Abstract
Vitamin A (retinol) is a critical micronutrient required for the control of stem cell functions, cell differentiation, and cell metabolism in many different cell types, both during embryogenesis and in the adult organism. However, we must obtain vitamin A from food sources. Thus, the uptake and metabolism of vitamin A by intestinal epithelial cells, the storage of vitamin A in the liver, and the metabolism of vitamin A in target cells to more biologically active metabolites, such as retinoic acid (RA) and 4-oxo-RA, must be precisely regulated. Here, I will discuss the enzymes that metabolize vitamin A to RA and the cytochrome P450 Cyp26 family of enzymes that further oxidize RA. Because much progress has been made in understanding the regulation of ALDH1a2 (RALDH2) actions in the intestine, one focus of this review is on the metabolism of vitamin A in intestinal epithelial cells and dendritic cells. Another focus is on recent data that 4-oxo-RA is a ligand required for the maintenance of hematopoietic stem cell dormancy and the important role of RARβ (RARB) in these stem cells. Despite this progress, many questions remain in this research area, which links vitamin A metabolism to nutrition, immune functions, developmental biology, and nuclear receptor pharmacology.
Introduction and focus
Vitamin A (all-trans retinol, ROL), a lipid-soluble micronutrient, is absolutely required for mammalian life. Without vitamin A, mammals develop many clinical pathologies, from xerophthalmia (dryness and inflammation of the conjunctiva and cornea of the eye) to a greatly increased susceptibility to infections (Sherwin et al. 2012, Penkert et al. 2019, Surman et al. 2020, Chai et al. 2022). Mammals must obtain vitamin A from their diet as they cannot synthesize vitamin A (Sommer 2008). Vitamin A is found in meat and dairy products, and pro-vitamin A sources, especially beta-carotene, are found in vegetables (Ross & Moran 2020).
Presumably, because of the essential roles of vitamin A and because periods of nutrient limitation, including famines, have occurred throughout the course of history, ingested vitamin A is delivered, via chylomicrons (small particles of triglycerides, phospholipids, proteins, and cholesterol) to the liver for longer-term storage (Harrison 2005, Blaner et al. 2016). In the liver, vitamin A is converted to retinyl esters (REs) by the enzyme lecithin:retinol acyl transferase (LRAT), primarily in the stellate cells, after vitamin A is transferred to these stellate cells from hepatocytes (Blomhoff et al. 1984, Batten et al. 2004, Wongsiriroj et al. 2014, Saeed et al. 2019, O’Connor et al. 2022). These REs are stored for future use so that seasonal and other variations in dietary supplies do not prevent the target cell types that require vitamin A (most cell types in the body) from obtaining the vitamin A needed to carry out appropriate molecular activities. The term ‘retinoids’ is used to describe vitamin A and its various metabolites, including retinoic acid (RA).
Homeostasis is defined as a process by which an organism adjusts to external, sometimes hostile stimuli, to maintain stable signaling internally. Homeostasis of retinoids requires multiple metabolic processes, including the storage and release of vitamin A from the liver RE stores, the transport of vitamin A into various cell types in the body (Blaner et al. 2016), the metabolism of vitamin A to all-trans retinoic acid (RA), and the further oxidative metabolism of RA, to allow for the proper levels of biologically active retinoids to be achieved in specific cell types in the body. Since RA regulates stem cell differentiation and is active at nanomolar concentrations in cells, levels of this signaling molecule must be precisely regulated in a spatiotemporal manner during embryogenesis and throughout life (Gudas & Wagner 2011). Of course, it follows that disruption of vitamin A homeostasis can likely result in pathologies. For example, overnutrition seen in obesity can negatively affect vitamin A metabolism and signaling (Trasino et al. 2015b), leading to diminished immune functions, increased susceptibility to respiratory viral infections, and poor responses to vaccinations (Penkert et al. 2020).
We know, in both animal models and in humans, that levels of RA that are too high or too low can cause major pathological changes both during development (Rutledge et al. 1994, Lee et al. 2012, Lee et al. 2017b) and in the adult (Touma et al. 2009, Stevens et al. 2015, Trasino et al. 2015a, Defnet et al. 2021). This review focuses on how retinol is metabolized to more bioactive retinoids, such as RA, in specific cell types, at the correct times and in the correct amounts. The role of the bioactive retinoid, 11-cis-retinaldehye, in vision and the metabolism of vitamin A to 11-cis-retinaldehyde are not covered here, but an excellent review covers this topic (Dewett et al. 2021). This review will focus on selected, recent literature on the topic of vitamin A (retinol) metabolism and the roles of this metabolism in maintaining cell function and regulating differentiation.
Retinoids act primarily, but not exclusively, by binding to retinoic acid receptors on DNA
RA, a metabolite of vitamin A, is an endogenous agonist for the RA receptors α, β, and γ (RARα, β, and γ (RARA, RARB, RARG); also named NR1B1, NR1B2, and NR1B), which are members of the nuclear receptor protein family. Depending on the context, these nuclear receptors can act as either repressors or activators of gene transcription (Fig. 1). They possess both a ligand binding domain and a DNA binding domain. The endogenously produced ligand, RA, induces a ‘molecular switch’ that involves changing the regulatory proteins bound to the RARs, often turning the RARs, which are dimerized with retinoid X receptors (RXRs) α, β, and γ, from repressors to activators of transcription (Nagy & Schwabe 2004). Transcriptional activation takes place via binding of the RA-bound RARs to enhancers containing retinoic acid response elements (RAREs) that exist in promoters and/or introns of primary RA target genes (those genes to which the RARs directly bind) such as Hoxa1, Hoxb1, and RARβ (LaRosa & Gudas 1988, de The et al. 1990, Langston & Gudas 1992, Marshall et al. 1994, Langston et al. 1997, Huang et al. 1998).
Metabolism of vitamin A (retinol) in cells and major actions of retinoic acid in cells. All-trans retinol is oxidized to retinaldehyde and to retinoic acid; further oxidation by Cyp26a1, b1, and c1 can also take place. Retinoic acid moves to the nucleus where it acts as an endogenous agonist for the retinoic acid receptors (RARs) α, β, and γ when these receptors are in a heterodimer with the RXRs α, β, and γ. Then, transcriptional activation or repression of primary target genes, those genes with RAREs (retinoic acid response elements/enhancers to which the RARs bind), takes place. RARα can also function in the cytoplasm, where in the absence of RA it inhibits the translation of target RNAs in neurons; in this case the ligand, RA, blocks this effect. 4-Hydroxy-RA and 4-oxo-RA both can act as endogenous agonists for the RARs in model systems, and recent data indicate a role in animal models in hematopoietic stem cells.
Citation: Journal of Molecular Endocrinology 69, 4; 10.1530/JME-22-0082
Although most studies of RARs have focused on their actions in the nucleus, recently RARα has also been shown to act in the cytoplasm of cells in the hippocampus of the brain as an ‘RA-induced postsynaptic regulator of protein synthesis’ (Hsu et al. 2019). Additionally, RA can activate extracellular signal-regulated kinase 1/2 (ERK1/2) via an RAR-independent mechanism (Persaud et al. 2013).
RARs α, β, and γ all bind RA, but with different affinities (Aström et al. 1990), and synthetic retinoids that selectively bind one type of RAR have also been synthesized for use in the treatment of a number of different diseases (Gudas 2022). 4-Oxo-retinol is also an agonist for the RARs (Achkar et al. 1996). Pertinent to this discussion, the RARs α, β, and γ exert different functions in different cell types and tissues, indicating some unique functions of the three RARs in animals, despite the fact that all three RARs bind RA and are expressed in most cell types (Chiang et al. 1998, Sarti et al. 2013, Cabezas-Wallscheid et al. 2017, Uchibe et al. 2017, Shibata et al. 2021, Ciancia et al. 2022). Furthermore, RA can signal within the same cell or can be secreted to influence cells nearby. In fact, RA ‘morphogen’ gradients assist in the patterning of organs during development (Schilling et al. 2012). I will focus on how retinoids are metabolized to produce the biologically active derivatives that are required for the development or function of specific cell types.
Metabolism of vitamin A to retinaldehyde reveals a sexually dimorphic impact on energy metabolism and the key roles of retinoids in development
The short-chain dehydrogenases/reductases (SDR) enzyme family (Kavanagh et al. 2008, Belyaeva et al. 2019, Napoli & Yoo 2020), consists of many members, some of which can metabolize retinol to retinaldehyde (retinal, RAL) (Fig. 1). One member of this SDR family, the NAD-dependent enzyme retinol dehydrogenase (RDH10), carries out the oxidation of retinol to retinaldehyde. RDH10 is required for survival during embryogenesis, and without RDH10, there is a major deficiency in RA, resulting in the failure of many developmental processes (Cammas et al. 2007, Sandell et al. 2007, Farjo et al. 2011, Rhinn et al. 2011, Sandell et al. 2012, D'Aniello et al. 2015). Genetic studies in mice demonstrate that RDH10 regulates energy expenditure (Wang et al. 2020). Notably, heterozygous RDH10+/− male mice show relatively small decreases in tissue RA (<25%), but, when placed on a high-fat diet, males decrease fatty-acid oxidation and develop insulin resistance. In contrast, female RDH10+/− mice do not show these changes, though both males and females exhibit increased adiposity on a high-fat diet compared to WT mice. Additionally, in males, running endurance decreases, while for females, running endurance increases. These sexually dimorphic effects are in part the result of different amounts of reduction in RA levels in these RDH10+/− male vs female mice, since low-dose RA, given chronically, can correct these metabolic pathologies (Yang et al. 2018, Zhao et al. 2021).
