scholarly journals Vitamin A5/X, a new food to lipid hormone concept for a nutritional ligand to control RXR-mediated signaling

2020 ◽  
Author(s):  
Wojciech Krezel ◽  
Aurea Rivas ◽  
Monika Szklenar ◽  
Marion Ciancia ◽  
Rosana Alvarez ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
Retinoic Acid Receptors ◽  
Organic Chemical ◽  
New Class ◽  
Human Food Chain ◽  
Mouse Study ◽  
Β Carotene

Abstract Background: Vitamin A is a family of derivatives synthesized from carotenoids acquired from the diet and can be converted in animals to bioactive forms essential for life. The vitamin A1 (all-trans-retinol / ATROL) and provitamin A1 (all-trans-β,β-carotene / ATBC) are precursors of all-trans-retinoic acid acting as a ligand for the retinoic acid receptors. The contribution of ATROL and ATBC to formation of 9-cis-13,14-dihydroretinoic acid (9CDHRA), the only endogenous retinoid acting as retinoid X receptor ligand remains unknown. Methods: Novel and well know retinoids and carotenoids were synthesized via organic chemical synthesis. Further, novel and well know retinoids / carotenoids were administered to in vitro oligodendrocyte cell culture and to in vivo oral supplemented mice with following HPLC-MS / UV-Vis based metabolomic evaluation of these administered retinoids / carotenoids. In addition, working memory analyses were performed in a mouse study. Results: In this study, we show that ATROL and ATBC are at best only weak and non-selective precursors of 9CDHRA. Instead, we identify 9-cis-13,14-dihydroretinol (9CDHROL) and 9-cis-13,14-dihydro-β,β-carotene (9CDHBC) as novel direct nutritional precursors of 9CDHRA, which are present endogenously in humans and the human food chain matrix. We also propose that the endogenous carotenoid 9-cis-β,β-carotene (9CBC) can also act as weak, indirect precursor of 9CDHRA via hydrogenation to 9CDHBC and further metabolism to 9CDHROL and/or 9CDHRA.Conclusion: In summary, since classical vitamin A1 is not an efficient 9CDHRA precursor, we conclude that this group of molecules constitutes as a new class of vitamin or a new independent member of the vitamin A family, named “Vitamin A5/X”.

scholarly journals Vitamin A5/X, a New Food to Lipid Hormone Concept for a Nutritional Ligand to Control RXR-Mediated Signaling

Nutrients ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 925
Author(s):  
Wojciech Krężel ◽  
Aurea Rivas ◽  
Monika Szklenar ◽  
Marion Ciancia ◽  
Rosana Alvarez ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
High Performance ◽  
New Class ◽  
Trans Retinoic Acid ◽  
All Trans Retinoic Acid ◽  
Human Food Chain ◽  
Β Carotene

Vitamin A is a family of derivatives synthesized from carotenoids acquired from the diet and can be converted in animals to bioactive forms essential for life. Vitamin A1 (all-trans-retinol/ATROL) and provitamin A1 (all-trans-β,β-carotene/ATBC) are precursors of all-trans-retinoic acid acting as a ligand for the retinoic acid receptors. The contribution of ATROL and ATBC to formation of 9-cis-13,14-dihydroretinoic acid (9CDHRA), the only endogenous retinoid acting as retinoid X receptor (RXR) ligand, remains unknown. To address this point novel and already known retinoids and carotenoids were stereoselectively synthesized and administered in vitro to oligodendrocyte cell culture and supplemented in vivo (orally) to mice with a following high-performance liquid chromatography-mass spectrometry (HPLC-MS)/UV-Vis based metabolic profiling. In this study, we show that ATROL and ATBC are at best only weak and non-selective precursors of 9CDHRA. Instead, we identify 9-cis-13,14-dihydroretinol (9CDHROL) and 9-cis-13,14-dihydro-β,β-carotene (9CDHBC) as novel direct nutritional precursors of 9CDHRA, which are present endogenously in humans and the human food chain matrix. Furthermore, 9CDHROL displayed RXR-dependent promnemonic activity in working memory test similar to that reported for 9CDHRA. We also propose that the endogenous carotenoid 9-cis-β,β-carotene (9CBC) can act as weak, indirect precursor of 9CDHRA via hydrogenation to 9CDHBC and further metabolism to 9CDHROL and/or 9CDHRA. In summary, since classical vitamin A1 is not an efficient 9CDHRA precursor, we conclude that this group of molecules constitutes a new class of vitamin or a new independent member of the vitamin A family, named “Vitamin A5/X”.

