Competition between ethanol clearance and retinoic acid biosynthesis in the induction of fetal alcohol syndrome

2018 ◽  
Vol 96 (2) ◽  
pp. 148-160 ◽  
Author(s):  
Yehuda Shabtai ◽  
Abraham Fainsod
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
Dehydrogenase Activity ◽  
Vitamin A Deficiency ◽  
Biologically Active ◽  
Retinoic Acid Signaling ◽  
Fetal Alcohol ◽  
Acid Biosynthesis ◽  
Retinaldehyde Dehydrogenase ◽  
Retinoic Acid Biosynthesis

Several models have been proposed to explain the neurodevelopmental syndrome induced by exposure of human embryos to alcohol, which is known as fetal alcohol spectrum disorder (FASD). One of the proposed models suggests a competition for the enzymes required for the biosynthesis of retinoic acid. The outcome of such competition is development under conditions of reduced retinoic acid signaling. Retinoic acid is one of the biologically active metabolites of vitamin A (retinol), and regulates numerous embryonic and differentiation processes. The developmental malformations characteristic of FASD resemble those observed in vitamin A deficiency syndrome as well as from inhibition of retinoic acid biosynthesis or signaling in experimental models. There is extensive biochemical and enzymatic overlap between ethanol clearance and retinoic acid biosynthesis. Several lines of evidence suggest that in the embryo, the competition takes place between acetaldehyde and retinaldehyde for the aldehyde dehydrogenase activity available. In adults, this competition also extends to the alcohol dehydrogenase activity. Ethanol-induced developmental defects can be ameliorated by increasing the levels of retinol, retinaldehyde, or retinaldehyde dehydrogenase. Acetaldehyde inhibits the production of retinoic acid by retinaldehyde dehydrogenase, further supporting the competition model. All of the evidence supports the reduction of retinoic acid signaling as the etiological trigger in the induction of FASD.

scholarly journals Generation of Retinaldehyde for Retinoic Acid Biosynthesis

Biomolecules ◽  
2019 ◽  
Vol 10 (1) ◽  
pp. 5 ◽  
Author(s):  
Olga V. Belyaeva ◽  
Mark K. Adams ◽  
Kirill M. Popov ◽  
Natalia Y. Kedishvili
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
Tissue Distribution ◽  
Acid Biosynthesis ◽  
Physiological Processes ◽  
Current State ◽  
Trans Retinoic Acid ◽  
Irreversible Oxidation ◽  
All Trans Retinoic Acid ◽  
Retinoic Acid Biosynthesis

The concentration of all-trans-retinoic acid, the bioactive derivative of vitamin A, is critically important for the optimal performance of numerous physiological processes. Either too little or too much of retinoic acid in developing or adult tissues is equally harmful. All-trans-retinoic acid is produced by the irreversible oxidation of all-trans-retinaldehyde. Thus, the concentration of retinaldehyde as the immediate precursor of retinoic acid has to be tightly controlled. However, the enzymes that produce all-trans-retinaldehyde for retinoic acid biosynthesis and the mechanisms responsible for the control of retinaldehyde levels have not yet been fully defined. The goal of this review is to summarize the current state of knowledge regarding the identities of physiologically relevant retinol dehydrogenases, their enzymatic properties, and tissue distribution, and to discuss potential mechanisms for the regulation of the flux from retinol to retinaldehyde.

scholarly journals Regulation and perturbation of testicular functions by vitamin A

Reproduction ◽  
2002 ◽  
pp. 173-180 ◽  
Author(s):  
G Livera ◽  
V Rouiller-Fabre ◽  
C Pairault ◽  
C Levacher ◽  
R Habert
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
Leydig Cells ◽  
Vitamin A Deficiency ◽  
Cell Metabolism ◽  
Biologically Active ◽  
Proliferation And Differentiation ◽  
Beta Receptors ◽  
Alpha Receptors ◽  
Testicular Lesions