At the molecular level, RDH10 transcription is increased by the transcription factor FoxO1 in cultured liver cells when serum is removed (Obrochta et al. 2015). In cultured embryonic stem cells, oxidation of retinol by RDH10 is required for ethanol to induce primary RA target genes such as Hoxa1, Cyp26a1, and Stra6. Intriguingly, ethanol also increases RDH10 mRNA levels by a mechanism not yet clear (Serio et al. 2019).
The SDR enzyme dehydrogenase/reductase SDR member 3 (DHRS3) is an NADPH-dependent enzyme which, conversely, reduces retinaldehyde to retinol and causes embryonic lethality because of excess RA (Feng et al. 2010a, Billings et al. 2013, Adams et al. 2014, Wang et al. 2018). An association of RDH10 with DHR3 exists and this association facilitates the activities of each of these proteins (Adams et al. 2021). Various other SDR family members have been reported to exhibit oxidoreductase activity using retinoid substrates in numerous tissues. For instance, Dhrs9 plays a critical role in the hair follicle cycle and in inhibiting squamous cell carcinomas (Everts & Akuailou 2021).
Oxidation of retinaldehyde (RAL) to retinoic acid regulates cell development and function
Following the conversion of retinol to retinaldehyde, RAL is irreversibly oxidized to RA by members of the ALDH1A family of enzymes, ALDH1a1, ALDH1a2, and ALDH1a3 (formerly RALDH1,2,3) (Chen et al. 2018, Pequerul et al. 2020). These enzymes ALDH1a1, 2, and 3 also catalyze the oxidation of aliphatic aldehydes, such as hexanal and 4-hydroxy-2-nonenal. Enzymes in this family are expressed at different levels in various cell types and most likely play tissue-specific roles in the production of RA from RAL (Niederreither et al. 1999, Mic et al. 2000, Dupe et al. 2003, Arnold et al. 2015, Lee et al. 2017a). The key role of ALDH1a2 in development is underscored by the report of humans with two different missense variants in ALDH1a2 that result in a severe, multiple congenital anomaly syndrome with neonatal lethality (Beecroft et al. 2021). Other members of this ALDH1A family include ALDH1a1, which contributes to the synthesis of RA in adipose tissue (Elizondo et al. 2009, Haenisch et al. 2021, Rubinow et al. 2022), and ALDH1a3, which is active in cardiac atrial appendage progenitor cells (Puttini et al. 2018). As might be expected, higher RA levels generally reduce the expression of ALDH1a2 in RA-target cells (Billings et al. 2013). A vitamin A-deficient diet causes an increase in ALDH1a2, a decrease in ALDH1a1, and no significant change in ALDH1a3 transcript levels in murine kidneys ( van der Mijn 2022). These changes in ALDH1a2 indicate that the synthesis of RA can be modulated in response to intracellular levels of RA; when RA levels are low, ALDH1a2 transcripts are increased in some organs, such as the liver and kidney.
Since the reaction catalyzed by ALDH1a2 is such a critical step in the synthesis of RA from RAL (Fig. 1), it is not surprising that the ALDH1a2 gene is transcriptionally controlled by several different transcription factors. Information is available about how ALDH1a2 transcription is regulated in some tissues, both during development and in the activation of dendritic cells, key cells that initiate and modulate immune responses (Stagg 2018). For instance, the T-box transcription factor, TBX5, controls ALDH1A2 transcription in the foregut lateral plate mesoderm during development, ultimately generating RA and activating endodermal Shh (Sonic hedgehog) expression (Rankin et al. 2021). ALDH1a2 levels are also increased by estrogen in human endometrium (Deng et al. 2003).
The metabolism of retinaldehyde to retinoic acid by ALDH1a2 in subtypes of dendritic cells modulates immunity
Dendritic cells (DCs) capture and present antigens to naive T-cells, generating antigen-specific immune responses. Here, we focus on the DCs in the intestine, where many advances in our understanding of the actions of ALDH1a2 on DC function have been elucidated. The intestinal immune system exhibits some differences from the systemic immune system. Cells in the intestinal tract are exposed to large numbers of antigens, many of which are from harmless substances, and Treg cells, a type of T-cell, are primarily responsible for immunosuppression in the intestine (Coombes & Maloy 2007). During homeostasis, a subtype of DCs, CD103+ DCs, assists in maintaining intestinal tolerance by migrating to mesenteric lymph nodes, the lymph nodes between layers of the mesentery, a membrane that attaches the intestine to the abdominal wall. There these intestinal DCs (i) induce the gut-homing receptors CCR9 and α4β7 on T and B-cells, (ii) promote the development of Foxp3+ regulatory T-cells, and (iii) promote IgA class switching in naïve B-cells (Johansson-Lindbom et al. 2005, Schulz et al. 2009) (Fig. 2). Notably, RA, produced in CD103+ DCs by transcriptional activation of ALDH1a2, plays a major role in regulating these processes (Iwata et al. 2004, Coombes et al. 2007, Hammerschmidt et al. 2011, Gyöngyösi et al. 2013, Sato et al. 2013). Furthermore, in the presence of RA, naive T-cells can no longer properly differentiate into T-helper 17 (Th17 cells). Additionally, T-cell production of interleukin-4 and interferon-γ, cytokines that block T-reg differentiation, is reduced by RA (Bettelli et al. 2006, Sun et al. 2007, Xiao et al. 2008). In aggregate, these effects of DCs that produce RA in the intestine influence the balance between Treg and Th17 cells, favoring Treg cells. Importantly, in contrast to this CD103+ subtype of DCs in the intestine, DCs in the spleen and lymph nodes draining the skin generally do not exhibit high ALDH1a2 expression (Molenaar et al. 2011, Villablanca et al. 2011).
Vitamin A actions in the intestine influence immunity. Dendritic cells (DCs) from the bone marrow produce some ALDH1A2 and migrate to the intestine. There, Vitamin A from the diet is metabolized by intestinal epithelial cells (enterocytes) into retinoic acid (RA). By association with the epithelial cells that produce RA, these intestinal DCs, characterized by the expression of CD103, produce more ALDH1a2, as RA can activate ALDH1A2 transcription. These intestinal DCs then generate RA for IgM+ B-cells present in the lamina propria of the intestine, allowing them to undergo class switching to IgA. In the mesenteric lymph nodes, these DCs, after migration from the lamina propria, provide RA to B cells. B-cells recirculate from the mesenteric lymph nodes via the bloodstream and enter the intestine using α4β7, becoming IgA-secreting plasma cells. These high ALDH1A2-expressing DCs also drive T-cells to differentiate into T-Reg cells rather than TH17 T-cells. Panel on the right: In the DCs, RA from the enterocytes binds to the RAR:RXR heterodimer and, along with GM-CSF, drives transcription of the ALDH1a2 gene, which leads to more RA synthesis from retinaldehyde. The protein tristetraprolin is involved in degrading ALDH1A2 mRNA, so in the absence of tristetraprolin, an RNA-binding protein, more RA is present since the ALDH1A2 transcript is more stable in the DCs.
Citation: Journal of Molecular Endocrinology 69, 4; 10.1530/JME-22-0082
How is the ALDH1a2 gene transcriptionally activated in CD103+ DCs to produce the RA that influences intestinal immunity? First, bone marrow-derived DCs express some ALDH1a2 that produces RA, and RA then promotes a mucosal differentiated DC phenotype (Iliev et al. 2009, Feng et al. 2010b). In bone marrow-derived DCs, a heterodimer of the transcription factors PU.1 and IRF4 bind at -1961/-1952 of the ALDH1a2 promoter to activate transcription (Yashiro et al. 2018). These mucosal DCs continuously arrive in the intestine from the circulation (Jaensson et al. 2008). In the intestine, epithelial cells (enterocytes) absorb and metabolize vitamin A from the diet. The RA produced by this enterocyte metabolism induces further differentiation of these DCs in the intestine and initiates greater induction of ALDH1a2 transcription in these intestinal DCs (Molenaar et al. 2011, McDonald et al. 2012, Roe et al. 2017, Rivera et al. 2022) (Fig. 2). There is evidence that the induction of ALDH1a2 transcription occurs via RARβ binding to two potential RAREs located within 1 kb 5’ of the ALDH1a2 transcription start site (Zhu et al. 2013). GM-CSF (granulocyte macrophage-colony stimulating factor) and IL-4 plus RA can greatly increase ALDH1a2 transcripts in DC cells (Yokota et al. 2009). Cooperative binding of the transcription factor Sp1 and the RARα/RXR heterodimer, binding at a RARE half site in the ALDH1a2 promoter just upstream of the transcription start site, is required for RA and GM-CSF to enhance ALDH1a2 transcription (Ohoka et al. 2014) (Fig. 2). Notch signaling is also required for the transcriptional activation of ALDH1a2 in DCs (Zaman et al. 2017). Thus, RA is both a product of ALDH1a2 and a transcriptional activator of ALDH1a2 in these DCs. Furthermore, ALDH1a2 activity in these DCs declines with age, suggesting that the increased inflammation associated with aging results in part from a reduction in antigen-specific Treg cell production (Takano et al. 2020). A key question that remains unanswered is how vitamin A and/or RA is transferred from the enterocytes into DCs to stimulate their differentiation in the intestine and to initiate RA production from ALDH1a2. Similarly, we do not understand how the RA produced by DCs is transferred to and transported into T-cells to stimulate their differentiation into Treg cells. B and T-cells in the immune system express both RARα and RARγ constitutively so they can respond to the RA produced by DCs (Ballow et al. 2003). RARβ actions in enterocytes are essential for both the generation of gut-homing CD4+ T-cells and IgA-producing B-cells, but not for the production of Treg cells in the intestine (Gattu et al. 2019).
