id: MODULE:intestinal_retinoid_absorption title: Intestinal absorption of dietary vitamin A — PNLIP/PNLIPRP2/PLB1 retinyl ester hydrolysis, SCARB1/CD36 carotenoid uptake, BCO1 central cleavage, retinal reduction, CRBP2 binding, LRAT re-esterification, chylomicron export, ABCA1 retinol efflux and ISX feedback description: >- Animals cannot make vitamin A and obtain it from the diet either as preformed retinyl esters of animal foods or as provitamin A carotenoids of plants, chiefly beta-carotene. Both forms are absorbed by the enterocytes of the proximal small intestine. Dietary retinyl esters must first be hydrolysed: in the lumen by pancreatic triglyceride lipase (PNLIP, with its cofactor colipase) and pancreatic lipase-related protein 2 (PNLIPRP2), and at the brush border by phospholipase B1 (PLB1). The free retinol released enters the enterocyte, largely by diffusion. Carotenoids are taken up across the brush border membrane with the help of the class B scavenger receptors SR-BI (SCARB1) and CD36. In the cytosol the carotenoid oxygenase BCO1 cleaves beta-carotene at its central double bond into two molecules of all-trans-retinal, which is reduced to all-trans-retinol by an NADPH-dependent retinal reductase whose identity in human enterocytes is not settled (AKR1B10 and RDH11 are candidates). Retinol from both sources is bound by cellular retinol-binding protein 2 (CRBP2, RBP2), an abundant intestine-specific carrier, and re-esterified with long-chain fatty acids, mainly by LRAT. The new retinyl esters, together with unconverted carotenoids, are packaged into chylomicrons and secreted into the lymph. Some free retinol leaves the cell across the basolateral membrane, partly by an ABCA1-dependent route, and reaches the portal blood. Carotenoid absorption and cleavage are under negative feedback: retinoic acid induces the intestine-specific homeobox transcription factor ISX, which represses transcription of the SCARB1 and BCO1 genes. Loss of SR-BI impairs beta-carotene absorption in mice, loss of CRBP2 reduces retinol uptake and hepatic vitamin A stores, and loss of ISX derepresses SCARB1 and BCO1. status: DRAFT scope: CONCRETE evidence: - source_id: PW:0000141 title: retinol metabolic pathway statement: >- The module boundary follows the RGD Pathway Ontology record and diagram for this term, which despite its name describe intestinal absorption of dietary vitamin A. The diagram draws dietary retinyl esters hydrolysed to all-trans-retinol (Pnlip, Pnliprp2, Plb1), carotenoids taken up (Scarb1, Cd36) and converted to retinal (Bcmo1), retinal reduced to cellular retinol (Akr1b10, NADPH to NADP+), cellular retinol associated with Rbp2, re-esterified (Lrat) or released as circulating retinol (Abca1), with passive diffusion of retinol drawn as a label. The RGD-curated human gene set is ABCA1, AKR1B10, ALDH1A2, BCO1, CD36, LRAT, PLB1, PNLIP, PNLIPRP2, RBP2 and SCARB1. Derived through projects/RGD_PATHWAY_ONTOLOGY (pathways/PW_0000141.yaml). - source_id: file:projects/RGD_PATHWAY_ONTOLOGY/pathways/PW_0000141.yaml title: RGD PW:0000141 record text (project snapshot) statement: >- The RGD record assigns luminal and brush-border hydrolysis of dietary retinyl esters to the two pancreatic lipases and phospholipase B1. supporting_text: The pancreatic lipases Pnlip and Pnliprp2, known as Ptl and Plrp-2, respectively and the phospholipase B1 located in the brush border membrane of absorptive cells, carry out the reaction. - source_id: file:projects/RGD_PATHWAY_ONTOLOGY/pathways/PW_0000141.yaml title: RGD PW:0000141 record text (project snapshot) statement: >- The RGD record describes the two fates of enterocyte retinol bound to RBP2: LRAT re-esterification and ABCA1-mediated efflux. supporting_text: In the cell, free retinol is in complex with Rbp2 retinol binding protein and is re-esterified to retinyl esters (RE) by Lrat or is released into the circulation via Abca1-mediated efflux - source_id: file:projects/RGD_PATHWAY_ONTOLOGY/pathways/PW_0000141.yaml title: RGD PW:0000141 record text (project snapshot) statement: >- The RGD record describes ISX feedback on Scarb1 and Bcmo1 in prose, although ISX is not drawn or listed among the RGD genes. supporting_text: Expression of Isx results in repression of Scarb1 and Bcmo1 genes, providing a negative feedback loop between cellular dietary vitamin A metabolites and its uptake and production. - source_id: GO:0042572 title: retinol metabolic process statement: >- The skos:closeMatch GO mapping of PW:0000141 (RGD page GO xref, PW definition xref and lexical match; projects/RGD_PATHWAY_ONTOLOGY/data/module_seeds.yaml). It is kept as a module-level concept because the pathway produces, binds and esterifies retinol, but it is broader than this module, which covers only its intestinal absorption arm; GO:0098856 intestinal lipid absorption is added beside it for that reason. - source_id: PMID:21718801 title: Mechanisms involved in the intestinal absorption of dietary vitamin A and provitamin A carotenoids. statement: >- The review that RGD cites for most of the pathway genes summarises the same sequence of steps: carotenoid cleavage and retinal reduction, retinyl ester hydrolysis, re-esterification by LRAT and chylomicron export. supporting_text: In the intestinal mucosa β-carotene is converted to retinal by β-C 15,15′ oxygenase 1 (BCO1) and the retinal is then reduced to retinol by a retinal reductase - source_id: PMID:21718801 title: Mechanisms involved in the intestinal absorption of dietary vitamin A and provitamin A carotenoids. statement: Re-esterified retinol leaves the