9-cis-13,14-Dihydroretinoic Acid Is an Endogenous Retinoid Acting as RXR Ligand in Mice

Rühl, Ralph; Krzyżosiak, Agnieszka; Niewiadomska-Cimicka, Anna; Rochel, Natacha; Széles, Lajos; Vaz, Belén; Wietrzych-Schindler, Marta; Álvarez, Susana; Szklenar, Monika; Nagy, László; Lera, Ángel R. de; Krężel, Wojciech

doi:10.1371/journal.pgen.1005213

Cited by 109 publications

(114 citation statements)

References 57 publications

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“…9-cis-RA or 9-cis-13,14-DHRA) (3, 4, 7), we analyzed plasma from vitamin A deficient mice (VAD) (24). Prior to PHZ treatment, we validated the presence of vitamin A deficiency using mass spectrometry detection of plasma retinol (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…9-cis-RA and 9-cis-13,14-DHRA have been proposed as natural RXRA ligands in mouse serum, brain, and liver (3, 4, 7). However, when we examined plasma in a vitamin A deficient (VAD) mouse model, in which the retinol concentrations were undetectable (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…However, several groups reported 9-cis-RA to be absent or below detectable limits in testis, liver, heart, lung, and serum (5, 6). Another vitamin A metabolite, 9-cis-13,14-dihydroretinoic acid (9-cis-13,14-DHRA), was reported to be an endogenous RXR ligand in mouse serum, brain, and liver, although it is unclear if it is present in hematopoietic cells (7). Using a luciferase reporter assay, Lengqvist et al .…”

Section: Introductionmentioning

confidence: 99%

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Endogenous retinoid X receptor ligands in mouse hematopoietic cells

et al. 2017

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The retinoid X receptor α (RXRA) has been implicated in diverse hematological processes. However, it is unknown whether natural ligands of RXRA are present in hematopoietic cells. We adapted our upstream activation sequence-green fluorescent protein (UAS-GFP) reporter mouse to detect natural RXRA ligands in vivo. We observed reporter activity in diverse, primary mouse hematopoietic cells in vivo. We found that reporter activity increased during granulocyte colony stimulating factor (GCSF)–induced granulopoiesis and following phenylhydrazine (PHZ)–induced anemia, suggesting the presence of dynamically regulated natural RXRA ligands in hematopoietic cells. We found that mouse plasma could activate Gal4-UAS reporter cells in vitro, and plasma from mice treated with GCSF and PHZ recapitulated the patterns we observed in vivo. Severe vitamin A depletion had only a mild effect on RXRA reporter activity, whereas short-term fatty acid restriction reduced reporter activity, implicating fatty acids as plasma RXRA ligands. Through differential extraction, coupled with mass spectrometry, we identified the long chain fatty acid C24:5 as a natural RXRA ligand, which was dynamically increased in concentration in response to hematopoietic stress. Collectively, these data demonstrate that natural RXRA ligands are present and are dynamically increased in vivo in mouse hematopoietic cells.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Endogenous retinoid X receptor ligands in mouse hematopoietic cells

et al. 2017

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“…Sensing the lipid milieu by RXR, in concert with other nuclear receptors, plays critical roles in physiology, including the regulation of organogenesis, lipid metabolism, and skin homeostasis (1). RXR is able to bind vitamin A derivatives 9-cis-retinoic acid and 9-cis-13,14-dihydroretinoic acid as well as fatty acids such as docosahexanoic acid and phytanic acid (1,2). The receptor has three isotypes, RXRα, RXRβ, and RXRγ, which appear to be functionally interchangeable in tissues in which more than one isotype is expressed (3).…”

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confidence: 99%

Retinoid X receptor suppresses a metastasis-promoting transcriptional program in myeloid cells via a ligand-insensitive mechanism