The protein tristetraprolin, encoded by the Zfp36 gene, has many activities, including reducing the expression of IL-23 and IL-6, mediators of inflammation (Qian et al. 2011). Zfp36 null mice, therefore, exhibit a multiorgan inflammatory syndrome similar to spondyloarthritis (Molle et al. 2013). Recently it was shown that ALDH1a2 is one direct target of tristetraprolin, but that the increase in ALDH1a2 mRNA level observed in the absence of tristetraprolin (in Zfp36-deficient DCs) occurs via a non-transcriptional mechanism. Tristetraprolin is an AU-rich element (ARE) RNA binding protein, and tristetraprolin reduces the stability of ALDH1a2 mRNA in DC cells by binding to AREs in its 3’UTR and targeting ALDH1a2 mRNA for degradation by recruitment of deadenylases (Clement et al. 2011). When tristetraprolin is absent, ALDH1a2 mRNA is more stable, resulting in increases in T-reg homeostasis because of greater RA production by the DCs (La et al. 2021). Thus, ALDH1a2 is regulated both at the level of transcriptional activation and mRNA stability in intestinal DCs to control immune tolerance (Fig. 2).
It is likely that ALDH1a2 is activated in other cell types by inflammatory signals and cellular stress and/or damage, as is the case in the kidney (Nakamura et al. 2019) and in stellate cells of the liver, which also increase ALDH1a2 transcripts and, in the presence of DCs and TGFβ, induce FoxP3+ Treg cells (Dunham et al. 2013). ALDH1a2 is also induced and required for zebrafish fin and heart regeneration (Mathew et al. 2009, Kikuchi et al. 2011). More research very likely will reveal the regulation of ALDH1a2 in other cell types.
Oxidation of retinoic acid by cytochrome P-450 enzymes and the regulation of these enzymes in numerous cell types
Further oxidation of the RA ionone ring via hydroxylation at the C-4 position is catalyzed primarily by the CYP26 family of enzymes, CYP26A1, B1, and C1 (White et al. 1997, Taimi et al. 2004, Lutz et al. 2009, Thatcher et al. 2010, Helvig et al. 2011, Zhong et al. 2018, Isoherranen & Zhong 2019) (Fig. 1). Evidence indicates that retinoids are the only substrates for this CYP26 family of enzymes (Thatcher et al. 2010, Zhong et al. 2018). Oxidation of 4-hydroxy- to 4-keto-RA is also mediated by these enzymes (Roberts et al. 1980, Chen & Gudas 1996). Oxidized metabolites of RA are also conjugated by glucuronosyltransferases in Phase II metabolism for clearance (Barua & Olson 1986).
The Cyp26 enzymes are key proteins for regulating the internal levels of RA in cells. CYP26A1 is transcriptionally activated by RA via RAR/RXR binding to two RAREs in the CYP26A1 promoter (Loudig et al. 2000, Loudig et al. 2005). The CYP26A1 gene can also be transcriptionally activated by RA metabolites (Topletz et al. 2015), suggesting a role for CYP26A1 in RA elimination. Moreover, the transcription of CYP26A1 is controlled by epigenetic regulators, such as histone deacetylases, in addition to RA (Gillespie & Gudas 2007, Amat & Gudas 2011, Urvalek & Gudas 2014).
Knockouts of CYP26A1 and CYP26B1 are embryonically lethal (Niederreither et al. 2002), but if these enzymes are knocked out postnatally, dermatitis, splenomegaly, and inflammation ensue (Snyder et al. 2020). These postnatal knockout mice exhibited increased RA levels in the liver, serum, skin, and intestines, again underlining the importance of these enzymes in regulating the levels of RA in the body (Snyder et al. 2020). In humans, some individuals with missense mutations in CYP26B1 have survived, but with complex developmental anomalies (Morton et al. 2016, Grand et al. 2021). Inhibitors that are selective for CYP26B1 have been generated and may be of use for the treatment of keratinization disorders in the skin, for example, Darier disease (Veit et al. 2021).
During development, Cyp26a1 and Cyp26b1 play major roles in establishing gradients of RA and, thus, in regulating the differentiation of various stem cells (Abu-Abed et al. 2002, White et al. 2007, White & Schilling 2008, Drummond et al. 2013, Ono et al. 2020). For instance, Cyp26a1 is required for normal hindbrain patterning in embryos (Abu-Abed et al. 2001). The absence of Cyp26a1 results in altered spinal motor neuron subtype identity when embryonic stem cells are differentiated into neuronal cells, indicating a key role for retinoids in directing neural differentiation (Ricard & Gudas 2013). Normal testis development requires CYP26B1 since without CYP26B1 activity, the reproductive tract is feminized (Bowles et al. 2006, Bowles et al. 2018). Additionally, during lung development, the lack of Cyp26b1 activity results in fewer alveolar type 1 cells, failure of alveolar inflation, and postnatal lethality in rodents (Daniel et al. 2020). Spleen organogenesis and growth are impaired in mice that lack Cyp26b1 (Lenti et al. 2016). Cyp26b1 plays a key role in heart valve morphogenesis (Ahuja et al. 2022). In the developing prefrontal cortex of the brain, a frontal to temporal gradient of RA exists, and RA signaling is limited to the prefrontal cortex by CYP26B1, which is highly expressed in the prospective motor cortex. RARβ and CYP26B1 work together to produce proper patterning of the prefrontal and motor areas and prefrontal cortex-mediodorsal thalamus connections (Larsen et al. 2019, Shibata et al. 2021). In summary, the regulation of CYP26B1 and the ability of CYP26B1 to metabolize RA is probably critical for many aspects of development, especially in terms of establishing transient RA concentration gradients.
How is the transcription of Cyp26b1 regulated? Given the complex RA gradients that Cyp26b1 is involved in generating, the expectation is that the regulation of Cyp26b1 transcription is complex, and more data are needed in this area of research. For instance, during gonad development, the transcription factor Steroidogenic Factor 1 (SF1) and Sex-Determining Region Y-Box 9 (Sox9) positively regulate Cyp26b1 transcription, allowing for RA degradation and thus blocking germ cell differentiation in response to RA. Conversely, the Notch target Hairy/Enhancer-of-Split Related with YRPW Motif (Hey1), a repressor, binds to the Cyp26b1 promoter in Sertoli cells, blocking Cyp26b1 expression (Parekh et al. 2019). In most cell types the regulation of Cyp26b1 transcription is not well understood, but it is likely that it is complicated and cell type specific.
Biological activities of 4-OH-RA and 4-Oxo-RA and the maintenance of hematopoietic stem cells
An open question in this field is whether the other retinoid metabolites, for example, 4-OH-RA and 4-oxo-RA, are required for any cellular processes. These RA metabolites have biological activity (Pijnappel et al. 1993, Gaemers et al. 1996, Baron et al. 2005), but it is not clear that they play any essential roles in terms of the regulation of gene expression in mammals. In general, these more oxidized metabolites of RA are thought to be degradation products on the way to the elimination of RA from the body (Ghyselinck & Duester 2019). There is evidence that these oxidized metabolites of RA are not involved in mouse development (Niederreither et al. 2002), but, in this report, Cyp26b1 was intact, making it difficult to rigorously determine if 4-oxo-RA generated by Cyp26b1 has any developmental functions.
Recent studies on the effects of dietary vitamin A on dormancy in hematopoietic stem cells (HSCs) have identified some intriguing roles of RA and its oxidized metabolites. RA signaling can maintain quiescence in HSCs by reducing the rate of protein translation and lowering levels of reactive oxygen species, and this is associated with specific expression of RARβ (and not RARα and RARγ) in these dormant HSCs (Cabezas-Wallscheid et al. 2017). Moreover, these dormant HSCs can metabolize retinol to RA in a cell-autonomous fashion (Cabezas-Wallscheid et al. 2017). Recently, 4-oxo-RA, produced by Cyp26b1, was shown to be essential for HSC maintenance, and again, RARβ was also shown to be required for this HSC maintenance (Schönberger et al. 2022) (Fig. 3). 4-Oxo-RA was previously shown to be a potent agonist specifically for RARβ (Faria et al. 1999, Idres et al. 2002).
It is possible that in other cell types, Cyp26a1, rather than Cyp26b1, is required to generate 4-oxo-RA and that 4-oxo-RA is a key ligand required for transcriptional activation. Using a differentiation protocol that results in parietal endoderm, a type of epithelial cell, we showed that Cyp26a1 null embryonic stem cells displayed greatly increased intracellular RA levels and high levels of Hoxa1 mRNA, as might be expected, but surprisingly, also exhibited more resistance to RA-induced cell proliferation arrest and a large reduction in the parietal endoderm differentiation markers expressed later in the differentiation process, compared to WT embryonic stem cells (Langton & Gudas 2008). These data from embryonic stem cells suggest that RA metabolites, such as 4-oxo-RA, generated by Cyp26a1, are indeed required for the complete differentiation of embryonic stem cells into parietal endoderm cells (Fig. 3). Thus, oxidized metabolites of RA may be essential signaling molecules that can act as agonists for the RARs, indicating that the regulation of signaling in various cell types by vitamin A is more complex than previously thought. Much more interrogation is needed to determine how widespread this requirement for signaling by 4-oxo-RA is both during embryonic development and postnatally in mammals, as much of the data now in the literature indicate that Cyp26a1 and Cyp26b1 are primarily involved in reducing RA levels by inactivating the RA signal.
Vitamin A is metabolized to retinoic acid and then to 4-OH and 4-oxoRA. 4-Oxo-RA can act as an agonist with highest affinity for RAR β to mediate hematopoietic stem cell self-renewal and reduce cell differentiation and cell cycle transit (data from Schönberger et al. 2022).
Citation: Journal of Molecular Endocrinology 69, 4; 10.1530/JME-22-0082
Summary
The complexity of the metabolism of vitamin A to RA and 4-oxo-RA reflects the importance of these signaling molecules in diverse processes in numerous cell types and the observation that endogenous concentrations of RA that are either too high or too low can cause abnormalities during development. There is much more to learn in this fascinating area of research.