enterocyte in chylomicrons with other neutral lipids and intact carotenoids. supporting_text: The resulting retinyl esters are incorporated with other neutral lipid esters (i.e., triacylglycerols and cholesteryl esters) and intact carotenoids into chylomicrons and absorbed via the lymphatics - source_id: Reactome:R-HSA-975634 title: Retinoid metabolism and transport statement: Reactome describes the same enterocyte route for dietary carotenes and retinyl esters. supporting_text: Transport from enterocytes to the liver happens via chylomicrons module: id: intestinal_retinoid_absorption label: Intestinal absorption of dietary vitamin A module_type: METABOLIC_PATHWAY concepts: - preferred_term: retinol metabolic process term: id: GO:0042572 label: retinol metabolic process description: >- The closeMatch of PW:0000141. Broader than this module, which models the intestinal absorption arm only. - preferred_term: intestinal lipid absorption term: id: GO:0098856 label: intestinal lipid absorption description: >- Retinyl esters, retinol and carotenoids are dietary lipids absorbed alongside triacylglycerol and cholesterol, using shared lipases, scavenger receptors and chylomicrons. context: taxa: - preferred_term: Homo sapiens term: id: NCBITaxon:9606 label: Homo sapiens cell_types: - preferred_term: enterocyte term: id: CL:0000584 label: enterocyte description: >- The absorptive cell of the small intestine. Luminal hydrolysis acts just outside it, in the gut lumen and at its brush border. parts: - order: 1 role: hydrolysis of dietary retinyl esters in the gut lumen and at the brush border node: id: retinyl_ester_hydrolysis label: Luminal and brush-border retinyl ester hydrolysis (PNLIP, PNLIPRP2, PLB1) module_type: REACTION description: >- Dietary retinyl esters, mainly retinyl palmitate, cannot be absorbed intact and are hydrolysed to all-trans-retinol and fatty acid before uptake. Several lipases share the work, depending on how the ester is presented (emulsion droplets, mixed micelles or vesicles) and on age: colipase-dependent pancreatic triglyceride lipase (PNLIP) is the main pancreatic retinyl ester hydrolase, pancreatic lipase-related protein 2 (PNLIPRP2) hydrolyses micelle-solubilised esters, and phospholipase B1 (PLB1) is an intrinsic brush-border enzyme. They are modelled as alternatives in one variant set. The released retinol is taken up largely by diffusion, which has no protein participant here. evidence: - source_id: PMID:21718801 statement: More than one enzyme probably shares luminal retinyl ester hydrolysis, and a brush-border activity has been attributed to phospholipase B. supporting_text: Thus, more than one enzyme may be responsible for the complete hydrolysis of retinyl esters in the intestinal lumen. variant_sets: - id: retinyl_ester_hydrolase label: Retinyl ester hydrolase axis: enzyme and site of action (pancreatic lipases in the lumen versus brush-border phospholipase B1) selection: ONE_OR_MORE variants: - id: pnlip_variant label: PNLIP (pancreatic triglyceride lipase, with colipase) module_type: REACTION annotons: - id: pnlip_retinyl_ester_hydrolase label: PNLIP all-trans-retinyl-palmitate hydrolase participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PNLIP term: id: UniProtKB:P16233 label: Pancreatic triacylglycerol lipase function: preferred_term: all-trans-retinyl-palmitate hydrolase, all-trans-retinol forming activity term: id: GO:0047376 label: all-trans-retinyl-palmitate hydrolase, all-trans-retinol forming activity substrates: - preferred_term: all-trans-retinyl palmitate term: id: CHEBI:17616 label: all-trans-retinyl palmitate products: - preferred_term: all-trans-retinol term: id: CHEBI:17336 label: all-trans-retinol - preferred_term: hexadecanoate term: id: CHEBI:7896 label: hexadecanoate locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- Secreted pancreatic lipase that acts on emulsified and micellar retinyl esters and needs colipase (CLPS) to do so. GO:0047376 is an experimental GOA row (EXP, PMID:10769148). Its main function is triacylglycerol hydrolysis (GO:0004806); retinyl esters are digested by the same enzyme as the other dietary neutral lipid esters. evidence: - source_id: PMID:10769148 statement: Purified human PTL hydrolyses retinyl esters, and PTL is the major pancreatic retinyl ester hydrolase in rodents. supporting_text: Finally, purified human PTL exhibited similar enzymatic characteristics for triglyceride hydrolysis as well as for retinyl ester hydrolysis, indicating that RE is a substrate for PTL in vivo. - source_id: PMID:16497549 statement: Pancreatic lipase hydrolysis of retinyl palmitate depends on colipase. supporting_text: This hydrolysis was abolished when colipase was not added to the medium. - source_id: Reactome:R-HSA-975593 statement: Reactome models PNLIP:CLPS hydrolysis of retinyl palmitate in the lumen. supporting_text: Pancreatic lipase catalyses the hydrolysis of RE to all-trans-retinol (atROL) and fatty acid which are then both taken up by enterocytic cell membranes gocam_associations: - model: gomodel:66f5faaa00001204 activity: gomodel:66f5faaa00001204/66f5faaa00001321 title: Retinoid Metabolic Process 1 (Mouse) description: Mouse Pnlip GO:0050253 retinyl-palmitate esterase activity in the extracellular region. - model: gomodel:67086be200002592 activity: gomodel:67086be200002592/67086be200002614 title: Retinoid Metabolic Process 3 (Mouse) description: Mouse Pnlip GO:0050253 retinyl-palmitate esterase activity in the extracellular region. - id: pnliprp2_variant label: PNLIPRP2 (pancreatic lipase-related protein 2) module_type: