Multiple cytochrome P-450 genes are concomitantly regulated by vitamin A under steady-state conditions and by retinoic acid during hepatic first-pass metabolism

Vitamin A (retinol) is an essential precursor for the production of retinoic acid (RA), which in turn is a major regulator of gene expression, affecting cell differentiation throughout the body. Understanding how vitamin A nutritional status, as well as therapeutic retinoid treatment, regulates the expression of retinoid homeostatic genes is important for improvement of dietary recommendations and therapeutic strategies using retinoids. This study investigated genes central to processes of retinoid uptake and storage, release to plasma, and oxidation in the liver of rats under steady-state conditions after different exposures to dietary vitamin A (deficient, marginal, adequate, and supplemented) and acutely after administration of a therapeutic dose of all- trans-RA. Over a very wide range of dietary vitamin A, lecithin:retinol acyltransferase (LRAT) as well as multiple cytochrome P-450s (CYP26A1, CYP26B1, and CYP2C22) differed by diet and were highly correlated with one another and with vitamin A status assessed by liver retinol concentration (all correlations, P < 0.05). After acute treatment with RA, the same genes were rapidly and concomitantly induced, preceding retinoic acid receptor (RAR)β, a classical direct target of RA. CYP26A1 mRNA exhibited the greatest dynamic range (change of log 26 in 3 h). Moreover, CYP26A1 increased more rapidly in the liver of RA-primed rats than naive rats, evidenced by increased CYP26A1 gene expression and increased conversion of [3H]RA to polar metabolites. By in situ hybridization, CYP26A1 mRNA was strongly regulated within hepatocytes, closely resembling retinol-binding protein (RBP)4 in location. Overall, whether RA is produced endogenously from retinol or administered exogenously, changes in retinoid homeostatic gene expression simultaneously favor both retinol esterification and RA oxidation, with CYP26A1 exhibiting the greatest dynamic change.

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Gene expression of retinoic acid receptors, retinoid-X receptors, and cellular retinol-binding protein I in bone and its regulation by vitamin A.

Endocrinology ◽

10.1210/endo.136.12.7588278 ◽

1995 ◽

Vol 136 (12) ◽

pp. 5329-5335 ◽

Cited By ~ 18

Author(s):

H Harada ◽

R Miki ◽

S Masushige ◽

S Kato

Keyword(s):

Gene Expression ◽

Retinoic Acid ◽

Vitamin A ◽

Binding Protein ◽

Retinoic Acid Receptors ◽

Retinol Binding Protein ◽

Retinoid X Receptors ◽

X Receptors ◽

Cellular Retinol Binding Protein

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Inflammation induced by lipopolysaccharide does not prevent the vitamin A and retinoic acid-induced increase in retinyl ester formation in neonatal rat lungs

British Journal Of Nutrition ◽

10.1017/s0007114512003790 ◽

2012 ◽

Vol 109 (10) ◽

pp. 1739-1745 ◽

Cited By ~ 2

Author(s):

Lili Wu ◽

A. Catharine Ross

Keyword(s):

Gene Expression ◽

Retinoic Acid ◽

Vitamin A ◽

Retinol Binding Protein ◽

Neonatal Rat ◽

Control Group ◽

Retinyl Ester ◽

Protein Receptor ◽

Ester Formation ◽

Lecithin:Retinol Acyltransferase

Vitamin A (VA) plays an important role in post-natal lung development and maturation. Previously, we have reported that a supplemental dose of VA combined with 10 % of all-trans-retinoic acid (VARA) synergistically increases retinol uptake and retinyl ester (RE) storage in neonatal rat lung, while up-regulating several retinoid homeostatic genes including lecithin:retinol acyltransferase (LRAT) and the retinol-binding protein receptor, stimulated by retinoic acid 6 (STRA6). However, whether inflammation has an impact on the expression of these genes and thus compromises the ability of VARA to increase lung RE content is not clear. Neonatal rats, 7- to 8-d-old, were treated with VARA either concurrently with lipopolysaccharide (LPS; Expt 1) or 12 h after LPS administration (Expt 2); in both studies, lung tissue was collected 6 h after VARA treatment, when RE formation is maximal. Inflammation was confirmed by increased IL-6 and chemokine (C–C motif) ligand 2 (CCL2) gene expression in lung at 6 h and C-reactive protein in plasma at 18 h. In both studies, LPS-induced inflammation only slightly reduced, but did not prevent the VARA-induced increase in lung RE. Quantitative RT-PCR showed that co-administration of LPS with VARA slightly attenuated the VARA-induced increase of LRAT mRNA, but not of STRA6 or cytochrome P450 26B1, the predominant RA hydroxylase in lung. By 18 h post-LPS, expression had subsided and none of these genes differed from the level in the control group. Overall, the present results suggest that retinoid homeostatic gene expression is reduced modestly, if at all, by acute LPS-induced inflammation and that VARA is still effective in increasing lung RE under conditions of moderate inflammation.