Vitamin A alters the internal viscosity of fragments of limb-bud mesenchyme

Development ◽  
1980 ◽  
Vol 59 (1) ◽  
pp. 325-339
Author(s):  
T. E. Kwasigroch ◽  
D. M. Kochhar
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
Mesenchymal Cells ◽  
Limb Bud ◽  
Mouse Limb ◽  
Vitamin A Acid ◽  
Internal Viscosity ◽  
Fusion Experiments

Two techniques were used to examine the effect of vitamin A compounds (vitamin A acid = retinoic acid and vitamin A acetate) upon the relative strengths of adhesion among mouse limb-bud mesenchymal cells. Treatment with retinoic acid in vivo and with vitamin A acetate in vitro reduced the rate at which the fragments of mesenchyme rounded-up when cultured on a non-adhesive substratum, but these compounds did not alter the behavior of tissues tested in fragment-fusion experiments. These conflicting results indicate that the two tests measure different activities of cells and suggest that treatment with vitamin A alters the property(ies) of cells which regulate the internal viscosity of tissues.

Function of the retinoic acid receptors (RARs) during development (I). Craniofacial and skeletal abnormalities in RAR double mutants

Development ◽  
1994 ◽  
Vol 120 (10) ◽  
pp. 2723-2748 ◽  
Author(s):  
D. Lohnes ◽  
M. Mark ◽  
C. Mendelsohn ◽  
P. Dolle ◽  
A. Dierich ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
Congenital Malformations ◽  
Double Mutant ◽  
Congenital Abnormalities ◽  
Retinoic Acid Receptor ◽  
Retinoic Acid Receptors ◽  
Acid Receptor ◽  
Null Mutants

Numerous congenital malformations have been observed in fetuses of vitamin A-deficient (VAD) dams [Wilson, J. G., Roth, C. B., Warkany, J., (1953), Am. J. Anat. 92, 189–217]. Previous studies of retinoic acid receptor (RAR) mutant mice have not revealed any of these malformations [Li, E., Sucov, H. M., Lee, K.-F., Evans, R. M., Jaenisch, R. (1993) Proc. Natl. Acad. Sci. USA 90, 1590–1594; Lohnes, D., Kastner, P., Dierich, A., Mark, M., LeMeur, M., Chambon, P. (1993) Cell 73, 643–658; Lufkin, T., Lohnes, D., Mark, M., Dierich, A., Gorry, P., Gaub, M. P., Lemeur, M., Chambon, P. (1993) Proc. Natl. Acad. Sci. USA 90, 7225–7229; Mendelsohn, C., Mark, M., Dolle, P., Dierich, A., Gaub, M.P., Krust, A., Lampron, C., Chambon, P. (1994a) Dev. Biol. in press], suggesting either that there is a considerable functional redundancy among members of the RAR family during ontogenesis or that the RARs are not essential transducers of the retinoid signal in vivo. In order to discriminate between these possibilities, we have generated a series of RAR compound null mutants. These RAR double mutants invariably died either in utero or shortly after birth and presented a number of congenital abnormalities, which are reported in this and in the accompanying study. We describe here multiple eye abnormalities which are found in various RAR double mutant fetuses and are similar to those previously seen in VAD fetuses. Interestingly, we found further abnormalities not previously reported in VAD fetuses.(ABSTRACT TRUNCATED AT 250 WORDS)

Pathways of Retinoid Synthesis in Mouse Bone Marrow-Derived Macrophages and Hematopoietic Progenitors

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1009-1009
Author(s):  
Haixia Niu ◽  
Gayla Hadwiger ◽  
Hideji Fujiwara ◽  
John S. Welch
Keyword(s):  
Bone Marrow ◽  
Retinoic Acid ◽  
Vitamin A ◽  
Real Time Pcr ◽  
Hematopoietic Cells ◽  
Dominant Negative ◽  
Gfp Reporter ◽  
Enzymatic Pathways