REACTION annotons: - id: pnliprp2_retinyl_ester_hydrolase label: PNLIPRP2 retinyl-palmitate esterase participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PNLIPRP2 term: id: UniProtKB:P54317 label: Pancreatic lipase-related protein 2 function: preferred_term: retinyl-palmitate esterase activity term: id: GO:0050253 label: retinyl-palmitate esterase activity substrates: - preferred_term: all-trans-retinyl palmitate (in mixed micelles) term: id: CHEBI:17616 label: all-trans-retinyl palmitate products: - preferred_term: all-trans-retinol term: id: CHEBI:17336 label: all-trans-retinol - preferred_term: hexadecanoate term: id: CHEBI:7896 label: hexadecanoate locations: - preferred_term: extracellular region term: id: GO:0005576 label: extracellular region role_description: >- Colipase-independent pancreatic lipase with broad specificity (triacylglycerol, galactolipid and phospholipid lipase activities are experimental in human GOA). Retinyl palmitate hydrolysis was shown with the purified horse enzyme, only for micelle-solubilised ester and at about one third of the PL rate, so GO:0050253 is authored here from that evidence and is not a human experimental GOA row. Human PNLIPRP2 is polymorphic and many people carry an inactive allele (the gene is named gene/pseudogene by HGNC), which limits its contribution in adults. evidence: - source_id: PMID:16497549 statement: PLRP2 hydrolyses retinyl palmitate in mixed micelles but not in emulsions, and PLRP1 does not. supporting_text: PLRP2 hydrolyzes RP only when RP is solubilized in mixed micelles - id: plb1_variant label: PLB1 (brush-border phospholipase B1) module_type: REACTION annotons: - id: plb1_retinyl_ester_hydrolase label: PLB1 brush-border retinyl ester hydrolase participant: selector_type: GENE_PRODUCT gene_product: preferred_term: PLB1 term: id: UniProtKB:Q6P1J6 label: Phospholipase B1, membrane-associated function: preferred_term: retinyl-palmitate esterase activity term: id: GO:0050253 label: retinyl-palmitate esterase activity substrates: - preferred_term: all-trans-retinyl palmitate term: id: CHEBI:17616 label: all-trans-retinyl palmitate products: - preferred_term: all-trans-retinol term: id: CHEBI:17336 label: all-trans-retinol - preferred_term: hexadecanoate term: id: CHEBI:7896 label: hexadecanoate locations: - preferred_term: brush border membrane term: id: GO:0031526 label: brush border membrane role_description: >- Intrinsic brush-border membrane phospholipase B of the distal small intestine. The retinyl ester hydrolase purified from rat brush border is very probably this enzyme. In human GOA, GO:0050253 rests on IBA and Reactome TAS; there is no human experimental row. evidence: - source_id: PMID:8117729 statement: The rat brush-border retinyl ester hydrolase is immunologically identical to brush-border phospholipase B and prefers retinyl palmitate to phosphatidylcholine. supporting_text: A polyclonal antiserum against rat brush border phospholipase B reacted with the purified retinyl ester hydrolase, strongly suggesting that this enzyme was the same as that previously purified and characterized as a calcium-independent brush border phospholipase B - order: 2 role: carotenoid uptake across the brush border membrane node: id: carotenoid_uptake label: Class B scavenger receptor-facilitated carotenoid uptake (SCARB1, CD36) module_type: TRANSPORT_STEP description: >- Beta-carotene and other provitamin A carotenoids are taken up from mixed micelles across the apical brush border. Uptake is saturable and facilitated by the class B scavenger receptors SR-BI (SCARB1), which predominates in the duodenum and is needed for beta-carotene absorption in mice, and CD36. Neither receptor is specific for carotenoids: both also take up cholesterol, phospholipids and fatty acids, and GO has no molecular function term for this lipid-uptake activity, so the annotons carry the carotenoid transport process without a function term. Unconverted carotenoids pass on to chylomicrons; the fraction that is cleaved enters the BCO1 step. concepts: - preferred_term: carotenoid transport term: id: GO:0046867 label: carotenoid transport evidence: - source_id: PMID:15766282 statement: SR-BI and CD36 in the brush border membrane facilitate beta-carotene absorption, and SR-BI is essential for it in mice on a high-fat diet. supporting_text: SR-BI is essential for beta-carotene absorption, at least in mice on a high fat diet. variant_sets: - id: class_b_scavenger_receptor label: Class B scavenger receptor axis: receptor paralogue (SR-BI predominant in the duodenum; CD36 more distal) selection: ONE_OR_MORE variants: - id: scarb1_variant label: SCARB1 (SR-BI) module_type: TRANSPORT_STEP annotons: - id: scarb1_carotenoid_uptake label: SR-BI facilitated carotenoid uptake participant: selector_type: GENE_PRODUCT gene_product: preferred_term: SCARB1 (SR-BI) term: id: UniProtKB:Q8WTV0 label: Scavenger receptor class B member 1 processes: - preferred_term: carotenoid transport term: id: GO:0046867 label: carotenoid transport locations: - preferred_term: brush border membrane term: id: GO:0031526 label: brush border membrane role_description: >- High-density lipoprotein receptor (GO:0070506, IDA) that mediates selective lipid uptake. Here it facilitates beta-carotene, alpha-carotene and beta-cryptoxanthin uptake into enterocytes but not retinol uptake. No function term is asserted (see node description). Its transcription is repressed by ISX (part 8). evidence: - source_id: PMID:17644776 statement: SR-BI inhibition decreases carotenoid uptake by Caco-2 cells but does not affect