Analysis of Mouse Retinal Dehydrogenase Type 2 Promoter and Expression

doi:10.1006/geno.2001.6546

Genomics

Volume 74, Issue 2, 1 June 2001, Pages 245-250

https://doi.org/10.1006/geno.2001.6546 Get rights and content

Abstract

The mouse RALDH2 gene spans >50 kb, has a structure similar to that of human class 1 aldehyde dehydrogenase genes, and localizes to the central region of chromosome 9 by single-strand polymorphism analysis. Expression of mouse RALDH2 was detected in testis, lung, brain, and heart (Northern blot) and in liver and kidney (RNase protection assays). Expression was not detected by RNase protection assay in testis of vitamin A-deficient rats, and all-trans-retinoic acid dosing did not increase expression in vitamin A-deficient rat testis. A 2.3-kb section of the gene 5′ to the transcription start site included neither retinoic acid nor retinoid X response elements, but included TATA and CCAAT motifs and AP, AHR, CREB, ER, Ets, and SREBP sites. The promoter initiated transcription of a luciferase reporter in human embryonic kidney cells (EBNA) and mouse Leydig- (TM3) and Sertoli-derived (TM4) cell lines, but neither all-trans-retinoic acid nor 9-cis-retinoic acid affected reporter transcription. These data suggest that relatively weak RALDH2 expression in vitamin A-deficient testis reflects vastly decreased numbers of germ cells, the major site of expression.