Abstract Introduction: Retinoid receptors are nuclear hormone receptors which are dynamically regulated during terminal myeloid maturation. Retinoic acid receptor α (RARA) is the target of at least ten fusion proteins that lead to acute promyelocytic leukemia (APL). All trans-retinoic acid (ATRA) has been thought to be the principle natural ligand for RARs and it has been used for the treatment of patients with APL. However, the enzymatic pathways that regulate natural retinoids metabolism in hematopoietic cells have not been well defined. ATRA is synthesized from vitamin A through two sequential steps. Vitamin A is oxidized by an alcohol dehydrogenase to yield retinal, which is then irreversibly oxidized by an aldehyde dehydrogenase (ALDH) to generate retinoic acid (RA). At least 19 different human ALDHs have been identified. Among them, ALDH1A1, ALDH1A2 and ALDH1A3 have been shown to oxidize all trans-retinal to ATRA with high affinity, which can be inhibited by diethylaminobenzaldehyde (DEAB). Whether other ALDHs participate in RA metabolism is unknown. Our study identified two distinct retinoid metabolism pathways that are active in bone marrow (BM) progenitors and in macrophages (Mφ). Methods: Gal4-UAS reporter system was used to detect natural RARA ligands in mouse primary hematopoietic cells. We transduced UAS-GFP mouse BM cells with retrovirus that expresses a fusion protein containing the DNA binding domain of Gal4 (which recognizes the UAS promoter) and the ligand binding domain of RARA. An IRES mCherry cassette was included for normalization purposes. Transduced cells were cultured in vitro, or transplanted into lethally irradiated recipient mice. Cells with intracellular RARA ligands activate GFP expression. GFP and mCherry expression were evaluated by flow cytometry. Real-time PCR and Affymetrix array were used to quantify ALDH expression. We identified RARA ligands by mass spectrometry (MS). Results: In vitro, we found that both mouse BM Kit+ cells (Kit+ progenitors) and BM-derived macrophages (BMMφ) could synthesize active RARA ligands via different pathways, but only when the cell culture media was supplemented with vitamin A. Kit+ progenitors utilize DEAB-sensitive ALDH pathways, whereas BMMφ use DEAB-insensitive pathways. By real-time PCR we found Kit+ progenitors have high expression of Aldh1a1, Aldh1a2 and Aldh1a3, whereas BMMφ have no detectable expression of these enzymes. We compared gene expression in Kit+ progenitors and BMMφ by Affymetrix profiling and found that Aldh3b1 was overexpressed in BMMφ. Ectopic expression of Aldh3b1 in 293T cells resulted activation of the same GFP reporter, which could be abrogated by two different antagonist, Ro41-5253 and BMS493, suggesting that Aldh3b1 generated an RARA specific ligand, which we subsequently identified as ATRA via MS. Reciprocally, we found that siRNA knock down of Aldh3b1 in BMMφ reduced the transactivation of the RARA-dependent GFP reporter. The X-RARA fusions have been proposed to act via dominant-negative mechanisms, decreasing retinoid-dependent transcription and myeloid maturation. Surprisingly, in vivo, only rare GFPdim cells were observed in BM cells and no GFP positive cells in peritoneal Mφ of UAS-GFP/Gal4-RARA transplant mice. As positive control, we treated mice with ATRA and observed a dose-dependent GFP increase in both cell types, suggesting that the in vivo reporter can respond to ATRA, but ATRA is not synthesized during adult hematopoiesis, and that dominant-negative inhibition of ATRA-dependent transcription may not be the predominant pathogenic effect of the X-RARA fusion oncoproteins. Conclusion: We have found that at least two distinct enzymatic pathways may be utilized in primary hematopoietic cells to synthesize active RARA ligands from vitamin A. Mouse BM Kit+ progenitors predominantly employ a set of DEAB-sensitive enzymes (Aldh1a1, Aldh1a2 and Aldh1a3), whereas Mφ utilize DEAB-insensitive pathways. We identified Aldh3b1 as a likely candidate and shown that it is capable of ATRA synthesis in vitro. Although these enzymes are expressed in primary BM cells, we found that this does not result in active intracellular RARA ligands in monocytes or Mφ in vivo, suggesting that the rate-limiting step in retinoid synthesis in vivo is likely to involve additional enzymes required for intracellular transport of protein-bound, serum-available vitamin A. Disclosures No relevant conflicts of interest to declare.

Retinoic Acid Inhibits Monocyte to Macrophage Survival and Differentiation

Blood ◽  
1998 ◽  
Vol 91 (12) ◽  
pp. 4796-4802 ◽  
Author(s):  
Marina Kreutz ◽  
Jana Fritsche ◽  
Ute Ackermann ◽  
Stefan W. Krause ◽  
Reinhard Andreesen
Keyword(s):  
Retinoic Acid ◽  
Vitamin A ◽  
Leukemic Cells ◽  
Northern Analysis ◽  
Enzyme Linked Immunosorbent Assay ◽  
Mrna Levels ◽  
Blood Monocytes ◽  
Csf Production