Declaration of interest
The author declares that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review.
Funding
L J G is supported by grants R01DK113088 and R21 AA027637, and by Weill Cornell funds.
Acknowledgements
L J G is supported by grants R01DK113088 and R21 AA027637, and by Weill Cornell funds. Thanks to Dr John Wagner and Dr Jianjun Xie for critically reading this manuscript and preparing this for publication.
References
Abu-Abed S, Dolle P, Metzger D, Beckett B, Chambon P & Petkovich M 2001 The retinoic acid-metabolizing enzyme, CYP26A1, is essential for normal hindbrain patterning, vertebral identity, and development of posterior structures. Genes and Development 15 226–240. (https://doi.org/10.1101/gad.855001)
Abu-Abed S, MacLean G, Fraulob V, Chambon P, Petkovich M & Dolle P 2002 Differential expression of the retinoic acid-metabolizing enzymes CYP26A1 and CYP26B1 during murine organogenesis. Mechanisms of Development 110 173–177. (https://doi.org/10.1016/s0925-4773(0100572-x)
Achkar CC, Derguini F, Blumberg B, Langston A, Levin AA, Speck J, Evans RM, Bolado J, Nakanishi K, Buck J, et al.1996 4-Oxoretinol, a new natural ligand and transactivator of the retinoic acid receptors. PNAS 93 4879–4884. (https://doi.org/10.1073/pnas.93.10.4879)
Adams MK, Belyaeva OV, Wu L & Kedishvili NY 2014 The retinaldehyde reductase activity of DHRS3 is reciprocally activated by retinol dehydrogenase 10 to control retinoid homeostasis. Journal of Biological Chemistry 289 14868–14880. (https://doi.org/10.1074/jbc.M114.552257)
Adams MK, Belyaeva OV, Wu L, Chaple IF, Dunigan-Russell K, Popov KM & Kedishvili NY 2021 Characterization of subunit interactions in the hetero-oligomeric retinoid oxidoreductase complex. Biochemical Journal 478 3597–3611. (https://doi.org/10.1042/BCJ20210589)
Ahuja N, Hiltabidle MS, Rajasekhar H, Voss S, Lu SZ, Barlow HR, Cowdin MA, Daniel E, Vaddaraju V, Anandakumar T, et al.2022 Endothelial Cyp26b1 restrains murine heart valve growth during development. Developmental Biology 486 81–95. (https://doi.org/10.1016/j.ydbio.2022.03.003)
Amat R & Gudas LJ 2011 RARgamma is required for correct deposition and removal of Suz12 and H2A.Z in embryonic stem cells. Journal of Cellular Physiology 226 293–298. (https://doi.org/10.1002/jcp.22420)
Arnold SL, Kent T, Hogarth CA, Schlatt S, Prasad B, Haenisch M, et al.2015 Importance of ALDH1A enzymes in determining human testicular retinoic acid concentrations. Journal of Lipid Research 56 342–357. (https://doi.org/10.1194/jlr.M054718)
Aström A, Pettersson U, Krust A, Chambon P & Voorhees JJ 1990 Retinoic acid and synthetic analogs differentially activate retinoic acid receptor dependent transcription. Biochemical and Biophysical Research Communications 173 339–345. (https://doi.org/10.1016/s0006-291x(0581062-9)
Ballow M, Wang X, Xiang S & Allen C 2003 Expression and regulation of nuclear retinoic acid receptors in human lymphoid cells. Journal of Clinical Immunology 23 46–54. (https://doi.org/10.1023/a:1021900331580)
Baron JM, Heise R, Blaner WS, Neis M, Joussen S, Dreuw A, Marquardt Y, Saurat JH, Merk HF, Bickers DR, et al.2005 Retinoic acid and its 4-oxo metabolites are functionally active in human skin cells in vitro. Journal of Investigative Dermatology 125 143–153. (https://doi.org/10.1111/j.0022-202X.2005.23791.x)
Barua AB & Olson JA 1986 Retinoyl beta-glucuronide: an endogenous compound of human blood. American Journal of Clinical Nutrition 43 481–485. (https://doi.org/10.1093/ajcn/43.4.481)
Batten ML, Imanishi Y, Maeda T, Tu DC, Moise AR, Bronson D, Possin D, Van Gelder RN, Baehr W & Palczewski K 2004 Lecithin-retinol acyltransferase is essential for accumulation of all-trans-retinyl esters in the eye and in the liver. Journal of Biological Chemistry 279 10422–10432. (https://doi.org/10.1074/jbc.M312410200)
Beecroft SJ, Ayala M, McGillivray G, Nanda V, Agolini E, Novelli A, Digilio MC, Dotta A, Carrozzo R, Clayton J, et al.2021 Biallelic hypomorphic variants in ALDH1A2 cause a novel lethal human multiple congenital anomaly syndrome encompassing diaphragmatic, pulmonary, and cardiovascular defects. Human Mutation 42 506–519. (https://doi.org/10.1002/humu.24179)
Belyaeva OV, Adams MK, Popov KM & Kedishvili NY 2019 Generation of retinaldehyde for retinoic acid biosynthesis. Biomolecules 10 5. (https://doi.org/10.3390/biom10010005)
Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL & Kuchroo VK 2006 Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature 441 235–238. (https://doi.org/10.1038/nature04753)
Billings SE, Pierzchalski K, Butler Tjaden NE, Pang XY, Trainor PA, Kane MA & Moise AR 2013 The retinaldehyde reductase DHRS3 is essential for preventing the formation of excess retinoic acid during embryonic development. FASEB Journal 27 4877–4889. (https://doi.org/10.1096/fj.13-227967)
Blaner WS, Li Y, Brun PJ, Yuen JJ, Lee SA & Clugston RD 2016 Vitamin A absorption, storage and mobilization. Sub-Cellular Biochemistry 81 95–125. (https://doi.org/10.1007/978-94-024-0945-1_4)
Blomhoff R, Holte K, Naess L & Berg T 1984 Newly administered [3H]retinol is transferred from hepatocytes to stellate cells in liver for storage. Experimental Cell Research 150 186–193. (https://doi.org/10.1016/0014-4827(8490713-4)
Bowles J, Feng CW, Ineson J, Miles K, Spiller CM, Harley VR, Sinclair AH & Koopman P 2018 Retinoic acid antagonizes testis development in mice. Cell Reports 24 1330–1341. (https://doi.org/10.1016/j.celrep.2018.06.111)
Bowles J, Knight D, Smith C, Wilhelm D, Richman J, Mamiya S, Yashiro K, Chawengsaksophak K, Wilson MJ, Rossant J, et al.2006 Retinoid signaling determines germ cell fate in mice. Science 312 596–600. (https://doi.org/10.1126/science.1125691)
Cabezas-Wallscheid N, Buettner F, Sommerkamp P, Klimmeck D, Ladel L, Thalheimer FB, Pastor-Flores D, Roma LP, Renders S, Zeisberger P, et al.2017 Vitamin A-retinoic acid signaling regulates hematopoietic stem cell dormancy. Cell 169 807.e19–823.e19. (https://doi.org/10.1016/j.cell.2017.04.018)
Cammas L, Romand R, Fraulob V, Mura C & Dolle P 2007 Expression of the murine retinol dehydrogenase 10 (Rdh10) gene correlates with many sites of retinoid signalling during embryogenesis and organ differentiation. Developmental Dynamics 236 2899–2908. (https://doi.org/10.1002/dvdy.21312)
Chai Z, Lyu Y, Chen Q, Wei CH, Snyder LM, Weaver V, Sebastian A, Albert I, Li Q, Cantorna MT, et al.2022 Transcriptional profiling of the small intestine and the colon reveals modulation of gut infection with citrobacter rodentium according to the vitamin A status. Nutrients 14 1563. (https://doi.org/10.3390/nu14081563)
Chen AC & Gudas LJ 1996 An analysis of retinoic acid-induced gene expression and metabolism in AB1 embryonic stem cells. Journal of Biological Chemistry 271 14971–14980. (https://doi.org/10.1074/jbc.271.25.14971)
Chen Y, Zhu JY, Hong KH, Mikles DC, Georg GI, Goldstein AS, Amory JK & Schönbrunn E 2018 Structural basis of ALDH1A2 inhibition by irreversible and reversible small molecule inhibitors. ACS Chemical Biology 13 582–590. (https://doi.org/10.1021/acschembio.7b00685)
Chiang MY, Misner D, Kempermann G, Schikorski T, Giguere V, Sucov HM, Gage FH, Stevens CF & Evans RM 1998 An essential role for retinoid receptors RARbeta and RXRgamma in long-term potentiation and depression. Neuron 21 1353–1361. (https://doi.org/10.1016/s0896-6273(0080654-6)
Ciancia M, Rataj-Baniowska M, Zinter N, Baldassarro VA, Fraulob V, Charles AL, Alvarez R, Muramatsu SI, de Lera AR, Geny B, et al.2022 Retinoic acid receptor beta protects striatopallidal medium spiny neurons from mitochondrial dysfunction and neurodegeneration. Progress in Neurobiology 212 102246. (https://doi.org/10.1016/j.pneurobio.2022.102246)
Clement SL, Scheckel C, Stoecklin G & Lykke-Andersen J 2011 Phosphorylation of tristetraprolin by MK2 impairs AU-rich element mRNA decay by preventing deadenylase recruitment. Molecular and Cellular Biology 31 256–266. (https://doi.org/10.1128/MCB.00717-10)
Coombes JL & Maloy KJ 2007 Control of intestinal homeostasis by regulatory T cells and dendritic cells. Seminars in Immunology 19 116–126. (https://doi.org/10.1016/j.smim.2007.01.001)
