id: PW:0001004 rgd_url: https://rgd.mcw.edu/rgdweb/pathway/pathwayRecord.html?processType=view&species=Rat&acc_id=PW:0001004 title: retinoic acid metabolic pathway description_xrefs: - GO:0042573 description: Animal species cannot synthesize retinol or vitamin A. They derive it from precursor carotenoids such as beta-carotene via retinal and they can store it as retinyl esters (REs) which they can hydrolyze (liver is the largest REs storage). Thus, both plant and animal dietary sources can provide vitamin A. Vitamin A metabolites such as retinal and retinoic acid play essential roles in vision and a range of cellular processes. More recently, a role for retinol in mitochondrial signaling where it mayserve as a co-factor in redox sensing and energy homeostasis, has been postulated. The lipid retinol is subject to oxidation and as such is associated with carrier proteins such as Rbp4 in the circulation and Rbp1 inside cells. Rbp4 associates with transthyretin (Ttr) that also transports thyroxine (T4) and can act as a protease with important functions in the nervous system. The Ttr-Rbp4 association is stabilized by retinol but not by other retinoids. The ternary complex consists of a dimer of dimers Ttr tetramer with two Rbp4 molecules bound on either side of the dimers; in the complex, retinol also establishes contacts with Ttr ( PDB entry for the ternary complex ). Stra6 acts as a receptor for Rbp4 and as a transporter for retinol. Interestingly, Stra6 may also act as a signal transducer by inducing the Jak-Stat pathway. Inside the cell, retinol may be esterified to REs by the lecithin retinol acyltransferase Lrat in most tissues. REs are converted back to retinol by the action of retinyl ester hydrolase CES1. The human CES1 has a mouse but not a rat ortholog; several rat and mouse genes are potential REs hydrolases as well as a number of lipases (human CES1 gene shown). The ratio of apo- to holo-Rbp1 maintains a balanced flux of retinol to and from its REs storage. Apo-Rbp1 stimulates hydrolysis of REs while inhibiting retinol esterification. Alternatively, retinol may be reversibly converted to retinal by members of the short chain dehydrogenase/reductase family (SDR). In the retinal pigment epithelium, retinol is metabolized to cis-retinal to serve as the chromophore of the visual pigment. In other cells, retinal is the substrate for retinal dehydrogenases that irreversible convert it to all-trans retinoic acid (atRA) and other derivatives with atRA being the most potent molecule. atRA interacts with several proteins of the FABP family that exert distinct roles. Crabp2 and Fabp5 deliver atRA to particular nuclear receptors such as retinoid acid receptors (RARs) and a subset of peroxisome proliferator-activated receptors (PPAR), respectively. RARs form heterodimers with retinoid X receptors (RXR)s which partner with a number of other nuclear receptors, do not interact with atRA but favor 9-cisRA. Crabp1 on the other hand, relates to the processing and catabolism of retinoic acid. While the exact role of Crabp1 is still to be documented, its overexpression increases the rate of atRA catabolism. Several members of the cytochrome P450 are involved in the process. atRA signaling is important for development, cell proliferation, differentiation and death, immune and nervous systems function. Alterations in these signaling pathways has been associated with several conditions including cancer. diagram_image: https://rgd.mcw.edu/pathway/PW0001004/retinoic%20acid%20metabolic%20pathway/pwmap.png pathway_studio_file: https://rgd.mcw.edu/pathway/PW0001004/retinoic%20acid%20metabolic%20pathway/retinoic%20acid%20metabolic%20pathway.gpp diagram_pathway_links: - id: PW:0001014 label: retinoic acid signaling pathway diagram_gene_links: - id: RGD:1352960 label: CES1 - id: RGD:2400 label: Crabp1 - id: RGD:62070 label: Crabp2 - id: RGD:70997 label: Fabp5 - id: RGD:68362 label: Lrat - id: RGD:3543 label: Rbp1 - id: RGD:3546 label: Rbp4 - id: RGD:1307551 label: Stra6 - id: RGD:3916 label: Ttr diagram_chemicals: - id: CHEBI:15367 label: all-trans retinoic acid - id: CHEBI:50211 label: cell_retinol - id: CHEBI:15035 label: retinal - id: CHEBI:16179 label: retinyl esters diagram_edges: - source: Rbp1 relation: associated_with target: retinal - source: Rbp4 relation: associated_with target: Stra6 - source: Rbp4 relation: associated_with target: Ttr - source: all-trans retinoic acid relation: associated_with target: Crabp1 - source: all-trans retinoic acid relation: associated_with target: Crabp2 - source: all-trans retinoic acid relation: associated_with target: Fabp5 - source: all-trans retinoic acid relation: positively_affects target: atRA CYPs - source: all-trans retinoic acid relation: positively_affects target: retinoic acid signaling pathway - source: apo_Rbp1 relation: negatively_affects target: Lrat - source: cell_retinol relation: associated_with target: Rbp1 - source: cell_retinol relation: positively_affects target: retinyl esters - source: circ_retinol relation: associated_with target: Rbp4 - source: circ_retinol relation: associated_with target: Ttr - source: circ_retinol relation: positively_affects target: cell_retinol - source: retinal relation: mutually_affects target: cell_retinol - source: retinal relation: positively_affects target: all-trans retinoic acid - source: retinyl esters relation: positively_affects target: cell_retinol diagram_labels: - apo_Rbp1 --+> CES1 - atRAs catabolism diagram_other_links: - href: /wg/home/pathway2/molecular-pathways2/atra-cyps label: atRA CYPs - href: /wg/home/pathway2/molecular-pathways2/retinal-dehydrogenases label: retinal dehydrogenases - href: /wg/home/pathway2/molecular-pathways2/retinol-dehydrogenases label: retinol dehydrogenases - href: retinoic%20acid%20metabolic%20pathway/140675.html label: apo_Rbp1 references: - id: RGD:6484663 citation: D'Ambrosio DN, etal., Nutrients. 2011 Jan;3(1):63-103. - id: RGD:6484671 citation: Berry DC and Noy N, Biochim Biophys Acta. 2012 Jan;1821(1):168-76. 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Epub 2011 Oct 1.