retinol transport. supporting_text: Scavenger receptor class B type I (SR-BI) inhibition did not affect ROL transport but decreased carotenoid uptake. - source_id: PMID:23427331 statement: SR-BI and CD36 take part in cellular uptake of provitamin A carotenoids in Caco-2 and HEK cells. supporting_text: SR-BI and CD36 are involved in cellular uptake of provitamin A carotenoids - id: cd36_variant label: CD36 module_type: TRANSPORT_STEP annotons: - id: cd36_carotenoid_uptake label: CD36 facilitated carotenoid uptake participant: selector_type: GENE_PRODUCT gene_product: preferred_term: CD36 term: id: UniProtKB:P16671 label: Platelet glycoprotein 4 processes: - preferred_term: carotenoid transport term: id: GO:0046867 label: carotenoid transport locations: - preferred_term: brush border membrane term: id: GO:0031526 label: brush border membrane role_description: >- Multiligand scavenger receptor and long-chain fatty acid transporter (GO:0005324, IMP). Its role in carotenoid uptake rests on transfected cells and brush-border vesicles, with genetic association of CD36 variants with plasma provitamin A carotenoid levels, and is less established in vivo than that of SR-BI. No function term is asserted (see node description). evidence: - source_id: PMID:15766282 statement: Transfected SR-BI or CD36 confers on COS-7 cells uptake of dietary lipids including beta-carotene. supporting_text: Both scavenger receptors facilitate the uptake of dietary lipids such as beta-carotene, free and esterified cholesterol, phospholipids, and fatty acids into COS-7 cells. - source_id: PMID:23427331 statement: Variants in SCARB1 and CD36 associate with plasma provitamin A carotenoid concentrations. supporting_text: genetic variations in their encoding genes may modulate plasma concentrations of provitamin A carotenoids at a population level - order: 3 role: central cleavage of beta-carotene to retinal node: id: beta_carotene_cleavage label: BCO1 central cleavage of beta-carotene to all-trans-retinal module_type: REACTION description: >- The cytosolic non-heme iron oxygenase BCO1 cleaves all-trans-beta-carotene at the central 15,15' double bond to give two molecules of all-trans-retinal, the route by which provitamin A carotenoids become vitamin A. The mitochondrial eccentric-cleavage enzyme BCO2, which RGD mentions but does not draw, is not modelled. BCO1 transcription is repressed by ISX (part 8). concepts: - preferred_term: carotene catabolic process term: id: GO:0016121 label: carotene catabolic process annotons: - id: bco1_carotene_dioxygenase label: BCO1 beta-carotene 15,15'-dioxygenase participant: selector_type: GENE_PRODUCT gene_product: preferred_term: BCO1 term: id: UniProtKB:Q9HAY6 label: Beta,beta-carotene 15,15'-dioxygenase function: preferred_term: beta-carotene 15,15'-dioxygenase activity term: id: GO:0003834 label: beta-carotene 15,15'-dioxygenase activity substrates: - preferred_term: all-trans-beta-carotene term: id: CHEBI:17579 label: beta-carotene - preferred_term: O2 term: id: CHEBI:15379 label: dioxygen products: - preferred_term: all-trans-retinal (two molecules) term: id: CHEBI:17898 label: all-trans-retinal processes: - preferred_term: carotene catabolic process term: id: GO:0016121 label: carotene catabolic process locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- GO:0003834 and GO:0016121 are experimental GOA rows (IDA, PMID:11401432 and PMID:24668807; IMP, PMID:17951468). The cytosolic location follows the RGD record and the cited review; there is no experimental human cellular component row. evidence: - source_id: PMID:11401432 statement: Recombinant human BCO1 has beta,beta-carotene-15,15'-dioxygenase activity and is expressed in intestine. supporting_text: Biochemical analysis of baculovirus expressed human BCDO demonstrates the predicted beta,beta-carotene-15,15'-dioxygenase activity. - source_id: PMID:21718801 statement: Central cleavage by cytosolic BCO1 is the major route from beta-carotene to retinal. supporting_text: The major pathway is the central cleavage catalyzed by a cytosolic enzyme, β-C 15,15′-oxygenase 1 (BCO1), which cleaves β-C at its central double bond (15,15′) to yield retinal gocam_associations: - model: gomodel:67086be200002705 activity: gomodel:67086be200002705/67086be200002803 title: Retinoid Metabolic Process 4 (Mouse) description: >- Mouse Bco1 GO:0003834 beta-carotene 15,15'-dioxygenase activity, part of retinoid metabolic process; not causally connected to the other activities in the model. - order: 4 role: reduction of retinal to retinol node: id: retinal_reduction label: NADPH-dependent reduction of all-trans-retinal to all-trans-retinol (enzyme unresolved) module_type: REACTION description: >- Retinal made by BCO1 is reduced to retinol, which can then be bound by CRBP2 and esterified. The enzyme that does this in human enterocytes has not been identified. Two candidates with experimental NADP(H)-dependent all-trans-retinal reductase activity are modelled as variants: the cytosolic aldo-keto reductase AKR1B10, the small intestine reductase that RGD draws, and the ER-membrane short-chain dehydrogenase/reductase RDH11, which Reactome proposes. Both GO terms are written in the oxidative direction; the reaction is reversible and here runs toward retinol. evidence: - source_id: Reactome:R-HSA-975629 statement: Reactome states that the enterocyte retinal reductase is not identified and proposes RDH11. supporting_text: Although the enzyme catalysing retinal reduction in human enterocytes is not identified, the best candidate is retinol dehydrogenase 11 (RDH11, RalR1). gocam_associations: - model: gomodel:67086be200002705 activity: gomodel:67086be200002705/67086be200002846 title: Retinoid Metabolic Process 4 (Mouse) description: >- The mouse model fills this step with Dhrs3 GO:0052650 all-trans-retinol dehydrogenase (NADP+) activity, downstream of Rbp2 and upstream of Lrat. Pinned to the node, not to a variant, because DHRS3 is not modelled as an intestinal candidate here. variant_sets: - id: retinal_reductase label: Candidate retinal reductase axis: enzyme family and compartment (cytosolic aldo-keto reductase versus ER-membrane SDR) selection: ONE_OR_MORE variants: - id: akr1b10_variant label: AKR1B10 (small intestine reductase) module_type: REACTION annotons: - id: akr1b10_retinal_reductase label: AKR1B10 all-trans-retinal reductase (NADPH) participant: selector_type: GENE_PRODUCT gene_product: preferred_term: AKR1B10 term: id: UniProtKB:O60218 label: Aldo-keto reductase family 1 member B10 function: preferred_term: all-trans-retinol dehydrogenase (NADP+) activity term: id: GO:0052650 label: all-trans-retinol dehydrogenase (NADP+) activity substrates: - preferred_term: all-trans-retinal term: id: CHEBI:17898 label: all-trans-retinal - preferred_term: NADPH term: id: CHEBI:57783 label: NADPH(4-) - preferred_term: H+ term: id: CHEBI:15378 label: hydron products: - preferred_term: all-trans-retinol term: id: CHEBI:17336 label: all-trans-retinol - preferred_term: NADP+ term: id: CHEBI:58349 label: NADP(3-) locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Cytosolic aldo-keto reductase that reduces all-trans-, 9-cis- and 13-cis-retinal efficiently with NADPH (GO:0052650, IDA, PMID:12732097; EXP, PMID:18087047). It is broad in specificity and also detoxifies other aldehydes such as farnesal and anthracyclines. Its share of retinal reduction in the enterocyte in vivo has not been measured. evidence: - source_id: PMID:12732097 statement: Human small-intestine aldose reductase (AKR1B10) is an efficient cytosolic NADPH-dependent retinal reductase. supporting_text: Human AR and HSI AR were very efficient in the reduction of all- trans -, 9- cis - and 13- cis -retinal - id: rdh11_variant label: RDH11 (retinol dehydrogenase 11, RalR1) module_type: REACTION annotons: - id: rdh11_retinal_reductase label: RDH11 all-trans-retinal reductase (NADPH) participant: selector_type: GENE_PRODUCT gene_product: preferred_term: RDH11 term: id: UniProtKB:Q8TC12 label: Retinol dehydrogenase 11 function: preferred_term: all-trans-retinol dehydrogenase (NADP+) activity term: id: GO:0052650 label: all-trans-retinol dehydrogenase (NADP+) activity substrates: - preferred_term: all-trans-retinal term: id: CHEBI:17898 label: all-trans-retinal - preferred_term: NADPH term: id: CHEBI:57783 label: NADPH(4-) - preferred_term: H+ term: id: CHEBI:15378 label: hydron products: - preferred_term: all-trans-retinol term: id: CHEBI:17336 label: all-trans-retinol - preferred_term: NADP+ term: id: CHEBI:58349 label: NADP(3-) locations: - preferred_term: endoplasmic reticulum membrane term: id: GO:0005789 label: endoplasmic reticulum membrane role_description: >- ER-membrane SDR with a strong preference for NADP(H) that acts mainly as a retinaldehyde reductase; GO:0052650 is the first core function of the completed RDH11 gene review. It sits in the same membrane as LRAT, the next step. Not in the RGD gene set; included as the Reactome candidate. evidence: - source_id: file:human/RDH11/RDH11-ai-review.yaml statement: The RDH11 gene review gives GO:0052650 as its core activity, acting mainly in the reductive direction. supporting_text: acting predominantly in the reductive direction (retinal to retinol) - order: 5 role: binding of cellular retinol and retinal by CRBP2 node: id: crbp2_retinoid_binding label: CRBP2 (RBP2) binding of enterocyte retinol module_type: TRANSPORT_STEP description: >- Cellular retinol-binding protein 2 is one of the most abundant soluble proteins of jejunal enterocytes. It binds retinol from both the hydrolysis and the carotenoid routes (and retinal), keeps free retinoid low and presents retinol to the esterifying enzymes. Loss of CRBP2 in mice halves the saturable component of intestinal retinol uptake and lowers hepatic vitamin A stores. annotons: - id: rbp2_retinol_binding label: CRBP2 all-trans-retinol binding participant: selector_type: GENE_PRODUCT gene_product: preferred_term: RBP2 (CRBP2) term: id: UniProtKB:P50120 label: Retinol-binding protein 2 function: preferred_term: all-trans-retinol binding term: id: GO:1904768 label: all-trans-retinol binding substrates: - preferred_term: all-trans-retinol term: id: CHEBI:17336 label: all-trans-retinol locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: >- Intestine-specific FABP-family retinoid chaperone. In human GOA GO:1904768 rests on Reactome TAS and retinoid binding (GO:0005501) on TAS; there is no human experimental molecular function row. The mouse GO-CAMs model Rbp2 either as a molecular carrier or as an enzyme-substrate adaptor feeding retinol to the reductase and LRAT; the binding term is used here as the shared, least interpretive activity. evidence: - source_id: PMID:12138113 statement: CRBP2-null mice have impaired saturable retinol uptake and reduced hepatic vitamin A stores. supporting_text: The saturable component of intestinal retinol uptake is impaired in CRBP II(-/-) mice. - source_id: PMID:21718801 statement: CRBP2 is thought to present retinoids to enzymes and so direct their metabolism. supporting_text: More importantly, it may present retinoids to different enzymes and direct their metabolism gocam_associations: - model: gomodel:66f5faaa00001204 activity: gomodel:66f5faaa00001204/66f5faaa00001335 title: Retinoid Metabolic Process 1 (Mouse) description: Mouse Rbp2 GO:0140104 molecular carrier activity in the cytosol. - model: gomodel:67086be200002592 activity: gomodel:67086be200002592/67086be200002616 title: Retinoid Metabolic Process 3 (Mouse) description: Mouse Rbp2 GO:0140104 molecular carrier activity. - model: gomodel:67086be200002705 activity: gomodel:67086be200002705/67086be200002729 title: Retinoid Metabolic Process 4 (Mouse) description: Mouse Rbp2 GO:0140767 enzyme-substrate adaptor activity, upstream of Dhrs3 and Lrat. - order: 6 role: re-esterification of retinol node: id: retinol_esterification_ref label: LRAT esterification of all-trans-retinol description: >- Included by reference to the LRAT step of the retinoid visual cycle module, which models phosphatidylcholine-retinol O-acyltransferase activity on all-trans-retinol. LRAT is the main esterifying enzyme in the enterocyte at physiological retinol doses (Lrat-null mice absorb retinol mainly as free retinol in chylomicrons); an acyl-CoA-dependent activity, attributed to DGAT1, contributes at high doses and is not modelled. module_ref: retinoid_visual_cycle#retinol_esterification - order: 7 role: packaging of retinyl esters and carotenoids into chylomicrons and secretion into lymph node: id: chylomicron_export_ref label: Chylomicron assembly and ER export description: >- Included by reference to the chylomicron assembly module (MTTP, apoB-48, SAR1B). Newly made retinyl esters and intact carotenoids travel with triacylglycerol and cholesteryl esters in the chylomicron, which is the main exit route for absorbed vitamin A. module_ref: chylomicron_assembly_secretion - order: 8 role: transcriptional feedback repression of carotenoid uptake and cleavage by ISX optional: true node: id: isx_feedback label: ISX repression of SCARB1 and BCO1 transcription module_type: BIOLOGICAL_PROCESS description: >- Regulatory part, not a step that handles a retinoid. Retinoic acid, acting through the retinoic acid receptors, induces the intestine-specific homeobox transcription factor ISX, and ISX represses transcription of the SCARB1 and BCO1 genes. When vitamin A is plentiful, carotenoid uptake and cleavage are therefore turned down; in vitamin A deficiency ISX falls and both are derepressed. ISX acts on the target genes, not on carotenoids or retinoids, so it is modelled as a regulator of the uptake and cleavage nodes (NEGATIVELY_REGULATES connections) and not as a participant in them. Optional because absorption runs without it; it sets the rate. The RA induction step belongs to the retinoic acid receptor signalling module and is not repeated here. annotons: - id: isx_transcription_repressor label: ISX DNA-binding transcriptional repressor of SCARB1 and BCO1 participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ISX term: id: UniProtKB:Q2M1V0 label: Intestine-specific homeobox function: preferred_term: DNA-binding transcription repressor activity, RNA polymerase II-specific term: id: GO:0001227 label: DNA-binding transcription repressor activity, RNA polymerase II-specific targets: - preferred_term: SCARB1 gene - preferred_term: BCO1 gene processes: - preferred_term: negative regulation of transcription by RNA polymerase II term: id: GO:0000122 label: negative regulation of transcription by RNA polymerase II locations: - preferred_term: nucleus term: id: GO:0005634 label: nucleus role_description: >- Homeodomain transcription factor expressed in intestinal epithelium. Human GOA has only sequence-specific double-stranded DNA binding as experimental (IDA, PMID:28473536); GO:0001227 and GO:0000122 are IEA by orthology from mouse Isx and are authored here from the mouse knockout and the human-cell and mouse studies below. Whether ISX binds the SCARB1 and BCO1 promoters directly is stated in the cited work only for BCO1 (abstract-level), so the repression may be partly indirect. evidence: - source_id: PMID:18093975 statement: Isx-deficient mice have greatly increased intestinal Bcmo1 and SR-BI expression. supporting_text: beta-carotene 15,15'-monooxygenase (EC1.14.99.36 Bcmo1) and the class B type I scavenger receptor, which are involved in vitamin A synthesis and carotenoid uptake, respectively, were drastically increased in IsxLacZ/LacZ mice. - source_id: PMID:20061533 statement: Retinoic acid induces ISX through RARs, and ISX represses SR-BI and Bcmo1, in mice and human cell lines. supporting_text: Retinoic acid via retinoic acid receptors induced expression of the intestinal transcription factor ISX. ISX then repressed the expression of SR-B1 and the carotenoid-15,15'-oxygenase Bcmo1. - order: 9 role: basolateral efflux of free retinol optional: true node: id: retinol_efflux label: ABCA1-dependent basolateral efflux of free retinol module_type: TRANSPORT_STEP description: >- Part of the absorbed retinol leaves the enterocyte unesterified, outside lipoproteins, and reaches the portal circulation; this route matters most when chylomicron secretion is low (fasting, or abetalipoproteinemia). In Caco-2 cells the saturable component of retinol efflux is reduced by the ABCA1 inhibitor glyburide and by ABCA1 knockdown. Optional because it is a secondary exit route, and because whether ABCA1 moves retinol itself or acts indirectly through its phospholipid floppase activity and nascent HDL formation is not known. concepts: - preferred_term: retinol transport term: id: GO:0034633 label: retinol transport evidence: - source_id: PMID:17644776 statement: ABCA1 knockdown