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At least 973 records · Page 54Linked to original sources
PubMed1981

Nature of skin fragility in patients receiving retinoids for systemic effect.

The origin and frequency of skin fragility, a frequent side effect of oral synthetic retinoids, was studied in ten patients receiving isotretinoin (13-cis-retinoic acid) for disorders of keratinization and in hairless mice treated with isotretinoin and the aromatic retinoid, etretinate (RO 10-9359). Clinical skin fragility occurred in eight of ten patients, and experimental friction blisters could be induced by pencil eraser abrasion in nine of nine patients and in the hairless mice. Light and electron microscopy of friction blisters showed fraying or loss of the stratum corneum and outer layers of the viable epidermis, loss of desmosomes and tonofilaments, and intracellular and intercellular deposits of amorphous material that did not stain with stains for mucin. The skin fragility produced by oral synthetic retinoids is epidermal in origin, since (1) retinoids induce profound disruption of epidermal morphologic appearance, (2) an intraepidermal split is produced by experimental friction blisters, and (3) urinary hydroxyproline excretion in patients receiving retinoids, a measure of collagen catabolism, was not increased.

Adolescent↗
PubMed1980

[Evaluation of oral retinoid preventive action on human cutaneous epitheliomas (author's transl)].

Beneficial effects of oral retinoids in prophylaxis of epithelial neoplasias have been demonstrated by experimental works. In this study oral retinoid (RO 10-9359) was used in human dermatosis with high frequency of cutaneous malignancies: xeroderma pigmentosum with or without malignant neoplasias, Mibelli's porokeratosis with multifocal malignant degeneration, basal cell naevus syndrome with basal cell carcinomas, familial epithelioma of Ferguson-Smith and actinic keratosis. This work started in december 1977. Visible epitheliomas have been treated before trial. Initial dose of retinoid was 1 mg/kg daily, decreased depending on individual tolerance. Results were appreciated by comparising number of epitheliomas observed in years preceding retinoid therapy and number of them appearing during treatment; in two familial cases (basal cell naevus syndrom in twins and xeroderma pigmentosum in two brothers) comparison was made between treated and untreated patients. First results are very promising: an excellent response on solar keratosis is noted; epitheliomas occurrence seems actually to be prevented or delayed by oral retinoid therapy. Of course more numerous cases, a longer time, periods without treatment are necessary to confirm these interesting first results. On the other hand drug is not with this dose active on already constituted carcinomas.

Adolescent↗
PubMed1994

Dietary cottonseed protein can reduce the severity of retinoid-induced hypertriglyceridemia.

Hypertriglyceridemia is frequently noted as a side effect when retinoids (e.g., 13-cis-retinoic acid) are used in human chemoprevention trials. Dietary oilseed proteins (e.g., cottonseed and soy protein) are known to reduce the severity of diet-induced hypertriglyceridemia, but their influence on drug-induced hypertriglyceridemia has not been studied previously. In the present study, the ability of dietary cottonseed protein (as cottonseed flour) to prevent drug-induced hypertriglyceridemia was investigated by feeding male Fischer 344 rats diets having casein or cottonseed protein flour with or without 13-cis-retinoic acid. Animals were fed diets for 2 weeks. Retinoid administration was associated with the induction of hypertriglyceridemia and with changes in serum fatty acid profile, the most noticeable being lowered levels of arachidonic acid. Levels of this fatty acid were 35 and 54% of control levels for retinoid-treated animals fed casein and cottonseed flour, respectively. Animals fed cottonseed flour had lower serum triglyceride levels than ones fed casein for both retinoid-containing and control diets. Dietary cottonseed flour had no effect on food intake or body weight and did not affect serum drug levels. Thus, dietary cottonseed protein can reduce the severity of retinoid-induced hypertriglyceridemia without having adverse effects on food intake or growth; in addition, because levels of 13-cis-retinoic are unaffected by cottonseed protein, it is unlikely that the chemopreventive effectiveness of the drug will be compromised by the inclusion of this protein in the diet.