Coombes JL, Siddiqui KR, Arancibia-Carcamo CV, Hall J, Sun CM, Belkaid Y & Powrie F 2007 A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. Journal of Experimental Medicine 204 1757–1764. (https://doi.org/10.1084/jem.20070590)
Daniel E, Barlow HR, Sutton GI, Gu X, Htike Y, Cowdin MA & Cleaver O 2020 Cyp26b1 is an essential regulator of distal airway epithelial differentiation during lung development. Development 147 dev181560. (https://doi.org/10.1242/dev.181560)
D'Aniello E, Ravisankar P & Waxman JS 2015 Rdh10a provides a conserved critical step in the synthesis of retinoic acid during zebrafish embryogenesis. PLoS ONE 10 e0138588. (https://doi.org/10.1371/journal.pone.0138588)
de The H, Vivanco-Ruiz MM, Tiollais P, Stunnenberg H & Dejean A 1990 Identification of a retinoic acid responsive element in the retinoic acid receptor beta gene. Nature 343 177–180. (https://doi.org/10.1038/343177a0)
Defnet AE, Shah SD, Huang W, Shapiro P, Deshpande DA & Kane MA 2021 Dysregulated retinoic acid signaling in airway smooth muscle cells in asthma. FASEB Journal 35 e22016. (https://doi.org/10.1096/fj.202100835R)
Deng L, Shipley GL, Loose-Mitchell DS, Stancel GM, Broaddus R, Pickar JH & Davies PJ 2003 Coordinate regulation of the production and signaling of retinoic acid by estrogen in the human endometrium. Journal of Clinical Endocrinology and Metabolism 88 2157–2163. (https://doi.org/10.1210/jc.2002-021844)
Dewett D, Lam-Kamath K, Poupault C, Khurana H & Rister J 2021 Mechanisms of vitamin A metabolism and deficiency in the mammalian and fly visual system. Developmental Biology 476 68–78. (https://doi.org/10.1016/j.ydbio.2021.03.013)
Drummond DL, Cheng CS, Selland LG, Hocking JC, Prichard LB & Waskiewicz AJ 2013 The role of Zic transcription factors in regulating hindbrain retinoic acid signaling. BMC Developmental Biology 13 31. (https://doi.org/10.1186/1471-213X-13-31)
Dunham RM, Thapa M, Velazquez VM, Elrod EJ, Denning TL, Pulendran B & Grakoui A 2013 Hepatic stellate cells preferentially induce Foxp3+ regulatory T cells by production of retinoic acid. Journal of Immunology 190 2009–2016. (https://doi.org/10.4049/jimmunol.1201937)
Dupe V, Matt N, Garnier JM, Chambon P, Mark M & Ghyselinck NB 2003 A newborn lethal defect due to inactivation of retinaldehyde dehydrogenase type 3 is prevented by maternal retinoic acid treatment. PNAS 100 14036–14041. (https://doi.org/10.1073/pnas.2336223100)
Elizondo G, Medina-Díaz IM, Cruz R, Gonzalez FJ & Vega L 2009 Retinoic acid modulates retinaldehyde dehydrogenase 1 gene expression through the induction of GADD153-C/EBPbeta interaction. Biochemistry and Pharmacology 77 248–257. (https://doi.org/10.1016/j.bcp.2008.10.011)
Everts HB & Akuailou EN 2021 Retinoids in cutaneous squamous cell carcinoma. Nutrients 13 153. (https://doi.org/10.3390/nu13010153)
Faria TN, Mendelsohn C, Chambon P & Gudas LJ 1999 The targeted disruption of both alleles of RARbeta(2) in F9 cells results in the loss of retinoic acid-associated growth arrest. Journal of Biological Chemistry 274 26783–26788. (https://doi.org/10.1074/jbc.274.38.26783)
Farjo KM, Moiseyev G, Nikolaeva O, Sandell LL, Trainor PA & Ma JX 2011 RDH10 is the primary enzyme responsible for the first step of embryonic vitamin A metabolism and retinoic acid synthesis. Developmental Biology 357 347–355. (https://doi.org/10.1016/j.ydbio.2011.07.011)
Feng L, Hernandez RE, Waxman JS, Yelon D & Moens CB 2010a Dhrs3a regulates retinoic acid biosynthesis through a feedback inhibition mechanism. Developments in Biologicals 338 1–14. (https://doi.org/10.1016/j.ydbio.2009.10.029)
Feng T, Cong Y, Qin H, Benveniste EN & Elson CO 2010b Generation of mucosal dendritic cells from bone marrow reveals a critical role of retinoic acid. Journal of Immunology 185 5915–5925. (https://doi.org/10.4049/jimmunol.1001233)
Gaemers IC, van Pelt AM, van der Saag PT & de Rooij DG 1996 All-trans-4-oxo-retinoic acid: a potent inducer of in vivo proliferation of growth-arrested a spermatogonia in the vitamin A-deficient mouse testis. Endocrinology 137 479–485. (https://doi.org/10.1210/endo.137.2.8593792)
Gattu S, Bang YJ, Pendse M, Dende C, Chara AL, Harris TA, Wang Y, Ruhn KA, Kuang Z, Sockanathan S, et al.2019 Epithelial retinoic acid receptor β regulates serum amyloid A expression and vitamin A-dependent intestinal immunity. PNAS 116 10911–10916. (https://doi.org/10.1073/pnas.1812069116)
Ghyselinck NB & Duester G 2019 Retinoic acid signaling pathways. Development 146 dev167502. (https://doi.org/10.1242/dev.167502)
Gillespie RF & Gudas LJ 2007 Retinoic acid receptor isotype specificity in F9 teratocarcinoma stem cells results from the differential recruitment of coregulators to retinoic response elements. Journal of Biological Chemistry 282 33421–33434. (https://doi.org/10.1074/jbc.M704845200)
Grand K, Skraban CM, Cohen JL, Dowsett L, Mazzola S, Tarpinian J, Bedoukian E, Nesbitt A, Denenberg B, Lulis L, et al.2021 Nonlethal presentations of CYP26B1-related skeletal anomalies and multiple synostoses syndrome. American Journal of Medical Genetics: Part A 185 2766–2775. (https://doi.org/10.1002/ajmg.a.62387)
Gudas LJ & Wagner JA 2011 Retinoids regulate stem cell differentiation. Journal of Cellular Physiology 226 322–330. (https://doi.org/10.1002/jcp.22417)
Gudas LJ 2022 Synthetic retinoids Beyond cancer therapy. Annual Review of Pharmacology and Toxicology 62 155–175. (https://doi.org/10.1146/annurev-pharmtox-052120-104428)
Gyöngyösi A, Szatmari I, Pap A, Dezso B, Pos Z, Széles L, Varga T & Nagy L 2013 RDH10, RALDH2, and CRABP2 are required components of PPARγ-directed ATRA synthesis and signaling in human dendritic cells. Journal of Lipid Research 54 2458–2474. (https://doi.org/10.1194/jlr.M038984)
Haenisch M, Nguyen T, Fihn CA, Goldstein AS, Amory JK, Treuting P, Brabb T & Paik J 2021 Investigation of an ALDH1A1-specific inhibitor for suppression of weight gain in a diet-induced mouse model of obesity. International Journal of Obesity 45 1542–1552. (https://doi.org/10.1038/s41366-021-00818-1)
Hammerschmidt SI, Friedrichsen M, Boelter J, Lyszkiewicz M, Kremmer E, Pabst O & Förster R 2011 Retinoic acid induces homing of protective T and B cells to the gut after subcutaneous immunization in mice. Journal of Clinical Investigation 121 3051–3061. (https://doi.org/10.1172/JCI44262)
Harrison EH 2005 Mechanisms of digestion and absorption of dietary vitamin A. Annual Review of Nutrition 25 87–103. (https://doi.org/10.1146/annurev.nutr.25.050304.092614)
Helvig C, Taimi M, Cameron D, Jones G & Petkovich M 2011 Functional properties and substrate characterization of human CYP26A1, CYP26B1, and CYP26C1 expressed by recombinant baculovirus in insect cells. Journal of Pharmacological and Toxicological Methods 64 258–263. (https://doi.org/10.1016/j.vascn.2011.08.005)
Hsu YT, Li J, Wu D, Südhof TC & Chen L 2019 Synaptic retinoic acid receptor signaling mediates mTOR-dependent metaplasticity that controls hippocampal learning. PNAS 116 7113–7122. (https://doi.org/10.1073/pnas.1820690116)
Huang D, Chen SW, Langston AW & Gudas LJ 1998 A conserved retinoic acid responsive element in the murine Hoxb-1 gene is required for expression in the developing gut. Development 125 3235–3246 (https://doi.org/10.1242/dev.125.16.3235))
Idres N, Marill J, Flexor MA & Chabot GG 2002 Activation of retinoic acid receptor-dependent transcription by all-trans-retinoic acid metabolites and isomers. Journal of Biological Chemistry 277 31491–31498. (https://doi.org/10.1074/jbc.M205016200)
Iliev ID, Mileti E, Matteoli G, Chieppa M & Rescigno M 2009 Intestinal epithelial cells promote colitis-protective regulatory T-cell differentiation through dendritic cell conditioning. Mucosal Immunology 2 340–350. (https://doi.org/10.1038/mi.2009.13)
Isoherranen N & Zhong G 2019 Biochemical and physiological importance of the CYP26 retinoic acid hydroxylases. Pharmacology and Therapeutics 204 107400. (https://doi.org/10.1016/j.pharmthera.2019.107400)
Iwata M, Hirakiyama A, Eshima Y, Kagechika H, Kato C & Song SY 2004 Retinoic acid imprints gut-homing specificity on T cells. Immunity 21 527–538. (doi: 10.1016/j.immuni.2004.08.011)
