esters) to retinaldehyde production exhibit enhanced gene loss with 75% singletons out of 28 genes. The effect of this gene loss on RA signaling autoregulation was studied. Employing transient RA manipulations, homoeolog gene pairs were identified in which one homoeolog exhibits enhanced responses or looser regulation than the other, while in other pairs both homoeologs exhibit similar RA responses. CRISPR/Cas9 targeting of individual homoeologs to reduce their activity supports the hypothesis where the RA metabolic network gene loss results in tighter network regulation and more efficient RA robustness responses to overcome complex regulation conditions. Full article

(This article belongs to the Special Issue Retinoic Acid and Retinoid X Receptors)

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17 pages, 1976 KiB

Open AccessArticle

Retinoic Acid Receptors and the Control of Positional Information in the Regenerating Axolotl Limb

by Trey Polvadore and Malcolm Maden

Cells 2021, 10(9), 2174; https://doi.org/10.3390/cells10092174 - 24 Aug 2021

Cited by 3 | Viewed by 3639

Abstract

We know little about the control of positional information (PI) during axolotl limb regeneration, which ensures that the limb regenerates exactly what was amputated, and the work reported here investigates this phenomenon. Retinoic acid administration changes the PI in a proximal direction so [...] Read more.

We know little about the control of positional information (PI) during axolotl limb regeneration, which ensures that the limb regenerates exactly what was amputated, and the work reported here investigates this phenomenon. Retinoic acid administration changes the PI in a proximal direction so that a complete limb can be regenerated from a hand. Rather than identifying all the genes altered by RA treatment of the limb, we have eliminated many off-target effects by using retinoic acid receptor selective agonists. We firstly identify the receptor involved in this respecification process as RARα and secondly, identify the genes involved by RNA sequencing of the RARα-treated blastemal mesenchyme. We find 1177 upregulated genes and 1403 downregulated genes, which could be identified using the axolotl genome. These include several genes known to be involved in retinoic acid metabolism and in patterning. Since positional information is thought to be a property of the cell surface of blastemal cells when we examine our dataset with an emphasis on this aspect, we find the top canonical pathway is integrin signaling. In the extracellular matrix compartment, we find a MMP and several collagens are upregulated; several cell membrane genes and secretory factors are also upregulated. This provides data for future testing of the function of these candidates in the control of PI during limb regeneration. Full article

(This article belongs to the Special Issue Retinoic Acid and Retinoid X Receptors)

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Review

Jump to: Editorial, Research

14 pages, 4883 KiB

Open AccessReview

Machinery and Developmental Role of Retinoic Acid Signaling in Echinoderms

by Shumpei Yamakawa and Hiroshi Wada

Cells 2022, 11(3), 523; https://doi.org/10.3390/cells11030523 - 02 Feb 2022

Cited by 3 | Viewed by 1994

Abstract

Although a recent genomic survey revealed its ancient evolutionary origin in the animal kingdom, retinoic acid (RA) signaling was previously thought to be unique to chordates. Echinoderms are of critical interest in researching the evolutionary history of RA signaling, as they represent a [...] Read more.

Although a recent genomic survey revealed its ancient evolutionary origin in the animal kingdom, retinoic acid (RA) signaling was previously thought to be unique to chordates. Echinoderms are of critical interest in researching the evolutionary history of RA signaling, as they represent a basal group of deuterostomes. Furthermore, our previous works have suggested that echinoderms may possess the ancestral function of RA signaling for metamorphosis regulation. In this paper, to facilitate future studies of RA signaling in echinoderms, we provide an overview of RA machinery in echinoderms, identify its signaling components, and discuss its developmental role. Full article

(This article belongs to the Special Issue Retinoic Acid and Retinoid X Receptors)

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10 pages, 1486 KiB

Open AccessReview

Action and Interaction between Retinoic Acid Signaling and Blood–Testis Barrier Function in the Spermatogenesis Cycle

by Yu Zhou and Yunyan Wang

Cells 2022, 11(3), 352; https://doi.org/10.3390/cells11030352 - 21 Jan 2022

Cited by 13 | Viewed by 2813

Abstract

Spermatogenesis is a complex process occurring in mammalian testes, and constant sperm production depends on the exact regulation of the microenvironment in the testes. Many studies have indicated the crucial role of blood–testis barrier (BTB) junctions and retinoic acid (RA) signaling in the [...] Read more.

Spermatogenesis is a complex process occurring in mammalian testes, and constant sperm production depends on the exact regulation of the microenvironment in the testes. Many studies have indicated the crucial role of blood–testis barrier (BTB) junctions and retinoic acid (RA) signaling in the spermatogenesis process. The BTB consists of junctions between adjacent Sertoli cells, comprised mainly of tight junctions and gap junctions. In vitamin A-deficient mice, halted spermatogenesis could be rebooted by RA or vitamin A administration, indicating that RA is absolutely required for spermatogenesis. Accordingly, this manuscript will review and discuss how RA and the BTB regulate spermatogenesis and the interaction between RA signaling and BTB function. Full article

(This article belongs to the Special Issue Retinoic Acid and Retinoid X Receptors)

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8 pages, 938 KiB

Open AccessReview

Towards a Better Vision of Retinoic Acid Signaling during Eye Development

by Gregg Duester

Cells 2022, 11(3), 322; https://doi.org/10.3390/cells11030322 - 19 Jan 2022

Cited by 13 | Viewed by 2868

Abstract

Retinoic acid (RA) functions as an essential signal for development of the vertebrate eye by controlling the transcriptional regulatory activity of RA receptors (RARs). During eye development, the optic vesicles and later the retina generate RA as a metabolite of vitamin A (retinol). [...] Read more.