Animals↗
PubMedDate not supplied

Retinoids and differentiation treatment: a strategy for treatment in cancer.

The retinoids are a large group of compounds structurally related to vitamin A. Retinoids elicit specific biological responses by binding to and activating nuclear receptors. Information about the metabolism and storage of vitamin A and retinoids, their plasma transport and uptake and the retinoid dose efficient on target cell had to be established because retinoic acid (RA), the natural acidic derivative of vitamin A (retinol), is likely to be a key factor during specific phases of embryonic development and maintenance of normal differentiated phenotypes in adult, so vitamin A is involved in the normal morphological differentiation of the visual system. RA appears an important agent since it induces in vitro leukemic cells from acute promyelocytic leukemia (APL) to differentiate into mature functional granulocytes which lose their self-renewal ability and die spontaneously. In vivo, APL patients treated with oral all-trans retinoic acid (all-trans RA) alone achieve complete remission in 80% of the cases. APL results from a malignant process that leads to the accumulation in the blood and in the bone marrow of myeloid precursor cells characterized by an abnormal behavior and a differentiation arrest. APL is characterized cytogenetically by a t(15;17) translocation which involves both the PML gene on chromosome 15 and the RARa gene on chromosome 17 and gives rise to the PML/RARa fusion protein. The high sensitivity of the promyelocytic blasts to all-trans RA should be related to the presence in APL blast of an abnormal protein, the PML/RAR alpha. The antineoplastic effects of retinoids suggest that these drugs could be used therapeutically for the chemoprevention of cancer.

Animals↗
PubMedDate not supplied

Mechanism of growth inhibition of mammary carcinomas by glucarate and the glucarate: retinoid combination.

In synergistic combination 0.75 mmol/kg diet of N-(4-hydroxyphenyl) retinamide and 32 mmol/kg diet of glucarate inhibits the growth of primary rat mammary tumors, but are equally effective as single agents at 1.5 and 128 mmol/kg diet, respectively. Dose-response studies suggest that like retinoids, glucarate acts directly on tumor cells, rather than having an adjuvant effect. Although synergism is maintained down to at least 0.38 mmol/kg diet of the retinoid, experiments using Vitamin A-deficient diets indicates 128 mmol/kg glucarate acts independent of retinoid. Both alone and in combination, glucarate and retinoid inhibited the growth of human mammary tumor cells grown in the athymic mouse, the growth of rat mammary tumors in germfree rats and the hormone-independent MTW 9a/R rat mammary tumor. Like retinoids, glucarate suppresses protein kinase C and induces transforming growth factor-beta, in the mammary tumor cells.

9,10-Dimethyl-1,2-benzanthracene↗
PubMedDate not supplied

Retinoids and their receptors in modulation of differentiation, development, and prevention of head and neck cancers.