Kiss

Czimmerer

Nagy

et al. 2017

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

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Retinoid X receptor (RXR) regulates several key functions in myeloid cells, including inflammatory responses, phagocytosis, chemokine secretion, and proangiogenic activity. Its importance, however, in tumor-associated myeloid cells is unknown. In this study, we demonstrate that deletion of RXR in myeloid cells enhances lung metastasis formation while not affecting primary tumor growth. We show that RXR deficiency leads to transcriptomic changes in the lung myeloid compartment characterized by increased expression of prometastatic genes, including important determinants of premetastatic niche formation. Accordingly, RXR-deficient myeloid cells are more efficient in promoting cancer cell migration and invasion. Our results suggest that the repressive activity of RXR on prometastatic genes is mediated primarily through direct DNA binding of the receptor along with nuclear receptor corepressor (NCoR) and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) corepressors and is largely unresponsive to ligand activation. In addition, we found that expression and transcriptional activity of RXRα is down-modulated in peripheral blood mononuclear cells of patients with lung cancer, particularly in advanced and metastatic disease. Overall, our results identify RXR as a regulator in the myeloid cell-assisted metastatic process and establish lipid-sensing nuclear receptors in the microenvironmental regulation of tumor progression.is a member of the nuclear receptor superfamily of ligand-dependent transcription factors that bind various lipophilic hormones and lipid metabolites. Sensing the lipid milieu by RXR, in concert with other nuclear receptors, plays critical roles in physiology, including the regulation of organogenesis, lipid metabolism, and skin homeostasis (1). RXR is able to bind vitamin A derivatives 9-cis-retinoic acid and 9-cis-13,14-dihydroretinoic acid as well as fatty acids such as docosahexanoic acid and phytanic acid (1, 2). The receptor has three isotypes, RXRα, RXRβ, and RXRγ, which appear to be functionally interchangeable in tissues in which more than one isotype is expressed (3). RXR has a unique integrative function in nuclear receptor signaling because of its ability to form homodimers as well as heterodimers with several other members of the superfamily, such as PPAR, LXR, RAR, and VDR. RXR and its heterodimers have a profound effect on the function of myeloid cells by linking cellular metabolism and immune function (4, 5). Specific activation of RXR has been shown to up-regulate chemokine expression, promote phagocytosis of apoptotic cells, and attenuate antiviral responses in myeloid cells (6-8). To further delineate the function of the receptor, we recently mapped the genomic binding sites of RXR in macrophages and identified a network of RXR-bound enhancers that control angiogenic genes including Vegfa, Hbegf, Litaf, and Hipk2 (9). Activation of these enhancers by RXR induced a proangiogenic transcriptional program and phenotype (9). Interestingly, we found that half of the 5...

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“…We previously showed that all- trans -13,14-dihydroretinoic acid can activate the retinoic acid receptors (RAR), albeit, less potently than the cognate ligand of these receptors, namely ATRA [13]. In addition to trans -configured dihydroretinoids, others have detected the presence in serum and tissues of cis -configured dihydroretinoids, which have also been suggested to act as ligands of nuclear receptors [11, 14, 15]. Altogether, these observations suggest that the activity of RetSat could be involved in the generation of novel retinoid metabolites, with interesting and potentially important biological functions.…”

Section: Introductionmentioning

confidence: 99%

Retinol saturase modulates lipid metabolism and the production of reactive oxygen species

Pang

Wang

Jurczak

et al. 2017

Archives of Biochemistry and Biophysics

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Retinol saturase (RetSat) catalyzes the saturation of double bonds of all-trans-retinol leading to the production of dihydroretinoid metabolites. Beside its role in retinoid metabolism, there is evidence that RetSat modulates the cellular response to oxidative stress and plays critical roles in adipogenesis and the accumulation of lipids. Here, we explore the relationship between RetSat, lipid metabolism and oxidative stress using in vitro and in vivo models with altered expression of RetSat. Our results reveal that RetSat is a potent modulator of the cellular response to oxidative stress and the generation of reactive oxygen species (ROS). The levels of reactive aldehydes products of lipid peroxidation, as measured based on thiobarbituric acid reactivity, are increased in RetSat overexpressing cells and, conversely, reduced in cells and tissues with reduced or absent expression of RetSat compared to controls. Despite increased weight gain, neutral lipid accumulation and alterations in hepatic lipid composition, RetSat−/− mice exhibit normal responses to insulin. In conclusion, our findings further expand upon the role of RetSat in oxidative stress and lipid metabolism and could provide insight in the significance of alterations of RetSat expression as observed in metabolic disorders.

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9-cis-13,14-Dihydroretinoic Acid Is an Endogenous Retinoid Acting as RXR Ligand in Mice

Cited by 109 publications

References 57 publications

Endogenous retinoid X receptor ligands in mouse hematopoietic cells

Endogenous retinoid X receptor ligands in mouse hematopoietic cells

Retinoid X receptor suppresses a metastasis-promoting transcriptional program in myeloid cells via a ligand-insensitive mechanism

Retinol saturase modulates lipid metabolism and the production of reactive oxygen species

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