Jaensson E, Uronen-Hansson H, Pabst O, Eksteen B, Tian J, Coombes JL, Berg PL, Davidsson T, Powrie F, Johansson-Lindbom B, et al.2008 Small intestinal CD103+ dendritic cells display unique functional properties that are conserved between mice and humans. Journal of Experimental Medicine 205 2139–2149. (https://doi.org/10.1084/jem.20080414)
Johansson-Lindbom B, Svensson M, Pabst O, Palmqvist C, Marquez G, Förster R & Agace WW 2005 Functional specialization of gut CD103+ dendritic cells in the regulation of tissue-selective T cell homing. Journal of Experimental Medicine 202 1063–1073. (https://doi.org/10.1084/jem.20051100)
Kavanagh KL, Jörnvall H, Persson B & Oppermann U 2008 Medium- and short-chain dehydrogenase/reductase gene and protein families : the SDR superfamily: functional and structural diversity within a family of metabolic and regulatory enzymes. Cellular and Molecular Life Sciences 65 3895–3906. (https://doi.org/10.1007/s00018-008-8588-y)
Kikuchi K, Holdway JE, Major RJ, Blum N, Dahn RD, Begemann G & Poss KD 2011 Retinoic acid production by endocardium and epicardium is an injury response essential for zebrafish heart regeneration. Developmental Cell 20 397–404. (https://doi.org/10.1016/j.devcel.2011.01.010)
La C, de Toeuf B, Bindels LB, Van Maele L, Assabban A, Melchior M, Smout J, Köhler A, Nguyen M, Thomas S, et al.2021 The RNA-binding protein tristetraprolin regulates RALDH2 expression by intestinal dendritic cells and controls local Treg homeostasis. Mucosal Immunology 14 80–91. (https://doi.org/10.1038/s41385-020-0302-x)
Langston AW & Gudas LJ 1992 Identification of a retinoic acid responsive enhancer 3' of the murine homeobox gene Hox-1.6. Mechanisms of Development 38 217–227. (https://doi.org/10.1016/0925-4773(9290055-o)
Langston AW, Thompson JR & Gudas LJ 1997 Retinoic acid-responsive enhancers located 3' of the Hox A and Hox B homeobox gene clusters. Functional analysis. Journal of Biological Chemistry 272 2167–2175. (https://doi.org/10.1074/jbc.272.4.2167)
Langton S & Gudas LJ 2008 CYP26A1 knockout embryonic stem cells exhibit reduced differentiation and growth arrest in response to retinoic acid. Developmental Biology 315 331–354. (https://doi.org/10.1016/j.ydbio.2007.12.021)
LaRosa GJ & Gudas LJ 1988 Early retinoic acid-induced F9 teratocarcinoma stem cell gene ERA-1: alternate splicing creates transcripts for a homeobox-containing protein and one lacking the homeobox. Molecular and Cellular Biology 8 3906–3917. (https://doi.org/10.1128/mcb.8.9.3906-3917.1988)
Larsen R, Proue A, Scott EP, Christiansen M & Nakagawa Y 2019 The Thalamus regulates retinoic acid signaling and development of parvalbumin interneurons in postnatal mouse prefrontal cortex. eNeuro 6 ENEURO.0018-19.2019. (https://doi.org/10.1523/ENEURO.0018-19.2019)
Lee LM, Leung CY, Tang WW, Choi HL, Leung YC, McCaffery PJ, Wang CC, Woolf AS & Shum AS 2012 A paradoxical teratogenic mechanism for retinoic acid. PNAS 109 13668–13673. (https://doi.org/10.1073/pnas.1200872109)
Lee JH, Protze SI, Laksman Z, Backx PH & Keller GM 2017a Human pluripotent stem cell-derived atrial and ventricular cardiomyocytes develop from distinct mesoderm populations. Cell Stem Cell 21 179.e4–194.e4. (https://doi.org/10.1016/j.stem.2017.07.003)
Lee LM, Leung MB, Kwok RC, Leung YC, Wang CC, McCaffery PJ, Copp AJ & Shum AS 2017b Perturbation of retinoid homeostasis increases malformation risk in embryos exposed to pregestational diabetes. Diabetes 66 1041–1051. (https://doi.org/10.2337/db15-1570)
Lenti E, Farinello D, Yokoyama KK, Penkov D, Castagnaro L, Lavorgna G, Wuputra K, Sandell LL, Tjaden NE, Bernassola F, et al.2016 Transcription factor TLX1 controls retinoic acid signaling to ensure spleen development. Journal of Clinical Investigation 126 2452–2464. (https://doi.org/10.1172/JCI82956)
Loudig O, Babichuk C, White J, Abu-Abed S, Mueller C & Petkovich M 2000 Cytochrome P450RAI(CYP26) promoter: a distinct composite retinoic acid response element underlies the complex regulation of retinoic acid metabolism. Molecular Endocrinology 14 1483–1497. (https://doi.org/10.1210/mend.14.9.0518)
Loudig O, Maclean GA, Dore NL, Luu L & Petkovich M 2005 Transcriptional co-operativity between distant retinoic acid response elements in regulation of Cyp26A1 inducibility. Biochemical Journal 392 241–248. (https://doi.org/10.1042/BJ20050874)
Lutz JD, Dixit V, Yeung CK, Dickmann LJ, Zelter A, Thatcher JE, et al.2009 Expression and functional characterization of cytochrome P450 26A1, a retinoic acid hydroxylase. Biochemistry and Pharmacology 77 258–268. (https://doi.org/10.1016/j.bcp.2008.10.012)
Marshall H, Studer M, Popperl H, Aparicio S, Kuroiwa A, Brenner S & Krumlauf R 1994 A conserved retinoic acid response element required for early expression of the homeobox gene Hoxb-1. Nature 370 567–571. (https://doi.org/10.1038/370567a0)
Mathew LK, SenGupta S, Franzosa JA, Perry J, La Du J, Andreasen EA & Tanguay RL 2009 Comparative expression profiling reveals an essential role for raldh2 in epimorphic regeneration. Journal of Biological Chemistry 284 33642–33653. (https://doi.org/10.1074/jbc.M109.011668)
McDonald KG, Leach MR, Brooke KWM, Wang C, Wheeler LW, Hanly EK, Rowley CW, Levin MS, Wagner M, Li E, et al.2012 Epithelial expression of the cytosolic retinoid chaperone cellular retinol binding protein II is essential for in vivo imprinting of local gut dendritic cells by lumenal retinoids. American Journal of Pathology 180 984–997. (https://doi.org/10.1016/j.ajpath.2011.11.009)
Mic FA, Molotkov A, Fan X, Cuenca AE & Duester G 2000 RALDH3, a retinaldehyde dehydrogenase that generates retinoic acid, is expressed in the ventral retina, otic vesicle and olfactory pit during mouse development. Mechanisms of Development 97 227–230. (https://doi.org/10.1016/s0925-4773(0000434-2)
Molenaar R, Knippenberg M, Goverse G, Olivier BJ, de Vos AF, O'Toole T & Mebius RE 2011 Expression of retinaldehyde dehydrogenase enzymes in mucosal dendritic cells and gut-draining lymph node stromal cells is controlled by dietary vitamin A. Journal of Immunology 186 1934–1942. (https://doi.org/10.4049/jimmunol.1001672)
Molle C, Zhang T, Ysebrant de Lendonck L, Gueydan C, Andrianne M, Sherer F, Van Simaeys G, Blackshear PJ, Leo O & Goriely S 2013 Tristetraprolin regulation of interleukin 23 mRNA stability prevents a spontaneous inflammatory disease. Journal of Experimental Medicine 210 1675–1684. (https://doi.org/10.1084/jem.20120707)
Morton JE, Frentz S, Morgan T, Sutherland-Smith AJ & Robertson SP 2016 Biallelic mutations in CYP26B1: a differential diagnosis for Pfeiffer and Antley-Bixler syndromes. American Journal of Medical Genetics: Part A 170 2706–2710. (https://doi.org/10.1002/ajmg.a.37804)
Nagy L & Schwabe JW 2004 Mechanism of the nuclear receptor molecular switch. Trends in Biochemical Sciences 29 317–324. (https://doi.org/10.1016/j.tibs.2004.04.006)
Nakamura J, Sato Y, Kitai Y, Wajima S, Yamamoto S, Oguchi A, Yamada R, Kaneko K, Kondo M, Uchino E, et al.2019 Myofibroblasts acquire retinoic acid-producing ability during fibroblast-to-myofibroblast transition following kidney injury. Kidney International 95 526–539. (https://doi.org/10.1016/j.kint.2018.10.017)
Napoli JL & Yoo HS 2020 Retinoid metabolism and functions mediated by retinoid binding-proteins. Methods in Enzymology 637 55–75. (https://doi.org/10.1016/bs.mie.2020.02.004)
Niederreither K, Subbarayan V, Dollé P & Chambon P 1999 Embryonic retinoic acid synthesis is essential for early mouse post-implantation development. Nature Genetics 21 444–448. (https://doi.org/10.1038/7788)
Niederreither K, Abu-Abed S, Schuhbaur B, Petkovich M, Chambon P & Dolle P 2002 Genetic evidence that oxidative derivatives of retinoic acid are not involved in retinoid signaling during mouse development. Nature Genetics 31 84–88. (https://doi.org/10.1038/ng876)
Obrochta KM, Krois CR, Campos B & Napoli JL 2015 Insulin regulates retinol dehydrogenase expression and all-trans-retinoic acid biosynthesis through FoxO1. Journal of Biological Chemistry 290 7259–7268. (https://doi.org/10.1074/jbc.M114.609313)