Retinoic acid (RA) functions as an essential signal for development of the vertebrate eye by controlling the transcriptional regulatory activity of RA receptors (RARs). During eye development, the optic vesicles and later the retina generate RA as a metabolite of vitamin A (retinol). Retinol is first converted to retinaldehyde by retinol dehydrogenase 10 (RDH10) and then to RA by all three retinaldehyde dehydrogenases (ALDH1A1, ALDH1A2, and ALDH1A3). In early mouse embryos, RA diffuses to tissues throughout the optic placode, optic vesicle, and adjacent mesenchyme to stimulate folding of the optic vesicle to form the optic cup. RA later generated by the retina is needed for further morphogenesis of the optic cup and surrounding perioptic mesenchyme; loss of RA at this stage leads to microphthalmia and cornea plus eyelid defects. RA functions by binding to nuclear RARs at RA response elements (RAREs) that either activate or repress transcription of key genes. Binding of RA to RARs regulates recruitment of transcriptional coregulators such as nuclear receptor coactivator (NCOA) or nuclear receptor corepressor (NCOR), which in turn control binding of the generic coactivator p300 or the generic corepressor PRC2. No genes have been identified as direct targets of RA signaling during eye development, so future studies need to focus on identifying such genes and their RAREs. Studies designed to learn how RA normally controls eye development in vivo will provide basic knowledge valuable for determining how developmental eye defects occur and for improving strategies to treat eye defects. Full article

(This article belongs to the Special Issue Retinoic Acid and Retinoid X Receptors)

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13 pages, 2473 KiB

Open AccessFeature PaperReview

Retinoid Agonists in the Targeting of Heterotopic Ossification

by Robert J. Pignolo and Maurizio Pacifici

Cells 2021, 10(11), 3245; https://doi.org/10.3390/cells10113245 - 19 Nov 2021

Cited by 7 | Viewed by 3336

Abstract

Retinoids are metabolic derivatives of vitamin A and regulate the function of many tissues and organs both prenatally and postnatally. Active retinoids, such as all trans-retinoic acid, are produced in the cytoplasm and then interact with nuclear retinoic acid receptors (RARs) to [...] Read more.

Retinoids are metabolic derivatives of vitamin A and regulate the function of many tissues and organs both prenatally and postnatally. Active retinoids, such as all trans-retinoic acid, are produced in the cytoplasm and then interact with nuclear retinoic acid receptors (RARs) to up-regulate the transcription of target genes. The RARs can also interact with target gene response elements in the absence of retinoids and exert a transcriptional repression function. Studies from several labs, including ours, showed that chondrogenic cell differentiation and cartilage maturation require (i) the absence of retinoid signaling and (ii) the repression function by unliganded RARs. These and related insights led to the proposition that synthetic retinoid agonists could thus represent pharmacological agents to inhibit heterotopic ossification (HO), a process that recapitulates developmental skeletogenesis and involves chondrogenesis, cartilage maturation, and endochondral ossification. One form of HO is acquired and is caused by injury, and another severe and often fatal form of it is genetic and occurs in patients with fibrodysplasia ossificans progressiva (FOP). Mouse models of FOP bearing mutant ACVR1R206H, characteristic of most FOP patients, were used to test the ability of the retinoid agonists selective for RARα and RARγ against spontaneous and injury-induced HO. The RARγ agonists were found to be most effective, and one such compound, palovarotene, was selected for testing in FOP patients. The safety and effectiveness data from recent and ongoing phase II and phase III clinical trials support the notion that palovarotene may represent a disease-modifying treatment for patients with FOP. The post hoc analyses showed substantial efficacy but also revealed side effects and complications, including premature growth plate closure in some patients. Skeletally immature patients will need to be carefully weighed in any future regulatory indications of palovarotene as an important therapeutic option in FOP. Full article

(This article belongs to the Special Issue Retinoic Acid and Retinoid X Receptors)

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18 pages, 603 KiB

Open AccessReview

The Interactions of Insulin and Vitamin A Signaling Systems for the Regulation of Hepatic Glucose and Lipid Metabolism

by Guoxun Chen

Cells 2021, 10(8), 2160; https://doi.org/10.3390/cells10082160 - 21 Aug 2021

Cited by 13 | Viewed by 3677

Abstract

The pandemics of obesity and type 2 diabetes have become a concern of public health. Nutrition plays a key role in these concerns. Insulin as an anabolic hormonal was discovered exactly 100 years ago due to its activity in controlling blood glucose level. [...] Read more.

The pandemics of obesity and type 2 diabetes have become a concern of public health. Nutrition plays a key role in these concerns. Insulin as an anabolic hormonal was discovered exactly 100 years ago due to its activity in controlling blood glucose level. Vitamin A (VA), a lipophilic micronutrient, has been shown to regulate glucose and fat metabolism. VA’s physiological roles are mainly mediated by its metabolite, retinoic acid (RA), which activates retinoic acid receptors (RARs) and retinoid X receptors (RXRs), which are two transcription factors. The VA status and activations of RARs and RXRs by RA and synthetic agonists have shown to affect the glucose and lipid metabolism in animal models. Both insulin and RA signaling systems regulate the expression levels of genes involved in the regulation of hepatic glucose and lipid metabolism. Interactions of insulin and RA signaling systems have been observed. This review is aimed at summarizing the history of diabetes, insulin and VA signaling systems; the effects of VA status and activation of RARs and RXRs on metabolism and RAR and RXR phosphorylation; and possible interactions of insulin and RA in the regulation of hepatic genes for glucose and lipid metabolism. In addition, some future research perspectives for understanding of nutrient and hormone interactions are provided. Full article

(This article belongs to the Special Issue Retinoic Acid and Retinoid X Receptors)

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