scholarly journals Knockout of Cyp26a1 and Cyp26b1 during post-natal life causes reduced lifespan, dermatitis, splenomegaly and systemic inflammation in mice

2020 ◽  
Author(s):  
Jessica M Snyder ◽  
Guo Zhong ◽  
Cathryn Hogarth ◽  
Weize Huang ◽  
Traci Topping ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
Mouse Models ◽  
Active Metabolite ◽  
Knockout Mouse ◽  
Inflammatory Cells ◽  
Severe Phenotype ◽  
Retinoid Homeostasis ◽  
Embryonic Lethal

AbstractAll-trans-retinoic acid (atRA), the active metabolite of vitamin A, is an essential signaling molecule. Global knockout of the atRA clearing enzymes Cyp26a1 or Cyp26b1 is embryonic lethal. In adults, inhibition of Cyp26a1 and Cyp26b1 increases atRA concentrations and signaling. However, post-natal knockout of Cyp26a1 does not cause a severe phenotype. We hypothesized that Cyp26b1 is the main atRA clearing Cyp in post-natal mammals. This hypothesis was tested by generating tamoxifen inducible knockout mouse models of Cyp26b1 alone or with Cyp26a1. Both mouse models showed dermatitis, blepharitis and splenomegaly. Histology showed infiltration of inflammatory cells including neutrophils and T-lymphocytes into the skin and hyperkeratosis/hyperplasia of the non-glandular stomach. The mice lacking both Cyp26a1 and Cyp26b1 also failed to gain weight and showed fat atrophy. There were significant changes in vitamin A homeostasis demonstrating the paramount role of Cyp26b1 in regulating retinoid homeostasis in post-natal life.

Understanding the physiological role of retinol-binding protein in vitamin A metabolism using transgenic and knockout mouse models

2003 ◽  
Vol 24 (6) ◽  
pp. 421-430 ◽  
Author(s):  
Loredana Quadro ◽  
Leora Hamberger ◽  
Vittorio Colantuoni ◽  
Max E. Gottesman ◽  
William S. Blaner
Keyword(s):  
Vitamin A ◽  
Mouse Models ◽  
Knockout Mouse ◽  
Binding Protein ◽  
Physiological Role ◽  
Retinol Binding Protein ◽  
Vitamin A Metabolism

scholarly journals Role of Vitamin A/Retinoic Acid in Regulation of Embryonic and Adult Hematopoiesis

Nutrients ◽  
2017 ◽  
Vol 9 (2) ◽  
pp. 159 ◽  
Author(s):  
Ana Cañete ◽  
Elena Cano ◽  
Ramón Muñoz-Chápuli ◽  
Rita Carmona
Keyword(s):  
Retinoic Acid ◽  
Vitamin A

scholarly journals Regulation of Hepatitis C Virus Infection by Cellular Retinoic Acid Binding Proteins through the Modulation of Lipid Droplet Abundance

2019 ◽  
Vol 93 (8) ◽  
Author(s):  
Bo-Ram Bang ◽  
Meng Li ◽  
Kuen-Nan Tsai ◽  
Haruyo Aoyagi ◽  
Shin-Ae Lee ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Life Cycle ◽  
Hepatitis C ◽  
Vitamin A ◽  
Active Metabolite ◽  
Antiviral Effect ◽  
Biologically Active ◽  
Viral Pathogens ◽  
Intrinsic Mechanism ◽  
Retinoic Acid Binding Proteins

ABSTRACTRetinoid (vitamin A) is an essential diet constituent that governs a broad range of biological processes. Its biologically active metabolite, all-transretinoic acid (ATRA), exhibits a potent antiviral property by enhancing both innate and adaptive antiviral immunity against a variety of viral pathogens, such as, but not limited to, HIV, respiratory syncytial virus (RSV), herpes simplex virus (HSV), and measles. Even though the hepatocyte is highly enriched with retinoid and its metabolite ATRA, it supports the establishment of efficient hepatitis C virus (HCV) replication. Here, we demonstrate the hepatocyte-specific cell-intrinsic mechanism by which ATRA exerts either a proviral or antiviral effect, depending on how it engages cellular retinoic acid binding proteins (CRABPs). We found that the engagement of CRABP1 by ATRA potently supported viral infection by promoting the accumulation of lipid droplets (LDs), which robustly enhanced the formation of a replication complex on the LD-associated endoplasmic reticulum (ER) membrane. In contrast, ATRA binding to CRABP2 potently inhibited HCV via suppression of LD accumulation. However, this antiviral effect of CRABP2 was abrogated due to the functional and quantitative predominance of CRABP1 in the hepatocytes. In summary, our study demonstrates that CRABPs serve as an on-off switch that modulates the efficiency of the HCV life cycle and elucidates how HCV evades the antiviral properties of ATRA via the exploitation of CRABP1 functionality.IMPORTANCEATRA, a biologically active metabolite of vitamin A, exerts pleiotropic biological effects, including the activation of both innate and adaptive immunity, thereby serving as a potent antimicrobial compound against numerous viral pathogens. Despite the enrichment of hepatocytes with vitamin A, HCV still establishes an efficient viral life cycle. Here, we discovered that the hepatocellular response to ATRA creates either a proviral or an antiviral environment depending on its engagement with CRABP1 or -2, respectively. CRABP1 supports the robust replication of HCV, while CRABP2 potently inhibits the efficiency of viral replication. Our biochemical, genetic, and microscopic analyses reveal that the pro- and antiviral effects of CRABPs are mediated by modulation of LD abundance, where HCV establishes the platform for viral replication and assembly on the LD-associated ER membrane. This study uncovered a cell-intrinsic mechanism by which HCV exploits the proviral function of CRABP1 to establish an efficient viral life cycle.