In addition to playing a fundamental role in very diverse processes such as vision and the growth and differentiation of numerous types of cell, vitamin A (retinol) and its principal biologically active derivative, retinoic acid, are clearly involved in the regulation of testicular functions in rodents. An excess of vitamin A leads to testicular lesions and spermatogenetic disorders, and a deficiency induces early cessation of spermatogenesis and adversely affects testosterone secretion. Furthermore, mice mutant for retinoic acid alpha receptors and retinoid X beta receptors are sterile. Retinoids appear to exert an action on the three main testicular types of cell (Sertoli, germinal and Leydig cells), as they act on the signalling pathways and Sertoli cell metabolism, and modify numerous factors secreted in Sertoli cells. Retinoids also appear to be necessary for the proliferation and differentiation of A spermatogonia, and for spermiogenesis. In addition, vitamin A deficiency leads to atrophy of the accessory sex organs after decreased testosterone production. Recent studies have shown that retinoids already affect these three types of cell in fetuses. Curiously, the effects of retinoids on fetal and adult testis seem opposed.

scholarly journals Generation of Retinaldehyde for Retinoic Acid Biosynthesis

2019 ◽  
Author(s):  
Olga V. Belyaeva ◽  
Mark K. Adams ◽  
Kirill M. Popov ◽  
Natalia Y. Kedishvili
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
Tissue Distribution ◽  
Acid Biosynthesis ◽  
Physiological Processes ◽  
Current State ◽  
Trans Retinoic Acid ◽  
Irreversible Oxidation ◽  
All Trans Retinoic Acid ◽  
Retinoic Acid Biosynthesis

The concentration of all-trans-retinoic acid, the bioactive derivative of vitamin A, is critically important for the optimal performance of numerous physiological processes. Either too little or too much of retinoic acid in developing or adult tissues is equally harmful. All-trans-retinoic acid is produced by the irreversible oxidation of all-trans-retinaldehyde. Thus, the concentration of retinaldehyde as the immediate precursor of retinoic acid has to be tightly controlled. However, the enzymes that produce all-trans-retinaldehyde for retinoic acid biosynthesis and the mechanisms responsible for the control of retinaldehyde levels have not yet been fully defined. The goal of this review is to summarize the current state of knowledge regarding the identities of physiologically relevant retinol dehydrogenases, their enzymatic properties and tissue distribution, and to discuss potential mechanisms for the regulation of the flux from retinol to retinaldehyde.

Complex regulation of TGF beta expression by retinoic acid in the vitamin A-deficient rat

Development ◽  
1991 ◽  
Vol 111 (4) ◽  
pp. 1081-1086 ◽  
Author(s):  
A.B. Glick ◽  
B.K. McCune ◽  
N. Abdulkarem ◽  
K.C. Flanders ◽  
J.A. Lumadue ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
Vitamin A Deficiency ◽  
Alveolar Epithelium ◽  
Tgf Beta ◽  
Basal Expression ◽  
Beta 2 ◽  
Complex Regulation ◽  
First Time

We report the results of a histochemical study, using polyclonal antipeptide antibodies to the different TGF beta isoforms, which demonstrates that retinoic acid regulates the expression of TGF beta 2 in the vitamin A-deficient rat. Basal expression of TGF beta 2 diminished under conditions of vitamin A deficiency. Treatment with retinoic acid caused a rapid and transient induction of TGF beta 2 and TGF beta 3 in the epidermis, tracheobronchial and alveolar epithelium, and intestinal mucosa. Induction of TGF beta 1 expression was also observed in the epidermis. In contrast to these epithelia, expression of the three TGF beta isoforms increased in vaginal epithelium during vitamin A deficiency, and decreased following systemic administration of retinoic acid. Our results show for the first time the widespread regulation of TGF beta expression by retinoic acid in vivo, and suggest a possible mechanism by which retinoics regulate the functions of both normal and pre-neoplastic epithelia.

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.

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