Retinoids suppress oral premalignant lesions (OPLs) and decrease the incidence of second primary tumors in head and neck (HN) cancer patients. The optimal clinical use of retinoids depends on the understanding of the mechanism by which they suppress carcinogenesis. It is thought that retinoids restore normal cell growth and differentiation by means of nuclear retinoic acid (RA) receptors (RAR alpha, beta, and gamma) and retinoid X receptors (RXR alpha, beta, and gamma). We used cultured HNSCC cell lines and surgical specimens from normal oral mucosa and from premalignant oral lesions and HN squamous cell carcinomas (HNSCCs) to understand fundamental aspects of retinoids mode of action. RA inhibited the growth and suppressed the aberrant squamous cell differentiation in the majority of HNSCC cell lines examined. Four cell lines expressed mRNAs for RAR alpha, RAR beta, RAR gamma, and RXR alpha. RA treatment increased the levels of the three RAR mRNAs in most of the cell lines but had no effect on the RXR mRNAs. An inverse relationship has been established between the level of RAR beta and squamous differentiation markers. The expression of retrovirally transduced RAR beta in a HNSCC cell line, which did not express RAR beta constitutively, showed a 1,000-fold increase in sensitivity to the suppression of squamous cell differentiation by RA. The expression of retrovirally transduced RAR gamma sense rendered the cells more sensitive, and expression of retrovirally transduced RAR gamma anti-sense made them less sensitive to growth inhibition by RA than parental cells. These results indicate that RAR beta may mediate suppression of squamous differentiation, whereas RAR gamma may mediate the growth inhibition. RAR alpha, RAR beta, RAR gamma, RXR alpha, and RXR beta mRNAs were detected by in situ hybridization in specimens from normal oral mucosa, and all but RAR-beta were also expressed in most of the adjacent normal, hyperplastic, dysplastic, and malignant HN tissues. In contrast, RAR beta mRNA was detected in only 70% of adjacent normal and hyperplastic HN lesions, and its expression was decreased further to 56% of dysplastic lesions and to 35% of SCCs. Likewise, RAR beta was expressed in only 40% of OPLs. Treatment of OPLs with 13-cis-RA increased RAR beta expression from 40% to 90% of the cases. The increase in RAR beta level was associated with clinical response. These results show that selective loss of RAR beta mRNA expression occurs in the early stages of carcinogenesis and may be involved in HN cancer development; and demonstrate that RAR beta is induced by 13-cis-RA in humans.

Cell Differentiation↗
PubMed2003

Function of RARgamma and RARalpha2 at the initiation of retinoid signaling is essential for avian embryo survival and for distinct events in cardiac morphogenesis.

Avian embryogenesis requires retinoid receptor activation by the vitamin A active form, retinoic acid (RA), during neurulation. We conducted loss-of-function analysis in quail embryos by nutritional deprivation of RA and by blocking generation of retinoid receptors. Here we identify a distinct role for RARalpha2 in cardiac inflow tract morphogenesis and for RARgamma in cardiac left/right orientation and looping morphogenesis. Blocking normal embryos with antisense oligonucleotides to RARalpha2 or RXRalpha diminishes GATA-4 transcripts, while blocking RARgamma or RXRalpha diminishes nodal and Pitx2 transcripts; the expression of these genes in the heart forming region resembles that of the vitamin A-deficient embryo. Blocking the function of RARgamma, RARalpha2, and RXRalpha recapitulates the complete vitamin A-deficient phenotype. RARgamma is the most potent mediator of the retinoid signal at this time of development. Our studies provide strong evidence that critical RA-requiring developmental events in the early avian embryo are regulated by means of distinct retinoid receptor signaling pathways.

Animals↗
PubMed1993

Thyroid hormone affects the gene expression of retinoid X receptors in the adult rat.

Gene expression of three nuclear retinoid X receptors (RXR alpha, beta and gamma) was examined by Northern blot analysis in various rat tissues. The RXR alpha mRNA (5.5 kb) was detected in most tissues and particularly expressed at a high level in the liver. The RXR beta transcripts (2.4 and 3.0 kb) were expressed ubiquitously, and particularly at high levels in the brain and testis. In the liver, heart, kidney and lung, the RXR gamma mRNA (2.0 kb) was specifically detected. Furthermore, we examined the effect of retinoid, vitamin D and thyroid hormone status on the gene expression of RXR alpha, beta and gamma. Though retinoid and vitamin D did not affect the mRNA levels of three RXRs, the mRNA levels of two genes were controlled by thyroid hormone. Namely, positive (RXR beta) and negative (RXR gamma) regulations by thyroid hormone were observed with no effect on the gene expression of RXR alpha. These results suggest that thyroid hormone might affect the signal transduction of retinoid, vitamin D and thyroid hormone by changing RXR levels.

Animals↗
PubMed1998

The apolipoprotein(a) promoter contains a retinoid response element.