O'Connor C, Varshosaz P & Moise AR 2022 Mechanisms of feedback regulation of vitamin A metabolism. Nutrients 14 1312. (https://doi.org/10.3390/nu14061312)
Ohoka Y, Yokota-Nakatsuma A, Maeda N, Takeuchi H & Iwata M 2014 Retinoic acid and GM-CSF coordinately induce retinal dehydrogenase 2 (RALDH2) expression through cooperation between the RAR/RXR complex and Sp1 in dendritic cells. PLoS ONE 9 e96512. (https://doi.org/10.1371/journal.pone.0096512)
Ono K, Sandell LL, Trainor PA & Wu DK 2020 Retinoic acid synthesis and autoregulation mediate zonal patterning of vestibular organs and inner ear morphogenesis. Development 147 dev192070. (https://doi.org/10.1242/dev.192070)
Parekh PA, Garcia TX, Waheeb R, Jain V, Gandhi P, Meistrich ML, Shetty G & Hofmann MC 2019 Undifferentiated spermatogonia regulate Cyp26b1 expression through NOTCH signaling and drive germ cell differentiation. FASEB Journal 33 8423–8435. (https://doi.org/10.1096/fj.201802361R)
Penkert RR, Rowe HM, Surman SL, Sealy RE, Rosch J & Hurwitz JL 2019 Influences of vitamin A on vaccine immunogenicity and efficacy. Frontiers in Immunology 10 1576. (https://doi.org/10.3389/fimmu.2019.01576)
Penkert RR, Cortez V, Karlsson EA, Livingston B, Surman SL, Li Y, Catharine Ross A, Schultz-Cherry S & Hurwitz JL 2020 Vitamin A corrects tissue deficits in diet-induced obese mice and reduces influenza infection After vaccination and challenge. Obesity 28 1631–1636. (https://doi.org/10.1002/oby.22929)
Pequerul R, Vera J, Giménez-Dejoz J, Crespo I, Coines J, Porté S, Rovira C, Parés X & Farrés J 2020 Structural and kinetic features of aldehyde dehydrogenase 1A (ALDH1A) subfamily members, cancer stem cell markers active in retinoic acid biosynthesis. Archives of Biochemistry and Biophysics 681 108256. (https://doi.org/10.1016/j.abb.2020.108256)
Persaud SD, Lin YW, Wu CY, Kagechika H & Wei LN 2013 Cellular retinoic acid binding protein I mediates rapid non-canonical activation of ERK1/2 by all-trans retinoic acid. Cellular Signalling 25 19–25. (https://doi.org/10.1016/j.cellsig.2012.09.002)
Pijnappel WW, Hendriks HF, Folkers GE, van den Brink CE, Dekker EJ, Edelenbosch C, van der Saag PT & Durston AJ 1993 The retinoid ligand 4-oxo-retinoic acid is a highly active modulator of positional specification. Nature 366 340–344. (https://doi.org/10.1038/366340a0)
Puttini S, Plaisance I, Barile L, Cervio E, Milano G, Marcato P, Pedrazzini T & Vassalli G 2018 ALDH1A3 is the key isoform that contributes to aldehyde dehydrogenase activity and affects in Vitro Proliferation in Cardiac Atrial Appendage Progenitor Cells. Frontiers in Cardiovascular Medicine 5 90. (https://doi.org/10.3389/fcvm.2018.00090)
Qian X, Ning H, Zhang J, Hoft DF, Stumpo DJ, Blackshear PJ & Liu J 2011 Posttranscriptional regulation of IL-23 expression by IFN-gamma through tristetraprolin. Journal of Immunology 186 6454–6464. (https://doi.org/10.4049/jimmunol.1002672)
Rankin SA, Steimle JD, Yang XH, Rydeen AB, Agarwal K, Chaturvedi P, Ikegami K, Herriges MJ, Moskowitz IP & Zorn AM 2021 Tbx5 drives Aldh1a2 expression to regulate a RA-Hedgehog-Wnt gene regulatory network coordinating cardiopulmonary development. eLife 10 e69288. (https://doi.org/10.7554/eLife.69288)
Rhinn M, Schuhbaur B, Niederreither K & Dollé P 2011 Involvement of retinol dehydrogenase 10 in embryonic patterning and rescue of its loss of function by maternal retinaldehyde treatment. PNAS 108 16687–16692. (https://doi.org/10.1073/pnas.1103877108)
Ricard MJ & Gudas LJ 2013 Cytochrome P450 cyp26a1 alters spinal motor neuron subtype identity in differentiating embryonic stem cells. Journal of Biological Chemistry 288 28801–28813. (https://doi.org/10.1074/jbc.M113.474254)
Rivera CA, Randrian V, Richer W, Gerber-Ferder Y, Delgado MG, Chikina AS, et al.2022 Epithelial colonization by gut dendritic cells promotes their functional diversification. Immunity 55 129 .e8–1 44.e8. (https://doi.org/10.1016/j.immuni.2021.11.008)
Roberts AB, Lamb LC & Sporn MB 1980 Metabolism of all-trans-retinoic acid in hamster liver microsomes: oxidation of 4-hydroxy- to 4-keto-retinoic acid. Archives of Biochemistry and Biophysics 199 374–383. (https://doi.org/10.1016/0003-9861(8090293-3)
Roe MM, Swain S, Sebrell TA, Sewell MA, Collins MM, Perrino BA, Smith PD, Smythies LE & Bimczok D 2017 Differential regulation of CD103 (αE integrin) expression in human dendritic cells by retinoic acid and toll-like receptor ligands. Journal of Leukocyte Biology 101 1169–1180. (https://doi.org/10.1189/jlb.1MA0316-131R)
Ross AC & Moran NE 2020 Our current dietary reference intakes for vitamin A-now 20 years old. Current Developments in Nutrition 4 nzaa096. (https://doi.org/10.1093/cdn/nzaa096)
Rubinow KB, Zhong G, Czuba LC, Chen JY, Williams E, Parr Z, Khandelwal S, Kim D, LaFrance J & Isoherranen N 2022. Evidence of depot-specific regulation of all-trans-retinoic acid biosynthesis in human adipose tissue. Clinical and Translational Science 15 1460–1471. (https://doi.org/10.1111/cts.13259)
Rutledge JC, Shourbaji AG, Hughes LA, Polifka JE, Cruz YP, Bishop JB & Generoso WM 1994 Limb and lower-body duplications induced by retinoic acid in mice. PNAS 91 5436–5440. (https://doi.org/10.1073/pnas.91.12.5436)
Saeed A, Yang J, Heegsma J, Groen AK, van Mil SWC, Paulusma CC, et al.2019 Farnesoid X receptor and bile acids regulate vitamin A storage. Scientific Reports 9 19493. (https://doi.org/10.1038/s41598-019-55988-w)
Sandell LL, Sanderson BW, Moiseyev G, Johnson T, Mushegian A, Young K, Rey JP, Ma JX, Staehling-Hampton K & Trainor PA 2007 RDH10 is essential for synthesis of embryonic retinoic acid and is required for limb, craniofacial, and organ development. Genes and Development 21 1113–1124. (https://doi.org/10.1101/gad.1533407)
Sandell LL, Lynn ML, Inman KE, McDowell W & Trainor PA 2012 RDH10 oxidation of vitamin A is a critical control step in synthesis of retinoic acid during mouse embryogenesis. PLoS ONE 7 e30698. (https://doi.org/10.1371/journal.pone.0030698)
Sarti F, Zhang Z, Schroeder J & Chen L 2013 Rapid suppression of inhibitory synaptic transmission by retinoic acid. Journal of Neuroscience 33 11440–11450. (https://doi.org/10.1523/JNEUROSCI.1710-13.2013)
Sato T, Kitawaki T, Fujita H, Iwata M, Iyoda T, Inaba K, Ohteki T, Hasegawa S, Kawada K, Sakai Y, et al.2013 Human CD1c⁺ myeloid dendritic cells acquire a high level of retinoic acid-producing capacity in response to vitamin D₃. Journal of Immunology 191 3152–3160. (https://doi.org/10.4049/jimmunol.1203517)
Schilling TF, Nie Q & Lander AD 2012 Dynamics and precision in retinoic acid morphogen gradients. Current Opinion in Genetics and Development 22 562–569. (https://doi.org/10.1016/j.gde.2012.11.012)
Schönberger K, Obier N, Romero-Mulero MC, Cauchy P, Mess J, Pavlovich PV, et al.2022 Multilayer omics analysis reveals a non-classical retinoic acid signaling axis that regulates hematopoietic stem cell identity. Cell Stem Cell 29 131 .e10–1 48.e10. (https://doi.org/10.1016/j.stem.2021.10.002)
Schulz O, Jaensson E, Persson EK, Liu X, Worbs T, Agace WW, et al.2009 Intestinal CD103+, but not CX3CR1+, antigen sampling cells migrate in lymph and serve classical dendritic cell functions. Journal of Experimental Medicine 206 3101–31 14. (https://doi.org/10.1084/jem.20091925)
Serio RN, Laursen KB, Urvalek AM, Gross SS & Gudas LJ 2019 Ethanol promotes differentiation of embryonic stem cells through retinoic acid receptor-gamma. Journal of Biological Chemistry 294 5536–5548. (https://doi.org/10.1074/jbc.RA118.007153)
Sherwin JC, Reacher MH, Dean WH & Ngondi J 2012 Epidemiology of vitamin A deficiency and xerophthalmia in at-risk populations. Transactions of the Royal Society of Tropical Medicine and Hygiene 106 205–214. (https://doi.org/10.1016/j.trstmh.2012.01.004)
Shibata M, Pattabiraman K, Lorente-Galdos B, Andrijevic D, Kim SK, Kaur N, Muchnik SK, Xing X, Santpere G, Sousa AMM, et al.2021 Regulation of prefrontal patterning and connectivity by retinoic acid. Nature 598 483–488. (https://doi.org/10.1038/s41586-021-03953-x)