reduces retinol efflux but not carotenoid efflux from Caco-2 cells. supporting_text: Inhibition of ABCA1 protein expression by small interfering RNAs decreased ROL efflux but not carotenoid efflux. annotons: - id: abca1_lipid_floppase label: ABCA1 ATPase-coupled lipid floppase at the basolateral membrane participant: selector_type: GENE_PRODUCT gene_product: preferred_term: ABCA1 term: id: UniProtKB:O95477 label: Phospholipid-transporting ATPase ABCA1 function: preferred_term: ATPase-coupled intramembrane lipid carrier activity term: id: GO:0140326 label: ATPase-coupled intramembrane lipid carrier activity locations: - preferred_term: basolateral plasma membrane term: id: GO:0016323 label: basolateral plasma membrane role_description: >- ABCA1's core activity (core function of the ABCA1 gene review; EXP and IDA rows) is ATP-driven phospholipid and cholesterol flopping that loads apoA-I into nascent HDL. Retinol is not shown to be a direct ABCA1 substrate, so the annoton carries ABCA1's own activity and no retinol transport process; the node concept records the observed outcome. The basolateral location follows the cited Caco-2 work. evidence: - source_id: file:human/ABCA1/ABCA1-ai-review.yaml statement: The ABCA1 review gives ATPase-coupled lipid floppase activity as its first core function. supporting_text: ATPase-coupled intramembrane lipid transporter activity - source_id: PMID:17644776 statement: The authors propose that retinol efflux is partly facilitated, probably by basolateral ABCA1. supporting_text: ROL efflux is partly facilitated, probably by the basolateral transporter ABCA1 connections: - source: retinyl_ester_hydrolysis target: crbp2_retinoid_binding connection_type: PROVIDES_INPUT_FOR description: Retinol released from dietary esters diffuses into the enterocyte and is bound by CRBP2. - source: carotenoid_uptake target: beta_carotene_cleavage connection_type: PROVIDES_INPUT_FOR description: Absorbed beta-carotene is the substrate of cytosolic BCO1. - source: beta_carotene_cleavage target: retinal_reduction connection_type: PROVIDES_INPUT_FOR description: All-trans-retinal from central cleavage is reduced to retinol. - source: retinal_reduction target: crbp2_retinoid_binding connection_type: PROVIDES_INPUT_FOR description: Carotenoid-derived retinol joins the CRBP2-bound pool. - source: crbp2_retinoid_binding target: retinol_esterification_ref connection_type: PROVIDES_INPUT_FOR description: CRBP2-bound retinol is the substrate of LRAT. - source: retinol_esterification_ref target: chylomicron_export_ref connection_type: PROVIDES_INPUT_FOR description: Newly made retinyl esters are packaged into chylomicrons. - source: carotenoid_uptake target: chylomicron_export_ref connection_type: PROVIDES_INPUT_FOR description: Carotenoids that escape cleavage are secreted intact in chylomicrons. - source: crbp2_retinoid_binding target: retinol_efflux connection_type: PROVIDES_INPUT_FOR description: Free retinol not esterified can leave across the basolateral membrane. - source: isx_feedback target: carotenoid_uptake connection_type: NEGATIVELY_REGULATES description: ISX represses SCARB1 transcription, lowering carotenoid uptake. - source: isx_feedback target: beta_carotene_cleavage connection_type: NEGATIVELY_REGULATES description: ISX represses BCO1 transcription, lowering retinal production from beta-carotene. knowledge_gaps: - gap_statement: >- The enzyme that reduces BCO1-derived all-trans-retinal to retinol in human enterocytes is not known. AKR1B10 (cytosolic) and RDH11 (ER membrane) reduce retinal with NADPH in vitro and are expressed in intestine, and a mouse GO-CAM uses DHRS3 for the step, but no loss-of-function study has measured the contribution of any of them to intestinal retinol formation from beta-carotene. gap_kind: - BIOLOGY status: OPEN significance: >- Decides whether carotenoid-derived retinal is reduced in the cytosol or at the ER membrane next to LRAT, and which gene variants could affect provitamin A conversion efficiency. - gap_statement: >- How ABCA1 supports basolateral efflux of free retinol is unknown: retinol has not been shown to be an ABCA1 substrate, and the effect could follow from ABCA1-dependent phospholipid efflux and nascent HDL formation. gap_kind: - BIOLOGY status: OPEN significance: >- Determines whether the non-chylomicron retinol exit route is a transporter step or a consequence of HDL biogenesis, and so whether it belongs to this module or to HDL assembly. notes: >- Derived from the RGD Pathway Ontology record and diagram PW:0000141 (retinol metabolic pathway) through the RGD_PATHWAY_ONTOLOGY project's diagram->module route; GO mapping GO:0042572 retinol metabolic process (skos:closeMatch). Despite its name, the RGD record and diagram describe intestinal absorption of dietary vitamin A, which is why this module is named for absorption rather than for retinol metabolism. The 11 RGD-curated human genes (RGD source rows in the human gene-pathway file) are ABCA1, AKR1B10, ALDH1A2, BCO1, CD36, LRAT, PLB1, PNLIP, PNLIPRP2, RBP2 and SCARB1; the other 72 genes attached to PW:0000141 come from KEGG map00830 and SMPDB and cover the whole retinol and retinoic acid network (UGTs, CYP2/3 enzymes, ADHs, RDHs, ER chaperones), so they were not used to set the boundary. Modelled as seven required parts and two optional ones: (1) retinyl ester hydrolysis, a variant set of PNLIP, PNLIPRP2 and PLB1; (2) carotenoid uptake, a variant set of SCARB1 and CD36; (3) BCO1 central cleavage; (4) retinal reduction, a variant set of the candidate reductases AKR1B10 and RDH11; (5) CRBP2 