Retinoids were previously shown to lower apolipoprotein(a) [apo(a)] mRNA levels, suggesting that the apo(a) promoter contains a retinoid response element (RRE). Scanning the apo(a) promoter for sequences related to the consensus RRE half-site (5'-PuG(G/T)TCA-3') uncovered four sites that could potentially function as RREs at -2915, -1875, -1036, and -407. The activity of these sites was assessed by their ability to compete with a very strong consensus DR5 RRE for binding to retinoic acid receptor (RARalpha) and retinoid X receptor (RXRalpha) heterodimers using electrophoretic mobility-shift assays. Only the -1036 site (5'-TGACCTTGTGATCC-'3) was an effective competitor of the DR5 RRE; therefore, it was designated as apo(a) RRE. Apo(a) RRE competed with DR5 RRE for RARalpha/RXRalpha binding with 1/10 the affinity of DR5 RRE, while a scrambled apo(a) RRE was inactive. These results suggested that apo(a) RRE is a potential candidate for mediating the effect retinoids have on apo(a) mRNA expression.

Binding, Competitive↗
PubMed2004

Retinoic acid receptor alpha and retinoid X receptor specific agonists reduce renal injury in established chronic glomerulonephritis of the rat.

Retinoids, derivatives of vitamin A, inhibit mesangial cell proliferation, glomerular inflammation, and extracellular matrix deposition in acute anti-Thy1.1 glomerulonephritis (Thy-GN) of the rat. We examined a model, chronic mesangioproliferative Thy-GN (MoAb 1-22-3), which is more akin to human disease. Treatment started on day 23 when Thy-GN had already been established. Nonnephritic control and Thy-GN rats were treated orally for 67 days with vehicle or with two doses of either the retinoic acid receptor alpha-specific agonist AGN 195183 (RARalpha agonist) or the retinoid X receptor specific agonist AGN 194204 (RXR agonist). Doses of either the RARalpha or the RXR agonist significantly reduced albuminuria and normalized blood pressure during the course of treatment. The glomerulosclerosis index, glomerular cell and interstitial cell counts, and area of the interstitial space were significantly lower in nephritic rats treated with the RARalpha agonist or RXR agonist than with vehicle. The RARalpha and RXR agonist significantly reduced the infiltration of the glomerulus by macrophages. The increase in glomerular TGFbeta1 and prepro-ET(1) gene expression in vehicle-treated nephritic rats was significantly attenuated by RARalpha or RXR agonists. Glomerular expression of RXRalpha and RARalpha receptor mRNA was significantly greater in vehicle-treated nephritic rats than in nonnephritic controls. Treatment with RARalpha or RXR agonists tended to normalize retinoid-receptor gene expression. Our data indicate that both RARalpha agonists and RXR agonists reduce renal damage in rats with established chronic glomerulonephritis. Receptor-specific retinoids may provide a novel therapeutic approach for the treatment of chronic glomerulonephritis.

Albuminuria↗
PubMed2003

Density functional and docking studies of retinoids for cancer treatment.

The retinoic acid receptor (RAR) and retinoid X receptor (RXR) are members of the nuclear receptor superfamily. The ligand-binding domain contains the ligand-dependent activation function. The isotypes RARalpha,beta and gamma are distinct pharmacological targets for retinoids involved in the treatment of various cancers and skin diseases. There is thus considerable interest in synthetic retinoids with isotype selectivity and reduced side effects. In this work we have focused on the retinoid acid receptor and three of its panagonists. We have carried out density functional geometry optimizations at the B3LYP/6-31G* level, computed two types of atomic charges and also electrostatic potentials. A docking program was used to investigate the interactions between the receptor and the three ligands. A theoretically more potent inhibitor, which was obtained by modifying one of the retinoic acids investigated, is proposed.