Abstract Vitamin A metabolites are potent differentiation-inducing agents for myelomonocytic cell lines in vitro and are successfully used for the treatment of patients with acute promyelocytic leukemia. However, little is known about the effects of vitamin A on normal hematopoietic cells. Therefore, we investigated the effect of vitamin A on differentiation and activation of human blood monocytes (MO). Culturing MO for up to 4 days with 9-cis retinoic acid (RA) and all-trans RA but not retinol reduced MO survival, with the remaining cells being morphologically comparable to control cells. Because macrophage colony-stimulating factor (M-CSF) is a well-known survival factor for MO, we measured the M-CSF content of MO culture supernatants using enzyme-linked immunosorbent assay and found that RA suppressed the constitutive secretion of M-CSF. Northern analysis showed that the M-CSF mRNA expression was only slightly reduced by RA treatment, suggesting regulation on the posttranscriptional level. In contrast to MO, M-CSF secretion by MO-derived macrophages (MAC) was not altered by RA, suggesting a differentiation-dependent switch in the responsiveness of MO/MAC to RA. Because M-CSF is not only a survival-promoting but also a differentiation-promoting factor for myeloid cells, we analyzed the effect of RA on MO to MAC maturation. RA suppressed the expression of the maturation-associated antigen carboxypeptidase M (CPM)/MAX.1 at both the protein and mRNA levels and modulated the lipopolysaccharide-stimulated cytokine secretion of MO/MAC. The addition of exogenous M-CSF to RA-containing MO cultures fails to overcome the RA-induced inhibition of MO differentiation. However, the survival rate was improved by exogenous M-CSF. We conclude that RA acts via two different mechanisms on monocyte survival and differentiation: posttranscriptionally by controlling M-CSF secretion, which decreases MO survival, and transcriptionally regulating the expression of differentiation-associated genes. The regulation of M-CSF production may contribute to the antileukemic effect of RA in vivo by reducing autocrine M-CSF production by leukemic cells.

scholarly journals Heteroarotinoids Inhibit Head and Neck Cancer Cell Lines in Vitro and in Vivo Through Both RAR and RXR Retinoic Acid Receptors

1999 ◽  
Vol 42 (21) ◽  
pp. 4434-4445 ◽  
Author(s):  
David Zacheis ◽  
Arindam Dhar ◽  
Shennan Lu ◽  
Matora M. Madler ◽  
Jozef Klucik ◽  
...  
Keyword(s):  
Head And Neck Cancer ◽  
Retinoic Acid ◽  
Head And Neck ◽  
Cell Lines ◽  
Cancer Cell ◽  
Neck Cancer ◽  
Cancer Cell Lines ◽  
Retinoic Acid Receptors

scholarly journals Both thyroid hormone and 9-cis retinoic acid receptors are required to efficiently mediate the effects of thyroid hormone on embryonic development and specific gene regulation in Xenopus laevis.

1997 ◽  
Vol 17 (8) ◽  
pp. 4738-4749 ◽  
Author(s):  
M Puzianowska-Kuznicka ◽  
S Damjanovski ◽  
Y B Shi
Keyword(s):  
Retinoic Acid ◽  
Thyroid Hormone ◽  
Xenopus Laevis ◽  
Hormone Receptors ◽  
Biological Effects ◽  
Retinoic Acid Receptors ◽  
Specific Gene ◽  
Xenopus Embryos

Tissue culture transfection and in vitro biochemical studies have suggested that heterodimers of thyroid hormone receptors (TRs) and 9-cis retinoic acid receptors (RXRs) are the likely in vivo complexes that mediate the biological effects of thyroid hormone, 3,5,3'-triiodothyronine (T3). However, direct in vivo evidence for such a hypothesis has been lacking. We have previously reported a close correlation between the coordinated expression of TR and RXR genes and tissue-dependent temporal regulation of organ transformations during Xenopus laevis metamorphosis. By introducing TRs and RXRs either individually or together into developing Xenopus embryos, we demonstrate here that RXRs are critical for the developmental function of TRs. Precocious expression of TRs and RXRs together but not individually leads to drastic, distinct embryonic abnormalities, depending upon the presence or absence of T3, and these developmental effects require the same receptor domains as those required for transcriptional regulation by TR-RXR heterodimers. More importantly, the overexpressed TR-RXR heterodimers faithfully regulate endogenous T3 response genes that are normally regulated by T3 only during metamorphosis. That is, they repress the genes in the absence of T3 and activate them in the presence of the hormone. On the other hand, the receptors have no effect on a retinoic acid (RA) response gene. Thus, RA- and T3 receptor-mediated teratogenic effects in Xenopus embryos occur through distinct molecular pathways, even though the resulting phenotypes have similarities.

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