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The glucocorticoid receptor represses, whereas C/EBPβ can enhance or repress CYP26A1 transcription
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C/EBPβ interacts with other transcription regulators, including the GR, nuclear factor Kappa B, and Activator Protein-1, to increase chromatin opening (Davis et al., 2018; Grøntved et al., 2013; Kabotyanski et al., 2006; Lane et al., 1999). C/EBPβ binding sites have been mapped to promoters regulated by retinoids (Elizondo et al., 2000; Wang et al., 2001), and an interaction between C/EBPβ and the RAR/RXR transcription complex occurs during adipogenesis (Schwarz et al., 1997). These data suggest that C/EBPβ augments RA-induced CYP26A1 transcription by contributing to chromatin opening.
Retinoic acid (RA) counters insulin’s metabolic actions. Insulin reduces liver RA biosynthesis by exporting FoxO1 from nuclei. RA induces its catabolism, catalyzed by CYP26A1. A CYP26A1 contribution to RA homeostasis with changes in energy status had not been investigated. We found that glucagon, cortisol, and dexamethasone decrease RA-induced CYP26A1 transcription, thereby reducing RA oxidation during fasting. Interaction between the glucocorticoid receptor and the RAR/RXR coactivation complex suppresses CYP26A1 expression, increasing RA’s elimination half-life. Interaction between CCAAT-enhancer-binding protein beta (C/EBPβ) and the major allele of SNP rs2068888 enhances CYP26A1 expression; the minor allele restricts the C/EBPβ effect on CYP26A1. The major and minor alleles associate with impaired human health or reduction in blood triglycerides, respectively. Thus, regulating CYP26A1 transcription contributes to adapting RA to coordinate energy availability with metabolism. These results enhance insight into CYP26A1 effects on RA during changes in energy status and glucocorticoid receptor modification of RAR-regulated gene expression.
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Crabp2 promoter analysis found no classical EREs; but ESR1 bound a region of DNA containing an imperfect ERE, ERE half sites, and Sp1 sites [41]. The Aldh1a2 promoter also contains a classical ERE, but studies have not confirmed ER binding [51]. Thus, estrogen directly regulated several RA synthesis proteins via ESR1 in many tissues.
Topical 17-beta-estradiol (E2) regulates the hair cycle, hair shaft differentiation, and sebum production. Vitamin A also regulates sebum production. Vitamin A metabolism proteins localized to the pilosebaceous unit (PSU; hair follicle and sebaceous gland); and were regulated by E2 in other tissues. This study tests the hypothesis that E2 also regulates vitamin A metabolism in the PSU. First, aromatase and estrogen receptors localized to similar sites as retinoid metabolism proteins during mid-anagen. Next, female and male wax stripped C57BL/6J mice were topically treated with E2, the estrogen receptor antagonist ICI 182,780 (ICI), letrozole, E2 plus letrozole, or vehicle control (acetone) during mid-anagen. E2 or one of its inhibitors regulated most of the vitamin A metabolism genes and proteins examined in a sex-dependent manner. Most components were higher in females and reduced with ICI in females. ICI reductions occurred in the premedulla, sebaceous gland, and epidermis. Reduced E2 also reduced RA receptors in the sebaceous gland and bulge in females. However, reduced E2 increased the number of retinal dehydrogenase 2 positive hair follicle associated dermal dendritic cells in males. These results suggest that estrogen regulates vitamin A metabolism in the skin. Interactions between E2 and vitamin A have implications in acne treatment, hair loss, and skin immunity.
Diabetogenic diet-induced insulin resistance associates with lipid droplet proteins and adipose tissue secretome, but not with sexual dimorphic adipose tissue fat accumulation in wistar rats
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On the other hand, the sex hormone, estradiol (E2) is a known regulator Aldh1 gene and therefore retinoic acid synthesis [28]. The Aldh1A2 isoform does possess estrogen response elements in the promoter region, which clearly signifies its role in the transcriptional regulation of this gene [29]. Studies from ovariectomized rats have demonstrated estradiol (E2)-dependant regulation of tissue specific Aldh1 expression [30].
The role of sexual dimorphic adipose tissue fat accumulation in the development of insulin resistance is well known. However, whether vitamin A status and/or its metabolic pathway display any sex- or depot (visceral/subcutaneous)-specific pattern and have a role in sexual dimorphic adipose tissue development and insulin resistance are not completely understood. Therefore, to assess this, 5 weeks old Wistar male and female rats of eight from each sex were provided either control or diabetogenic (high fat, high sucrose) diet for 26 weeks. At the end, consumption of diabetogenic diet increased the visceral fat depots (p < 0.001) in the males and subcutaneous depot (p < 0.05) in the female rats, compared to their sex-matched controls. On the other hand, it caused adipocyte hypertrophy (p < 0.05) of visceral depot (retroperitoneal) in the females and subcutaneous depot of the male rats. Although vitamin A levels displayed sex- and depot-specific increase due to the consumption of diabetogenic diet, the expression of most of its metabolic pathway genes in adipose depots remained unaltered. However, the mRNA levels of some of lipid droplet proteins (perilipins) and adipose tissue secretory proteins (interleukins, lipocalin-2) did display sexual dimorphism. Nonetheless, the long-term feeding of diabetogenic diet impaired the insulin sensitivity, thus affected glucose clearance rate and muscle glucose-uptake in both the sexes of rats. In conclusion, the chronic consumption of diabetogenic diet caused insulin resistance in the male and female rats, but did not corroborate with sexual dimorphic adipose tissue fat accumulation or its vitamin A status.
Oxidized frying oil and its polar fraction fed to pregnant mice are teratogenic and alter mRNA expressions of vitamin a metabolism genes in the liver of dams and their fetuses
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We previously observed a higher incidence of congenital malformations in the fetuses of dams fed an oxidized frying oil (OFO)-containing diet during pregnancy. In this study, we hypothesized that, during pregnancy, maternal ingestion of OFO, specifically the oxidized components (i.e. the polar fraction), modulates peroxisome proliferator-activated receptor (PPARα) or aryl hydrocarbon receptor (AhR) transactivity, altering the metabolism of retinoic acid (RA), a well-characterized morphogen, resulting in teratogenesis. Pregnant C57BL/6J mice were divided into four groups which, from d1 (conception) to d18, were fed a diet containing 10 g/100 g of fresh soybean oil (SO), OFO or the non-polar (NP) or polar (PO) fraction of OFO. Reporter assays testing the transactivity of PPARα and AhR showed that free fatty acids from OFO, specifically the PO fraction, up-regulated PPARα transactivity and down-regulated AhR transactivity. In vivo study showed that the PO fraction group had a significantly higher number of dead fetuses and resorptions per litter than the SO and NP fraction groups. The incidence of abnormalities in terms of gross morphology and skeletal ossification of the fetus was greatest in the PO fraction group, followed by the OFO group, both values being significantly higher than in the other two groups. Hepatic expression of genes encoding enzymes associated with RA synthesis and catabolism in dams and fetuses was differentially affected by PO fraction assault. We conclude that OFO-mediated teratogenesis is associated with disturbed RA metabolism in the dams and fetuses caused, at least in part, by modulation of PPARα and AhR transactivity by the oxidized components in OFO.
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Citation Excerpt :
A GATA site in the second intron binds GATA3 to initiate transcription. Further analysis of the RALDH2 promoter indicated the presence of a sterol regulatory element binding protein (SREBP) [190]. In fact, cholesterol induces RALDH1 and RALDH2 expression in liver, brain, kidney and heart [200].
All-trans-retinoic acid (atRA) provides essential support to diverse biological systems and physiological processes. Epithelial differentiation and its relationship to cancer, and embryogenesis have typified intense areas of interest into atRA function. Recently, however, interest in atRA action in the nervous system, the immune system, energy balance and obesity has increased considerably, especially concerning postnatal function. atRA action depends on atRA biosynthesis: defects in retinoid-dependent processes increasingly relate to defects in atRA biogenesis. Considerable evidence indicates that physiological atRA biosynthesis occurs via a regulated process, consisting of a complex interaction of retinoid binding-proteins and retinoid recognizing enzymes. An accrual of biochemical, physiological and genetic data have identified specific functional outcomes for the retinol dehydrogenases, RDH1, RDH10, and DHRS9, as physiological catalysts of the first step in atRA biosynthesis, and for the retinal dehydrogenases RALDH1, RALDH2, and RALDH3, as catalysts of the second and irreversible step. Each of these enzymes associates with explicit biological processes mediated by atRA. Redundancy occurs, but seems limited. Cumulative data support a model of interactions among these enzymes with retinoid binding-proteins, with feedback regulation and/or control by atRA via modulating gene expression of multiple participants. The ratio apo-CRBP1/holo-CRBP1 participates by influencing retinol flux into and out of storage as retinyl esters, thereby modulating substrate to support atRA biosynthesis. atRA biosynthesis requires the presence of both an RDH and an RALDH: conversely, absence of one isozyme of either step does not indicate lack of atRA biosynthesis at the site. This article is part of a Special Issue entitled: Retinoid and Lipid Metabolism.
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^☆: Sequence data from this article have been deposited with the EMB4 GenBank Data Libraries under Accession No. AF375057.