Binding Sites↗
PubMed1999

Greater synergism of retinoic acid receptor (RAR) agonists with vitamin D3 than that of retinoid X receptor (RXR) agonists with regard to growth inhibition and differentiation induction in monoblastic leukemia cells.

Retinoids and 1alpha,25-dihydroxyvitamin D3 (VD3) cooperatively induce the differentiation of myeloid leukemia cells. We investigated the role of retinoid receptors (RARs and RXRs) in the combined effects of retinoids and VD3 on growth inhibition and differentiation induction in human monoblastic leukemia U937 cells by using RAR- or RXR-selective retinoids. An isobologram analysis showed that both combinations were synergistic with regard to inhibiting the proliferation, and RAR agonists exhibited greater synergism with VD3 than did RXR agonists. RXR agonists alone induced nitroblue tetrazolium (NBT) reduction and expression of CD11b in U937 cells, whereas RAR agonists alone did not. On the other hand, RAR agonists and RXR agonists enhanced the differentiation induced by VD3, but RXR agonists required higher concentrations. An RAR antagonist inhibited the differentiation induced by RAR agonists plus VD3, but not that induced by RXR agonists plus VD3. Thus, RARs and RXRs act differently in their synergism with VD3. RAR agonists are more potent than RXR agonists with regard to synergism with VD3, and their combination may be useful in differentiation therapy against myeloid leukemia.

Alitretinoin↗
PubMed2001

Agonists of the retinoic acid- and retinoid X-receptors inhibit hepatocyte growth factor secretion and expression in U87 human astrocytoma cells.

Retinoids participate in the onset of differentiation, apoptosis and the inhibition of growth in a wide variety of normal and cancerous cells. Several recent reports have shown that hepatocyte growth factor (HGF), and its receptor, c-Met, are expressed at abnormally high levels in various human malignant gliomas and exert a strong proliferative action in an autocrine fashion. These results, consequently, imply that HGF and its receptor may represent a major contributor to the progression of such malignancies. Since astrocytomas are the most frequently occurring glioma, we have shown here that U87 cells - a well-established, human astrocytoma cell line - express both HGF and c-Met, thereby providing a suitable astrocytic tumor model for studying the potential role of HGF, functioning in an autocrine mode, in astrocytic tumorigenesis. Furthermore, we demonstrated the expression of the retinoic acid receptor (RAR) isoforms, RARalpha, -beta and -gamma, as well as the retinoid x-receptor (RxR) isoforms, RxRalpha and -beta, by RT-PCR and western blot analysis in these cells. Since ligands of the RARs and RxRs are known to exert growth inhibitory effects on various tumor cells which include some astrocytomas, we speculated that such effect of retinoids might be mediated via inhibition of HGF secretion in human astrocytoma cells. Indeed, we have shown that the RAR agonists, all-trans retinoic acid (ATRA) and (E)-4-[2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthylenyl)-1-propenyl] benzoic acid (TTNPB), inhibited HGF secretion with half maximal inhibition occurring at 3.0 microM and 15 nM, respectively, as did the RxR agonists, 9-cis- and 13-cis retinoic acid (9cRA and 13cRA, respectively), which exerted half-maximal inhibitory effects at 40 and 25 nM, respectively. These actions of the RAR and RxR agonists appear to be exerted at the transcriptional level as assessed by Northern blot analysis. Taken together, our results show for the first time that retinoids, acting via the RAR and RxRs, significantly inhibit both the secretion and expression of HGF, thereby interrupting a potentially highly tumorigenic autocrine loop in astrocytoma cells.

Antineoplastic Agents↗
PubMed1995

Synthesis and structure-activity relationships of stilbene retinoid analogs substituted with heteroaromatic carboxylic acids.

