Multiple Factors Contribute to the Toxicity of the Aromatic Retinoid, TTNPB (Ro 13-7410): Binding Affinities and Disposition

Pignatello, Michael; Kauffman, Frederick C.; Levin, Arthur A.

doi:10.1006/taap.1996.8047

Cited by 38 publications

(24 citation statements)

References 34 publications

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“…ATRA (RAR␣/␤/␥), TTNPB (pan-RAR agonist) (47), and GR104 (RAR␣) (48) concentration-dependently stimulated 45 Ca release from the calvarial bones with similar potencies (Fig. 5C).…”

Section: Atra (10mentioning

confidence: 80%

Retinoids Stimulate Periosteal Bone Resorption by Enhancing the Protein RANKL, a Response Inhibited by Monomeric Glucocorticoid Receptor

Conaway

Pirhayati

Persson

et al. 2011

Journal of Biological Chemistry

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Increased vitamin A (retinol) intake has been suggested to increase bone fragility. In the present study, we investigated effects of retinoids on bone resorption in cultured neonatal mouse calvarial bones and their interaction with glucocorticoids (GC). All-trans-retinoic acid (ATRA), retinol, retinalaldehyde, and 9-cis-retinoic acid stimulated release of 45 Ca from calvarial bones. The resorptive effect of ATRA was characterized by mRNA expression of genes associated with osteoclast differentiation, enhanced osteoclast number, and bone matrix degradation. In addition, the RANKL/OPG ratio was increased by ATRA, release of 45 Ca stimulated by ATRA was blocked by exogenous OPG, and mRNA expression of genes associated with bone formation was decreased by ATRA. All retinoid acid receptors (RAR␣/␤/␥) were expressed in calvarial bones. Agonists with affinity to all receptor subtypes or specifically to RAR␣ enhanced the release of 45 Ca and mRNA expression of Rankl, whereas agonists with affinity to RAR␤/␥ or RAR␥ had no effects. Stimulation of Rankl mRNA by ATRA was competitively inhibited by the RAR␣ antagonist GR110. Exposure of calvarial bones to GC inhibited the stimulatory effects of ATRA on 45 Ca release and Rankl mRNA and protein expression. This inhibitory effect was reversed by the glucocorticoid receptor (GR) antagonist RU 486. Increased Rankl mRNA stimulated by ATRA was also blocked by GC in calvarial bones from mice with a GR mutation that blocks dimerization (GR dim mice). The data suggest that ATRA enhances periosteal bone resorption by increasing the RANKL/OPG ratio via RAR␣ receptors, a response that can be inhibited by monomeric GR.

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“…ATRA (RAR␣/␤/␥), TTNPB (pan-RAR agonist) (47), and GR104 (RAR␣) (48) concentration-dependently stimulated 45 Ca release from the calvarial bones with similar potencies (Fig. 5C).…”

Section: Atra (10mentioning

confidence: 80%

Retinoids Stimulate Periosteal Bone Resorption by Enhancing the Protein RANKL, a Response Inhibited by Monomeric Glucocorticoid Receptor

Conaway

Pirhayati

Persson

et al. 2011

Journal of Biological Chemistry

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“…However, we have found no evidence for direct binding of either tRA or TTNPB to RIP14. tRA has been shown to undergo extensive cellular metabolism (9), and recent work has shown that TTNPB can also be metabolized to several compounds (34). Particularly because the time course of activation indicates a lag before the response of RIP14 to either compound, it is possible that the proximal activator of RIP14 is a retinoid metabolite.…”

Section: Discussionmentioning

confidence: 99%

Activation of the orphan receptor RIP14 by retinoids

Zavacki

Lehmann

Seol

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

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Retinoids are crucial regulators of a wide variety of processes in both developing and adult animals. These effects are thought to be mediated by the retinoic acid (RA) receptors and the retinoid X receptors (RXRs). We have identified an additional retinoid-activated receptor that is neither a retinoic acid receptors nor an RXR. RXR-interacting protein 14 (RIP14), a recently described orphan member of the nuclear receptor superfamily, can be activated by either all-trans-RA ( LG1069 activate RXR, and that tRA activates via both RIP14 and RXR. Despite the very effective activation of RIP14 by tRA or TTNPB, relatively high concentrations of these compounds are required, and no evidence for direct binding of either compound was obtained using several approaches. These results suggest that RIP14 is the receptor for an as-yetunidentified retinoid metabolite.Six retinoid receptors have been thought to mediate the diverse effects of retinoids in both developing and adult animals (1, 2). Three types of retinoic acid receptors (RAR) (RAR␣, -␤, and -␥) are activated by either all-trans-RA (tRA) or 9-cis-RA, and three types of retinoid X receptors (RXR) (RXR␣, -␤, and -␥) are activated specifically by 9-cis-RA (reviewed in ref.3). Both the RARs and RXRs are members of the nuclear hormone receptor superfamily, which also includes the receptors for steroids, thyroid hormone, vitamin D 3 , and other ligands (4). In addition to these conventional receptors, this family contains a number of proteins that have no known ligands and are termed ''orphan receptors.'' Nuclear receptors exert their effects by binding to specific DNA sequences called ''response elements'' and by either positively or negatively regulating transcription. The RARs and many other members of the superfamily bind as heterodimers with RXR to response elements comprised of direct repeats of a distinct hexameric sequence (RGGTCA) or bind to palindromic (head-to-head) or everted palindromic (tail-to-tail) arrangements of this hexamer.Recently, we used the yeast two hybrid system with RXR as ''bait'' to clone RXR interacting proteins (5). One of a number of proteins identified, RXR interacting protein 14 (RIP14), was an orphan receptor. RIP14 shows 82% amino acid sequence identity with the Drosophila ecdysone receptor (EcR) in the DNA binding domain, with Ϸ30-40% identity to other RXR heterodimer partners in the ligand binding domain. RIP14 is also the murine homolog of a rat orphan termed ''FXR'' (94% identity), which is reported to be activated by an unidentified metabolite of farnesol (6). In mice and rats, this orphan receptor is expressed primarily in the liver and kidney, with additional expression in gut and adrenal cortex (5, 6). As expected from the high degree of DNA binding domain similarity with the EcR, RIP14-RXR heterodimers also bind with high affinity to an EcR element (EcRE) from the Drosophila heat shock protein 27 (hsp27) promoter (5, 6).Here we report that RIP14 can be specifically activated by either tRA or the synthetic retinoid [...