Snyder JM, Zhong G, Hogarth C, Huang W, Topping T, LaFrance J, Palau L, Czuba LC, Griswold M, Ghiaur G, et al.2020 Knockout of Cyp26a1 and Cyp26b1 during postnatal life causes reduced lifespan, dermatitis, splenomegaly, and systemic inflammation in mice. FASEB Journal 34 15788–15804. (https://doi.org/10.1096/fj.202001734R)
Sommer A 2008 Vitamin A deficiency and clinical disease: an historical overview. Journal of Nutrition 138 1835–1839. (https://doi.org/10.1093/jn/138.10.1835)
Stagg AJ 2018 Intestinal dendritic cells in health and gut inflammation. Frontiers in Immunology 9 2883. (https://doi.org/10.3389/fimmu.2018.02883)
Stevens GA, Bennett JE, Hennocq Q, Lu Y, De-Regil LM, Rogers L, Danaei G, Li G, White RA, Flaxman SR, et al.2015 Trends and mortality effects of vitamin A deficiency in children in 138 low-income and middle-income countries between 1991 and 2013: a pooled analysis of population-based surveys. Lancet. Global Health 3 e528–e536. (https://doi.org/10.1016/S2214-109X(1500039-X)
Sun CM, Hall JA, Blank RB, Bouladoux N, Oukka M, Mora JR & Belkaid Y 2007 Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. Journal of Experimental Medicine 204 1775–1785. (https://doi.org/10.1084/jem.20070602)
Surman SL, Penkert RR, Sealy RE, Jones BG, Marion TN, Vogel P & Hurwitz JL 2020 Consequences of vitamin A deficiency: immunoglobulin dysregulation, squamous cell Metaplasia, infectious disease, and death. International Journal of Molecular Sciences 21 5570. (https://doi.org/10.3390/ijms21155570)
Taimi M, Helvig C, Wisniewski J, Ramshaw H, White J, Amad M, Korczak B & Petkovich M 2004 A novel human cytochrome P450, CYP26C1, involved in metabolism of 9-cis and all-trans isomers of retinoic acid. Journal of Biological Chemistry 279 77–85. (https://doi.org/10.1074/jbc.M308337200)
Takano T, Kotaki R, Park J, Yoshida T, Wakatsuki Y, Tanokura M, Miyakawa T, Takahashi K, Nakajima-Adachi H & Hachimura S 2020 Age-dependent decrease in the induction of regulatory T cells is associated with decreased expression of RALDH2 in mesenteric lymph node dendritic cells. Frontiers in Immunology 11 1555. (https://doi.org/10.3389/fimmu.2020.01555)
Thatcher JE, Zelter A & Isoherranen N 2010 The relative importance of CYP26A1 in hepatic clearance of all-trans retinoic acid. Biochemical Pharmacology 80 903–912. (https://doi.org/10.1016/j.bcp.2010.05.023)
Topletz AR, Tripathy S, Foti RS, Shimshoni JA, Nelson WL & Isoherranen N 2015 Induction of CYP26A1 by metabolites of retinoic acid: evidence that CYP26A1 is an important enzyme in the elimination of active retinoids. Molecular Pharmacology 87 430–441. (https://doi.org/10.1124/mol.114.096784)
Touma SE, Perner S, Rubin MA, Nanus DM & Gudas LJ 2009 Retinoid metabolism and ALDH1A2 (RALDH2) expression are altered in the transgenic adenocarcinoma mouse prostate model. Biochemical Pharmacology 78 1127–1138. (https://doi.org/10.1016/j.bcp.2009.06.022)
Trasino SE, Benoit YD & Gudas LJ 2015a Vitamin A deficiency causes hyperglycemia and loss of pancreatic beta-cell mass. Journal of Biological Chemistry 290 1456–1473. (https://doi.org/10.1074/jbc.M114.616763)
Trasino SE, Tang XH, Jessurun J & Gudas LJ 2015b Obesity leads to tissue, but not serum vitamin A deficiency. Scientific Reports 5 15893. (https://doi.org/10.1038/srep15893)
Uchibe K, Son J, Larmour C, Pacifici M, Enomoto-Iwamoto M & Iwamoto M 2017 Genetic and pharmacological inhibition of retinoic acid receptor γ function promotes endochondral bone formation. Journal of Orthopaedic Research 35 1096–1105. (https://doi.org/10.1002/jor.23347)
Urvalek AM & Gudas LJ 2014 Retinoic acid and histone deacetylases regulate epigenetic changes in embryonic stem cells. Journal of Biological Chemistry 289 19519–19530. (https://doi.org/10.1074/jbc.M114.556555)
van der Mijn JC, Chen Q, Laursen KB, Khani F, Wang X, Dorsaint P, Sboner A, Gross SS, Nanus DM & Gudas LJ 2022 Transcriptional and metabolic remodeling in clear cell renal cell carcinoma caused by ATF4 activation and the integrated stress response (ISR). Molecular Carcinogenesis [epub]. (https://doi.org/10.1002/mc.23437)
Veit JGS, De Glas V, Balau B, Liu H, Bourlond F, Paller AS, et al.2021 Characterization of CYP26B1-selective inhibitor, DX314, as a potential therapeutic for keratinization disorders. Journal of Investigative Dermatology 141 72 .e6–83.e6. (https://doi.org/10.1016/j.jid.2020.05.090)
Villablanca EJ, Wang S, de Calisto J, Gomes DC, Kane MA, Napoli JL, et al.2011 MyD88 and retinoic acid signaling pathways interact to modulate gastrointestinal activities of dendritic cells. Gastroenterology 141 176–18 5. (https://doi.org/10.1053/j.gastro.2011.04.010)
Wang S, Huang W, Castillo HA, Kane MA, Xavier-Neto J, Trainor PA & Moise AR 2018 Alterations in retinoic acid signaling affect the development of the mouse coronary vasculature. Developmental Dynamics 247 976–991. (https://doi.org/10.1002/dvdy.24639)
Wang S, Yu J, Kane MA & Moise AR 2020 Modulation of retinoid signaling: therapeutic opportunities in organ fibrosis and repair. Pharmacology and Therapeutics 205 107415. (https://doi.org/10.1016/j.pharmthera.2019.107415)
White JA, Beckett-Jones B, Guo YD, Dilworth FJ, Bonasoro J, Jones G & Petkovich M 1997 cDNA cloning of human retinoic acid-metabolizing enzyme (hP450RAI) identifies a novel family of cytochromes P450. Journal of Biological Chemistry 272 18538–18541 (https://doi.org/10.1074/jbc.272.30.18538))
White RJ, Nie Q, Lander AD & Schilling TF 2007 Complex regulation of cyp26a1 creates a robust retinoic acid gradient in the zebrafish embryo. PLoS Biology 5 e304. (https://doi.org/10.1371/journal.pbio.0050304)
White RJ & Schilling TF 2008 How degrading: Cyp26s in hindbrain development. Developmental Dynamics 237 2775–2790. (https://doi.org/10.1002/dvdy.21695)
Wongsiriroj N, Jiang H, Piantedosi R, Yang KJ, Kluwe J, Schwabe RF, et al.2014 Genetic dissection of retinoid esterification and accumulation in the liver and adipose tissue. Journal of Lipid Research 55 104–114. (https://doi.org/10.1194/jlr.M043844)
Xiao S, Jin H, Korn T, Liu SM, Oukka M, Lim B & Kuchroo VK 2008 Retinoic acid increases Foxp3+ regulatory T cells and inhibits development of Th17 cells by enhancing TGF-beta-driven Smad3 signaling and inhibiting IL-6 and IL-23 receptor expression. Journal of Immunology 181 2277–2284. (https://doi.org/10.4049/jimmunol.181.4.2277)
Yang D, Vuckovic MG, Smullin CP, Kim M, Lo CP, Devericks E, Yoo HS, Tintcheva M, Deng Y & Napoli JL 2018 Modest decreases in endogenous all-trans-retinoic acid produced by a mouse Rdh10 heterozygote provoke Major abnormalities in adipogenesis and lipid metabolism. Diabetes 67 662–673. (https://doi.org/10.2337/db17-0946)
Yashiro T, Yamaguchi M, Watanuki Y, Kasakura K & Nishiyama C 2018 The transcription factors PU.1 and IRF4 determine dendritic cell-specific expression of RALDH2. Journal of Immunology 201 3677–3682. (https://doi.org/10.4049/jimmunol.1800492)
Yokota A, Takeuchi H, Maeda N, Ohoka Y, Kato C, Song SY & Iwata M 2009 GM-CSF and IL-4 synergistically trigger dendritic cells to acquire retinoic acid-producing capacity. International Immunology 21 361–377. (https://doi.org/10.1093/intimm/dxp003)
Zaman TS, Arimochi H, Maruyama S, Ishifune C, Tsukumo SI, Kitamura A & Yasutomo K 2017 Notch balances Th17 and induced regulatory T cell functions in dendritic cells by regulating Aldh1a2 Expression. Journal of Immunology 199 1989–1997. (https://doi.org/10.4049/jimmunol.1700645)
Zhao Y, Vuckovic M, Yoo HS, Fox N, Rodriguez A, McKessy K & Napoli JL 2021 Retinoic acid exerts sexually dimorphic effects on muscle energy metabolism and function. Journal of Biological Chemistry 297 101101. (https://doi.org/10.1016/j.jbc.2021.101101)
Zhong G, Ortiz D, Zelter A, Nath A & Isoherranen N 2018 CYP26C1 is a hydroxylase of multiple active retinoids and interacts with cellular retinoic acid binding proteins. Molecular Pharmacology 93 489–503. (https://doi.org/10.1124/mol.117.111039)
Zhu B, Buttrick T, Bassil R, Zhu C, Olah M, Wu C, Xiao S, Orent W, Elyaman W & Khoury SJ 2013 IL-4 and retinoic acid synergistically induce regulatory dendritic cells expressing Aldh1a2. Journal of Immunology 191 3139–3151. (https://doi.org/10.4049/jimmunol.1300329)