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Opposing actions of cellular retinol-binding protein and alcohol dehydrogenase control the balance between retinol storage and degradation

Biochemical Journal ◽

10.1042/bj20040621 ◽

2004 ◽

Vol 383 (2) ◽

pp. 295-302 ◽

Cited By ~ 34

Author(s):

Andrei MOLOTKOV ◽

Norbert B. GHYSELINCK ◽

Pierre CHAMBON ◽

Gregg DUESTER

Keyword(s):

Retinoic Acid ◽

Vitamin A ◽

Alcohol Dehydrogenase ◽

Retinol Binding Protein ◽

Dietary Vitamin ◽

Gene Encoding ◽

Retinyl Ester ◽

Ester Formation ◽

Retinyl Esters ◽

Cellular Retinol Binding Protein

Vitamin A homoeostasis requires the gene encoding cellular retinol-binding protein-1 (Crbp1) which stimulates conversion of retinol into retinyl esters that serve as a storage form of vitamin A. The gene encoding alcohol dehydrogenase-1 (Adh1) greatly facilitates degradative metabolism of excess retinol into retinoic acid to protect against toxic effects of high dietary vitamin A. Crbp1−/−/Adh1−/− double mutant mice were generated to explore whether the stimulatory effect of CRBP1 on retinyl ester formation is due to limitation of retinol oxidation by ADH1, and whether ADH1 limits retinyl ester formation by opposing CRBP1. Compared with wild-type mice, liver retinyl ester levels were greatly reduced in Crbp1−/− mice, but Adh1−/− mice exhibited a significant increase in liver retinyl esters. Importantly, relatively normal liver retinyl ester levels were restored in Crbp1−/−/Adh1−/− mice. During vitamin A deficiency, the additional loss of Adh1 completely prevented the excessive loss of liver retinyl esters observed in Crbp1−/− mice for the first 5 weeks of deficiency and greatly minimized this loss for up to 13 weeks. Crbp1−/− mice also exhibited increased metabolism of a dose of retinol into retinoic acid, and this increased metabolism was not observed in Crbp1−/−/Adh1−/− mice. Our findings suggest that opposing actions of CRBP1 and ADH1 enable a large fraction of liver retinol to remain esterified due to CRBP1 action, while continuously allowing some retinol to be oxidized to retinoic acid by ADH1 for degradative retinoid turnover under any dietary vitamin A conditions.

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Retinoic Acid Receptor-α Gene Expression Is Modulated by Dietary Vitamin A and by Retinoic Acid in Chicken T Lymphocytes

Journal of Nutrition ◽

10.1093/jn/124.11.2139 ◽

1994 ◽

Vol 124 (11) ◽

pp. 2139-2146 ◽

Cited By ~ 18

Author(s):

Orna Halevy ◽

Yossef Arazi ◽

Doron Melamed ◽

Aharon Friedman ◽

David Sklan

Keyword(s):

Gene Expression ◽

Retinoic Acid ◽

T Lymphocytes ◽

Vitamin A ◽

Retinoic Acid Receptor ◽

Dietary Vitamin ◽

Acid Receptor ◽

Retinoic Acid Receptor Α

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The Effect of Vitamin A Supplementation on Retinoic Acid-Related Orphan Receptor γt (RORγt) and Interleukin-17 (IL-17) Gene Expression in Avonex-Treated Multiple Sclerotic Patients

Journal of Molecular Neuroscience ◽

10.1007/s12031-013-0058-9 ◽

2013 ◽

Vol 51 (3) ◽

pp. 749-753 ◽

Cited By ~ 16

Author(s):

Niyaz Mohammadzadeh Honarvar ◽

Mohammad Hossein Harirchian ◽

Fariba Koohdani ◽

Feridoun Siassi ◽

Mina Abdolahi ◽

...

Keyword(s):

Gene Expression ◽

Retinoic Acid ◽

Vitamin A ◽

Orphan Receptor ◽

Interleukin 17 ◽

Vitamin A Supplementation

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Dietary Vitamin A and Visceral Adiposity: A Modulating Role of the Retinol-Binding Protein 4 Gene

Journal of Nutrigenetics and Nutrigenomics ◽

10.1159/000442090 ◽

2015 ◽

Vol 8 (4-6) ◽

pp. 164-173 ◽

Cited By ~ 7

Author(s):

Katie Goodwin ◽

Michal Abrahamowicz ◽

Gabriel Leonard ◽

Michel Perron ◽

Louis Richer ◽

...