Retinoids elicit biological responses by activating a series of nuclear receptors. Six retinoid receptors belonging to two families are currently known: retinoic acid receptors (RAR alpha,beta,and gamma) and retinoid X receptors (RXR alpha,beta,and gamma). Stilbene retinoid analogs of retinoic acid (RA), such as (E)-4-[2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)prope n-1- yl]benzoic acid (TTNPB, 1) and (E)-4-[2-(5,6,7,8-tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl)pro pen-1- yl]benzoic acid (3-methyl-TTNPB, 2), display differential RAR and RXR activities, depending on the substituent at C3 of the naphthalene ring. We report here structural modifications of the benzoate moiety of 2 that result in analogs with greater RXR selectivity as well as those with pan-agonist (activate both RAR and RXR receptors) activities, analyze the structural features that impart receptor selectivity, and describe a stereoselective method for the synthesis of these analogs. The biological activities associated with the RAR and RXR receptors were examined by testing representative examples with different receptor activation profiles for their ability to induce tissue transglutaminase (Tgase) activity in a human promyelocytic leukemia cell line (HL-60 cdm-1) and to inhibit tumor-promoter-induced ornithine decarboxylase (ODC) activity in hairless mouse skin. These results suggest that RAR agonists and RXR agonists may have different therapeutic applications. Finally, we show that RXR agonists are significantly reduced in teratogenic potency relative to RAR agonists and may therefore have significant advantages in clinical practice.

Abnormalities, Drug-Induced↗
PubMed1997

Potentiation of VD-induced monocytic leukemia cell differentiation by retinoids involves both RAR and RXR signaling pathways.

Retinoids and vitamin D (VD) cooperate to induce the differentiation and inhibit the proliferation of human myelomonocytic leukemia cells. Two classes of retinoids receptors, the RARs and RXRs, respectively, can mediate these effects. RXR forms heterodimers with a variety of nuclear receptors, including RAR and the VD receptor. We have previously found that VD treatment increases RXR alpha levels in myelomonocytic leukemia cells. By immunoanalysis, we observed in the present work that the RAR alpha protein is expressed in proliferating U937, HL-60 and THP-1 human leukemia cells and that VD treatment induces alterations of its electrophoretic pattern, although with large differences between cell lines. In the three cell lines, 9-cis RA, an agonist of both RARs and RXRs, cooperated with VD more efficiently than all-trans RA and RAR-specific synthetic ligands, thus suggesting an involvement of both RAR and RXR pathways in cell differentiation. Using U937 cells as a model, we delineated the relative contributions of RAR and RXR by assessing the effects of receptor-selective synthetic retinoids. The synergy between VD and all-trans RA or RAR-specific agonists (TTNPB and Ro 40-6055) was abrogated by a RAR alpha-specific antagonist (Ro 41-5253), confirming an involvement of RAR alpha. However, the cooperation between VD and 9-cis RA, although reduced, was not suppressed by the antagonist, suggesting also an involvement of the RXR pathway. The role of RXR as a ligand-activated receptor was confirmed using RXR-specific agonists (CD2608 and LGD1069), which also proved able to cooperate with VD. Finally, while each synthetic agonist alone was significantly less potent than 9-cis RA, combinations of the RAR and RXR selective agonists TTNPB and LGD1069 appeared to be as effective as the pan agonist 9-cis-RA. These results confirm that various retinoids can cooperate with VD and demonstrate that, at a whole cell level, optimal effects require the activation of both RAR and RXR receptors.

Alitretinoin↗
PubMed2004

The transcription factor NGFI-B (Nur77) and retinoids play a critical role in acute neuroleptic-induced extrapyramidal effect and striatal neuropeptide gene expression.