¹: To whom correspondence should be addressed at Department of Nutritional Sciences and Toxicology, 119 Morgan Hall, MC#3104, University of California, Berkeley, CA 94720-3104. Telephone: (510) 642-0809. Fax: (510) 642-0535. E-mail: [email protected].

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Genomics

Abstract

References (29)

The cellular retinol-binding protein II gene: Sequence analysis of the rat gene, chromosomal localization in mice and humans, and documentation of its close linkage to the cellular retinol-binding protein gene

J. Biol. Chem.

Identification of human liver aldehyde dehydrogenases that catalyze the oxidation of aldophosphamide and retinaldehyde

Biochem. Pharmacol.

2,3,7,8-Tetrachlorodibenzo-p-dioxin induces diverse retinoic acid metabolites in multiple tissues of the Sprague–Dawley rat

Toxicol. Appl. Pharmacol.

ALDH6, a cytosolic retinaldehyde dehydrogenase prominently expressed in sensory neuroepithelia during development

J. Biol. Chem.

Molecular cloning, genomic organization and chromosomal localization of an additional human aldehyde dehydrogenase gene, ALDH6

Genomics

Mouse type-2 retinaldehyde dehydrogenase (RALDH2): Genomic organization, tissue-dependent expression, chromosome assignment and comparison to other types

Biochim. Biophys. Acta

Identification of mouse liver aldehyde dehydrogenases that catalyze the oxidation of retinaldehyde to retinoic acid

Biochem. Pharmacol.

cDNA cloning and expression of a human aldehyde dehydrogenase active with 9-cis-retinal and identification of a rat ortholog: ALDH12

J. Biol. Chem.

Interaction of retinoid binding proteins and enzymes in retinoid metabolism

Biophys. Biochem. Acta

Enzymatic characteristics of retinal dehydrogenase type I expressed in Escherichia coli

Biochem. Biophys. Acta

Biosynthesis of all-trans-retinoic acid from retinal—Recognition of retinal bound to cellular retinol-binding protein (type I) as substrate by a purified cytosolic dehydrogenase

J. Biol. Chem.

Distinct activation domains within cAMP response element-binding protein (CREB) mediate basal and cAMP-stimulated transcription

J. Biol. Chem.

Expression of the gut-enriched Krueppel-like factor gene during development and intestinal tumorigenesis

FEBS Lett.

Cloning of a cDNA encoding an aldehyde dehydrogenase and its expression in Escherichia coli—Recognition of retinal as substrate

J. Biol. Chem.

Cited by (30)

The glucocorticoid receptor represses, whereas C/EBPβ can enhance or repress CYP26A1 transcription

Estrogen regulates the expression of retinoic acid synthesis enzymes and binding proteins in mouse skin

Diabetogenic diet-induced insulin resistance associates with lipid droplet proteins and adipose tissue secretome, but not with sexual dimorphic adipose tissue fat accumulation in wistar rats

Oxidized frying oil and its polar fraction fed to pregnant mice are teratogenic and alter mRNA expressions of vitamin a metabolism genes in the liver of dams and their fetuses

Physiological insights into all-trans-retinoic acid biosynthesis

Adenovirus type 5 induces vitamin A-metabolizing enzymes in dendritic cells and enhances priming of gut-homing CD8 T cells

Short CommunicationAnalysis of Mouse Retinal Dehydrogenase Type 2 Promoter and Expression☆

Abstract

J. Biol. Chem.

Biochem. Pharmacol.

Toxicol. Appl. Pharmacol.

J. Biol. Chem.

Genomics

Biochim. Biophys. Acta

Biochem. Pharmacol.

J. Biol. Chem.

Biophys. Biochem. Acta

Biochem. Biophys. Acta

J. Biol. Chem.

J. Biol. Chem.

FEBS Lett.

J. Biol. Chem.

Short Communication
Analysis of Mouse Retinal Dehydrogenase Type 2 Promoter and Expression☆