Keyword(s):

Vitamin A ◽

Binding Protein ◽

Visceral Adiposity ◽

Retinol Binding Protein ◽

Dietary Vitamin ◽

Retinol Binding Protein 4

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Vitamin A Transporters in Visual Function: A Mini Review on Membrane Receptors for Dietary Vitamin A Uptake, Storage, and Transport to the Eye

Nutrients ◽

10.3390/nu13113987 ◽

2021 ◽

Vol 13 (11) ◽

pp. 3987

Author(s):

Nicasio Martin Ask ◽

Matthias Leung ◽

Rakesh Radhakrishnan ◽

Glenn P. Lobo

Keyword(s):

Cell Growth ◽

Vitamin A ◽

Visual Function ◽

Binding Protein ◽

Retinol Binding Protein ◽

Dietary Vitamin ◽

Peripheral Tissues ◽

Retinol Binding Protein 4 ◽

Retinyl Esters ◽

And Function

Vitamins are essential compounds obtained through diet that are necessary for normal development and function in an organism. One of the most important vitamins for human physiology is vitamin A, a group of retinoid compounds and carotenoids, which generally function as a mediator for cell growth, differentiation, immunity, and embryonic development, as well as serving as a key component in the phototransduction cycle in the vertebrate retina. For humans, vitamin A is obtained through the diet, where provitamin A carotenoids such as β-carotene from plants or preformed vitamin A such as retinyl esters from animal sources are absorbed into the body via the small intestine and converted into all-trans retinol within the intestinal enterocytes. Specifically, once absorbed, carotenoids are cleaved by carotenoid cleavage oxygenases (CCOs), such as Beta-carotene 15,15’-monooxygenase (BCO1), to produce all-trans retinal that subsequently gets converted into all-trans retinol. CRBP2 bound retinol is then converted into retinyl esters (REs) by the enzyme lecithin retinol acyltransferase (LRAT) in the endoplasmic reticulum, which is then packaged into chylomicrons and sent into the bloodstream for storage in hepatic stellate cells in the liver or for functional use in peripheral tissues such as the retina. All-trans retinol also travels through the bloodstream bound to retinol binding protein 4 (RBP4), where it enters cells with the assistance of the transmembrane transporters, stimulated by retinoic acid 6 (STRA6) in peripheral tissues or retinol binding protein 4 receptor 2 (RBPR2) in systemic tissues (e.g., in the retina and the liver, respectively). Much is known about the intake, metabolism, storage, and function of vitamin A compounds, especially with regard to its impact on eye development and visual function in the retinoid cycle. However, there is much to learn about the role of vitamin A as a transcription factor in development and cell growth, as well as how peripheral cells signal hepatocytes to secrete all-trans retinol into the blood for peripheral cell use. This article aims to review literature regarding the major known pathways of vitamin A intake from dietary sources into hepatocytes, vitamin A excretion by hepatocytes, as well as vitamin A usage within the retinoid cycle in the RPE and retina to provide insight on future directions of novel membrane transporters for vitamin A in retinal cell physiology and visual function.

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A highly efficient reporter system for identifying and characterizing in vitro expanded hematopoietic stem cells

10.1101/2021.06.18.448972 ◽

2021 ◽

Author(s):

James Lok Chi Che ◽

Daniel Bode ◽

Iwo Kucinski ◽

Alyssa H Cull ◽

Fiona Bain ◽

...

Keyword(s):

Gene Expression ◽

Stem Cells ◽

Hematopoietic Stem Cells ◽

Gene Expression Signature ◽

The Body ◽

Molecular Profile ◽

Functional Screening ◽

Hematopoietic Stem ◽

Wide Range ◽

Single Clone

Hematopoietic stem cells (HSCs) cultured outside the body are the fundamental component of a wide range of cellular and gene therapies. Recent efforts have achieved more than 200-fold expansion of functional HSCs, but their molecular characterization has not been possible due to the substantial majority of cells being non-HSCs and single cell-initiated cultures displaying substantial clone-to-clone variability. Using the Fgd5 reporter mouse in combination with the EPCR surface marker, we report exclusive identification of HSCs from non-HSCs in expansion cultures. Linking single clone functional transplantation data with single clone gene expression profiling, we show that the molecular profile of expanded HSCs is similar to actively cycling fetal liver HSCs and shares a gene expression signature with functional HSCs from all sources, including Prdm16, Fstl1 and Palld. This new tool can now be applied to a wide-range of functional screening and molecular experiments previously not possible due to limited HSC numbers.

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

BioMed Research International ◽

10.1155/2015/624627 ◽

2015 ◽

Vol 2015 ◽

pp. 1-14 ◽

Cited By ~ 54

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.

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