Despite extensive investigation, the cellular mechanisms responsible for neuroleptic actions remain elusive. We have previously shown that neuroleptics modulated the expression of some members of the ligand-activated transcription factors (nuclear receptors) including the nerve-growth factor inducible gene B (NGFI-B or Nur77) and retinoid X receptor (RXR) isoforms. Using genetic and pharmacological approaches, we investigated the role of NGFI-B and retinoids in acute behavioral and biochemical responses to dopamine antagonists. NGFI-B knockout (KO) mice display a profound alteration of haloperidol-induced catalepsy and striatal neuropeptide gene expression. Haloperidol-induced increase of striatal enkephalin mRNA is totally abolished in NGFI-B KO mice whereas the increase of neurotensin mRNA expression is reduced by 50%. Interestingly, catalepsy induced by raclopride, a specific dopamine D(2)/D(3) antagonist is completely abolished in NGFI-B-deficient mice whereas the cataleptic response to SCH 23390, a dopamine D(1) agonist, is preserved. Accordingly, the effects of haloperidol on striatal c-fos, Nor-1, and dynorphin mRNA expression are also preserved in NGFI-B-deficient mice. The cataleptic response and the increase of enkephalin mRNA expression induced by haloperidol can also be suppressed by administration of retinoid ligands 9-cis retinoic acid and docosahexaenoic acid. In addition, we demonstrate that haloperidol enhances colocalization of NGFI-B and RXRgamma1 isoform mRNAs, suggesting that both NGFI-B and a RXR isoform are highly coexpressed after haloperidol administration. Our data demonstrate, for the first time, that NGFI-B and retinoids are actively involved in the molecular cascade induced by neuroleptic drugs.

Alitretinoin↗
PubMed1996

Retinoid X receptor-selective ligands produce malformations in Xenopus embryos.

Retinoids exert pleiotropic effects on the development of vertebrates through the action of retinoic acid receptors (RAR) and retinoid X receptors (RXR). We have investigated the effect of synthetic retinoids selective for RXR and RAR on the development of Xenopus and zebrafish embryos. In Xenopus, both ligands selective for RAR and RXR caused striking malformations along the anterior-posterior axis, whereas in zebrafish only ligands specific for RAR caused embryonic malformations. In Xenopus, RAR- and RXR-selective ligands regulated the expression of the Xlim-1, gsc, and HoxA1 genes similarly as all-trans-retinoic acid. Nevertheless, RXR-selective ligands activated only an RXR responsive reporter but not an RAR responsive reporter introduced by microinjection into the Xenopus embryo, consistent with our failure to detect conversion of an RXR-selective ligand to different derivatives in the embryo. These results suggest that Xenopus embryos possess a unique response pathway in which liganded RXR can control gene expression. Our observations further illustrate the divergence in retinoid responsiveness between different vertebrate species.

Animals↗
PubMed2000

Interleukin-1beta suppresses retinoid transactivation of two hepatic transporter genes involved in bile formation.

Cytokines have been implicated in the pathogenesis of inflammatory cholestasis. This is due to transcriptional down-regulation of hepatic transporters including the Na(+)/bile acid cotransporter, ntcp, and the multispecific organic anion exporter, mrp2. We have recently shown that ntcp suppression by lipopolysaccharide in vivo is caused by down-regulation of transactivators including the previously uncharacterized Footprint B-binding protein. Both the ntcp FpB element and the mrp2 promoter contain potential retinoid-response elements. We hypothesized that retinoic acid receptor (RAR) and retinoid X receptor (RXR) heterodimers would activate these two genes and that cytokines that reduce bile flow might do so by suppressing nuclear levels of these transactivators. Retinoid transactivation and interleukin-1beta down-regulation of the ntcp and mrp2 promoters were mapped to RXRalpha:RARalpha-response elements. Gel mobility shift assays demonstrated specific binding of RXRalpha:RARalpha heterodimers to the ntcp and mrp2 retinoid-response elements. The RXRalpha:RARalpha complex was down-regulated by IL-1beta in HepG2 cells. An unexpected finding was that an adjacent CAAT-enhancer-binding protein element was required for maximal transactivation of the ntcp promoter by RXRalpha:RARalpha. Taken together, these studies demonstrate regulation of two hepatobiliary transporter genes by RXRalpha:RARalpha and describe a mechanism which likely contributes to their down-regulation during inflammation.

Albumins↗