scholarly journals The role of retinoic acid in embryonic and post-embryonic development

2000 ◽  
Vol 59 (1) ◽  
pp. 65-73 ◽  
Author(s):  
Malcolm Maden
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
Embryonic Development ◽  
Cell Regeneration ◽  
Spinal Cord Regeneration ◽  
Experimental Paradigm ◽  
Hair Cell Regeneration ◽  
X Receptors ◽  
Lung Regeneration

Retinoic acid (RA) is the bioactive metabolite of vitamin A (retinol) which acts on cells to establish or change the pattern of gene activity. Retinol is converted to RA by the action of two types of enzyme, retinol dehydrogenases and retinal dehydrogenases. In the nucleus RA acts as a ligand to activate two families of transcription factors, the RA receptors (RAR) and the retinoid X receptors (RXR) which heterodimerize and bind to the upstream sequences of RA-responsive genes. Thus, in addition to the well-established experimental paradigm of depriving animals of vitamin A to determine the role of RA in embryonic and post-embryonic development, molecular biology has provided us with two additional methodologies: knockout the enzymes or the RAR and RXR in the mouse embryo. The distribution of the enzymes and receptors, and recent experiments to determine the endogenous distribution of RA in the embryo are described here, as well as the effects on the embryo of knocking out the enzymes and receptors. In addition, recent studies using the classical vitamin A-deprivation technique are described, as they have provided novel insights into the regions of the embryo which crucially require RA, and the gene pathways involved in their development. Finally, the post-embryonic or regenerating systems in which RA plays a part are described, i.e. the regenerating limb, lung regeneration, hair cell regeneration in the ear and spinal cord regeneration in the adult.

scholarly journals Vitamin A, Cancer Treatment and Prevention: The New Role of Cellular Retinol Binding Proteins

2015 ◽  
Vol 2015 ◽  
pp. 1-14 ◽  
Author(s):  
Elena Doldo ◽  
Gaetana Costanza ◽  
Sara Agostinelli ◽  
Chiara Tarquini ◽  
Amedeo Ferlosio ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
Cancer Progression ◽  
Binding Proteins ◽  
Bone Growth ◽  
Animal Origin ◽  
Ovarian Cancer Cells ◽  
Tissue Remodelling ◽  
Wide Range

Retinol and vitamin A derivatives influence cell differentiation, proliferation, and apoptosis and play an important physiologic role in a wide range of biological processes. Retinol is obtained from foods of animal origin. Retinol derivatives are fundamental for vision, while retinoic acid is essential for skin and bone growth. Intracellular retinoid bioavailability is regulated by the presence of specific cytoplasmic retinol and retinoic acid binding proteins (CRBPs and CRABPs). CRBP-1, the most diffuse CRBP isoform, is a small 15 KDa cytosolic protein widely expressed and evolutionarily conserved in many tissues. CRBP-1 acts as chaperone and regulates the uptake, subsequent esterification, and bioavailability of retinol. CRBP-1 plays a major role in wound healing and arterial tissue remodelling processes. In the last years, the role of CRBP-1-related retinoid signalling during cancer progression became object of several studies. CRBP-1 downregulation associates with a more malignant phenotype in breast, ovarian, and nasopharyngeal cancers. Reexpression of CRBP-1 increased retinol sensitivity and reduced viability of ovarian cancer cellsin vitro. Further studies are needed to explore new therapeutic strategies aimed at restoring CRBP-1-mediated intracellular retinol trafficking and the meaning of CRBP-1 expression in cancer patients’ screening for a more personalized and efficacy retinoid therapy.

scholarly journals Role of Vitamin A in Mammary Gland Development and Lactation

Nutrients ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 80 ◽  
Author(s):  
M. Teresa Cabezuelo ◽  
Rosa Zaragozá ◽  
Teresa Barber ◽  
Juan R. Viña
Keyword(s):  
Retinoic Acid ◽  
Mammary Gland ◽  
Vitamin A ◽  
Vitamin A Deficiency ◽  
Retinoid Signaling ◽  
Nutritional Problem ◽  
Pregnancy And Lactation ◽  
Gland Development

Vitamin A (all-trans-retinol), its active derivatives retinal and retinoic acid, and their synthetic analogues constitute the group of retinoids. It is obtained from diet either as preformed vitamin A or as carotenoids. Retinal plays a biological role in vision, but most of the effects of vitamin A are exerted by retinoic acid, which binds to nuclear receptors and regulates gene transcription. Vitamin A deficiency is an important nutritional problem, particularly in the developing world. Retinol and carotenoids from diet during pregnancy and lactation influence their concentration in breast milk, which is important in the long term, not only for the offspring, but also for maternal health. In this study, we review the role of vitamin A in mammary gland metabolism, where retinoid signaling is required not only for morphogenesis and development of the gland and for adequate milk production, but also during the weaning process, when epithelial cell death is coupled with tissue remodeling.

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