binding; (6) LRAT esterification by module_ref to retinoid_visual_cycle#retinol_esterification; (7) chylomicron packaging by module_ref to chylomicron_assembly_secretion; (8, optional) ISX feedback; and (9, optional) ABCA1-dependent retinol efflux. Boundary decisions. (a) ALDH1A2, in the RGD gene set but not drawn, oxidises retinal to retinoic acid; that step is modelled in modules/retinoic_acid_metabolism.yaml and is not repeated. That module's notes record PW:0000141 as considered but not covered and point to a separate absorption module, which this is. (b) LRAT and chylomicron assembly are included by module_ref, as retinoic_acid_metabolism does for LRAT, so neither the enzyme nor the MTTP/apoB-48/SAR1B machinery is restated. DGAT1 (acyl-CoA:retinol acyltransferase at high retinol doses; a mouse GO-CAM gives Dgat1 GO:0050252) is in the KEGG/SMPDB gene list only and is left as context; Lrat-null mice still put some acyl-CoA-derived retinyl ester into chylomicrons (PMID:16115871). (c) Retinal reduction: RGD draws AKR1B10, Reactome proposes RDH11 and states that the enterocyte enzyme is not identified, and mouse GO-CAM gomodel:67086be200002705 uses Dhrs3. Both AKR1B10 and RDH11 have experimental GO:0052650 and are modelled as candidate variants; DHRS3 is mentioned only in the node-level GO-CAM pin because no intestinal evidence for it was found. The unknown enzyme is recorded as a knowledge gap; an experiment that would close it is enterocyte-specific deletion of each candidate with stable-isotope beta-carotene tracing into lymph retinyl esters. (d) Colipase (CLPS), required by PNLIP and modelled as an enzyme activator in the mouse GO-CAMs, is not in the RGD set and is described in the PNLIP role rather than modelled as an annoton. Carboxyl ester lipase is excluded because CEL-null mice absorb retinyl ester normally (PMID:21718801). (e) Retinol entry into the enterocyte is by diffusion and has no protein participant; SCARB1 and CD36 take up carotenoids but not retinol (PMID:23427331, PMID:17644776). (f) ISX is not one of the RGD genes; RGD describes its feedback in prose only. ISX acts on the SCARB1 and BCO1 genes, which are targets of a transcription factor, not substrates, so it is a regulator: it gets its own optional part whose annoton carries its transcription repressor activity, linked to the uptake and cleavage nodes by NEGATIVELY_REGULATES. It is not added to those nodes' participants, and no metabolic process term is given to it. The inducing signal (retinoic acid acting through RARs) is in modules/retinoic_acid_receptor_signaling.yaml; the module validator therefore warns that the feedback loop is cut (isx_feedback has no incoming activating edge here), which is expected. (g) ABCA1 retinol efflux is optional and its annoton carries ABCA1's own floppase activity, not a retinol term, because retinol is not shown to be an ABCA1 substrate. (h) Downstream fates are out of scope: chylomicron remnant uptake by liver, hepatic storage and RBP4/STRA6 delivery (in retinoic_acid_metabolism), the visual cycle, and eccentric cleavage by BCO2 (described by RGD, not drawn). Molecular functions and their support (QuickGO, checked 2026-11-10): PNLIP GO:0047376 (EXP, PMID:10769148); BCO1 GO:0003834 (IDA, PMID:11401432, PMID:24668807; IMP, PMID:17951468); AKR1B10 GO:0052650 (IDA, PMID:12732097; EXP, PMID:18087047); RDH11 GO:0052650 (core function of the completed RDH11 review); ABCA1 GO:0140326 (IDA and EXP; core function of the ABCA1 review). Authored without experimental human GOA support: PNLIPRP2 GO:0050253 (from the horse enzyme, PMID:16497549; human experimental rows are triacylglycerol, galactolipid and phospholipid lipase); PLB1 GO:0050253 (IBA and Reactome TAS; rat purification PMID:8117729); RBP2 GO:1904768 (Reactome TAS); ISX GO:0001227 and GO:0000122 (IEA by orthology; human experimental row is only sequence-specific DNA binding). SCARB1 and CD36 carry no function term: their facilitated lipid uptake has no matching GO molecular function, and their experimental terms (HDL particle receptor, fatty acid transporter, scavenger receptor) describe other roles. The process GO:0046867 carotenoid transport on SCARB1 and CD36 is not in their GOA; it is asserted from the mouse knockout and cell studies cited. Comparator check for processes: GO:0016121 is given only to BCO1, which does the chemistry; no carotenoid or retinoid process is given to ISX or ABCA1. GO-CAM: gocams/index.tsv (checked 2026-11-10) has no human production model for this pathway. The seed's best_gocam lead (gomodel:6197061700002397, CD36 fatty acid transport) is unrelated and is not linked. Mouse models are linked at activity level: Retinoid Metabolic Process 1 (gomodel:66f5faaa00001204; Pnlip, Rbp2), 3 (gomodel:67086be200002592; Pnlip, Rbp2) and 4 (gomodel:67086be200002705; Bco1, Rbp2, and Dhrs3 at the retinal reduction node). Their Lrat activities belong to the referenced visual-cycle node and their chylomicron retinoid-binding activities to the referenced chylomicron module, so they are not pinned here; Lpl and Ldlr act after secretion and are out of scope. Possible upstream issue: in gomodel:67086be200002705 the Bco1 activity is not causally connected to the retinal reduction or esterification activities, so the carotenoid branch is disconnected from the rest of that model. Gene reviews exist for LRAT, ABCA1 and RDH11; PNLIP, PNLIPRP2, PLB1, SCARB1, CD36, BCO1, AKR1B10, RBP2 and ISX have none. PANTHER family ids and PTNs are deliberately not asserted. Most cited publications are abstract-only in the cache; PMID:21718801 has full text.