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“…cells (Fig. S3) (26,27). In contrast to 9cRA, neither decreased the fold increase in insulin secretion after 1-h incubation with 23 mM of glucose vs. 3 mM, but both decreased basal insulin secretion stimulated by 3 mM.…”

mentioning

confidence: 86%

Identification of 9- cis -retinoic acid as a pancreas-specific autacoid that attenuates glucose-stimulated insulin secretion

Kane

Folias

Pingitore

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

100

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The all-trans-retinoic acid (atRA) isomer, 9-cis-retinoic acid (9cRA), activates retinoic acid receptors (RARs) and retinoid X receptors (RXRs) in vitro. RARs control multiple genes, whereas RXRs serve as partners for RARs and other nuclear receptors that regulate metabolism. Physiological function has not been determined for 9cRA, because it has not been detected in serum or multiple tissues with analytically validated assays. Here, we identify 9cRA in mouse pancreas by liquid chromatography/tandem mass spectrometry (LC/MS/MS), and show that 9cRA decreases with feeding and after glucose dosing and varies inversely with serum insulin. 9cRA reduces glucose-stimulated insulin secretion (GSIS) in mouse islets and in the rat β-cell line 832/13 within 15 min by reducing glucose transporter type 2 (Glut2) and glucokinase (GK) activities. 9cRA also reduces Pdx-1 and HNF4α mRNA expression, ∼8-and 80-fold, respectively: defects in Pdx-1 or HNF4α cause maturity onset diabetes of the young (MODY4 and 1, respectively), as does a defective GK gene (MODY2). Pancreas β-cells generate 9cRA, and mouse models of reduced β-cell number, heterozygous Akita mice, and streptozotocin-treated mice have reduced 9cRA. 9cRA is abnormally high in glucose-intolerant mice, which have β-cell hypertropy, including mice with diet-induced obesity (DIO) and ob/ob and db/db mice. These data establish 9cRA as a pancreas-specific autacoid with multiple mechanisms of action and provide unique insight into GSIS.retinol | vitamin A | rexinoids I mpaired glucose-stimulated insulin secretion (GSIS) develops through multiple mechanisms, including actions of metabolic hormones and inflammatory cytokines, products of metabolic overload, and endoplasmic reticulum stress; however, mechanisms of GSIS and impaired glucose tolerance remain incompletely understood (1-4). Also uncertain is the contribution of impaired glucose tolerance to diminished pancreatic β-cell function and mass associated with type 2 diabetes (5). GSIS relies on the pancreas, and pancreas development, islet formation, and function require normal vitamin A nutriture (6-8). Vitamin A restriction during development impairs islet development and promotes glucose intolerance in adult rodents. On the other hand, restricting vitamin A in mature diabetes-prone rats reduces diabetes and insulitis, possibly through enhancing glucose sensing and metabolism. Alltrans-retinoic acid (atRA), an activated metabolite of vitamin A, regulates pancreas development, and atRA does not enhance the incidence of diabetes in diabetes-prone rats fed a vitamin Adeficient diet (7, 9, 10). Although the contribution of vitamin A to pancreas development through atRA seems clear, mechanisms whereby vitamin A affects mature pancreas function have not been determined in depth, nor have the specific vitamin A metabolites been identified that contribute to GSIS control.atRA induces differentiation and regulates cell processes by activating the nuclear receptors RAR α, -β, and -γ, which regulate transcription and translation (11...

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Multiple Factors Contribute to the Toxicity of the Aromatic Retinoid, TTNPB (Ro 13-7410): Binding Affinities and Disposition

Cited by 38 publications

References 34 publications

Retinoids Stimulate Periosteal Bone Resorption by Enhancing the Protein RANKL, a Response Inhibited by Monomeric Glucocorticoid Receptor

Retinoids Stimulate Periosteal Bone Resorption by Enhancing the Protein RANKL, a Response Inhibited by Monomeric Glucocorticoid Receptor

Activation of the orphan receptor RIP14 by retinoids

Identification of 9- cis -retinoic acid as a pancreas-specific autacoid that attenuates glucose-stimulated insulin secretion

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