id: MODULE:enterohepatic_bile_salt_cycling title: Enterohepatic bile salt cycling transport relay; BSEP/ASBT/FABP6/OSTalpha-beta/NTCP description: 'Conjugated bile salts are not consumed by the digestion they enable: they are secreted into bile, act as detergents in the intestinal lumen, and are then reclaimed and returned to the liver, so that the whole bile salt pool recirculates many times a day and only a small fraction is lost in faeces. The relay is carried out by a small set of membrane transporters acting in a fixed order around a closed loop, each at a defined pole of a polarised epithelium: ATP-driven export across the hepatocyte canalicular (apical) membrane into bile (BSEP/ABCB11); sodium-coupled uptake across the apical brush border of the terminal ileal enterocyte (ASBT/SLC10A2); cytosolic shuttling across the enterocyte by a soluble bile acid binding protein (FABP6); basolateral efflux into portal blood by an obligate heteromeric facilitative transporter (OSTalpha/OSTbeta, SLC51A/SLC51B); and sodium-coupled reuptake across the hepatocyte basolateral (sinusoidal) membrane (NTCP/SLC10A1), closing the cycle. The hepatic uptake step has two parallel implementations - the sodium-dependent SLC10A1 route for conjugated bile salts and the sodium-independent OATP route for unconjugated and some conjugated species - which is modelled here as a variant set. Two paralogous members of one family (PANTHER:PTHR10361) supply the two sodium-coupled steps at opposite epithelial poles, and PAINT resolves this as a sub-branch split: the apical ileal node and the basolateral hepatic node are distinct ancestral nodes within the family. Loss of any single step produces a recognisable human disorder, which is the clearest evidence that the steps are required parts rather than redundant routes.' status: DRAFT scope: CONCRETE evidence: - source_id: GO:0015721 title: bile acid and bile salt transport statement: The module is grounded in bile acid and bile salt transport (GO:0015721); every part is a transport or cargo-binding step for bile salts, and each member protein carries this term. - source_id: Reactome:R-HSA-159418 title: Recycling of bile acids and salts statement: The step order and membership follow the human Reactome pathway "Recycling of bile acids and salts", which names ileal uptake by ASBT (SLC10A2), cytosolic traversal by ileal bile acid binding protein (FABP6), efflux from enterocytes, and hepatocyte uptake by NTCP (SLC10A1) with a lesser contribution from the organic anion transporting polypeptides. - source_id: PMID:33222321 title: Targeting the Four Pillars of Enterohepatic Bile Salt Cycling; Lessons From Genetics and Pharmacology statement: This review frames the cycle as four transporter "pillars" (BSEP, ASBT, OSTalpha/beta, NTCP), each with a human loss-of-function phenotype, which is the boundary adopted here; FABP6 is added as the cytosolic step named by Reactome. - source_id: PMID:35545671 title: Structural basis of sodium-dependent bile salt uptake into the liver. statement: Establishes the gated-pore sodium-coupled mechanism of the hepatic uptake step (UniProtKB:Q14973) and that NTCP is the main bile salt uptake system of the liver. - source_id: PMID:24867799 title: 'Sodium taurocholate cotransporting polypeptide (SLC10A1) deficiency: conjugated hypercholanemia without a clear clinical phenotype.' statement: Human NTCP deficiency gives extreme conjugated hypercholanemia with residual enterohepatic cycling, evidence that the basolateral hepatic uptake step is required for efficient recapture but is partly bypassed by the sodium-independent route modelled in the variant set. - source_id: file:human/SLC10A1/SLC10A1-ai-review.yaml title: SLC10A1 gene review (human) statement: The hepatic basolateral uptake step (UniProtKB:Q14973, GO:0008508, GO:0016323) matches the completed human SLC10A1 review, whose core function is sodium-coupled bile salt import at the basolateral plasma membrane. - source_id: file:human/SLC10A2/SLC10A2-ai-review.yaml title: SLC10A2 gene review (human) statement: The ileal apical uptake step (UniProtKB:Q12908, GO:0008508, GO:0016324) matches the human SLC10A2 review; SLC10A2 is the apical paralogue of the same PANTHER family. - source_id: PANTHER:PTN002570905 title: PANTHER:PTN002570905 statement: PAINT ancestral node supporting basolateral plasma membrane localization for the hepatic NTCP sub-branch; recovered from the GO_REF:0000033 WITH/FROM evidence on UniProtKB:Q14973 GO:0016323. - source_id: PANTHER:PTN002570923 title: PANTHER:PTN002570923 statement: PAINT ancestral node supporting apical plasma membrane localization for the ileal ASBT sub-branch; recovered from the GO_REF:0000033 WITH/FROM evidence on UniProtKB:Q12908 GO:0016324. The existence of two distinct nodes for the two poles is the phylogenetic counterpart of the apical/basolateral split modelled in this module. - source_id: PANTHER:PTN000040761 title: PANTHER:PTN000040761 statement: PAINT ancestral node for sodium-coupled bile acid symport shared by both SLC10 sub-branches; recovered from the GO_REF:0000033 WITH/FROM evidence on GO:0008508 for UniProtKB:Q14973 and UniProtKB:Q12908. notes: 'Scope: Vertebrate enterohepatic transport relay for conjugated bile salts, bounded at the membrane transport steps that move bile salts between hepatocyte, bile, intestinal lumen, enterocyte and portal blood. Bile acid synthesis from cholesterol, side-chain conjugation, bacterial deconjugation and dehydroxylation in the colon, and FXR/FGF19 transcriptional feedback are adjacent modules and are deliberately outside this boundary; they are referred to here only as the source, modification and regulation of the cargo this module moves. No module-level deep research report accompanies this module: the deep-research providers configured in this checkout were unavailable when it was written (Falcon returned 402 Payment Required, OpenAI 401), so the module was assembled from Reactome, the cached publications and the SLC10 gene reviews in this repository. Five participants - ABCB11, SLC51A, SLC51B, FABP6 and SLCO1B1 - do not yet have gene reviews here, so module QC will report them as coverage gaps; they are grounded on UniProt and PANTHER identifiers only. Bacterial modification of the cargo (deconjugation, 7-alpha-dehydroxylation) changes which species each transporter sees but adds no step performed by a host gene product, so it is left out of the parts list. Sodium stoichiometry is written inconsistently across the sources cited here, and the module deliberately lists sodium(1+) as a substrate without a coefficient rather than picking a side. Reactome:R-HSA-194187 writes the ASBT reaction with one Na+ per bile salt, while voltage-clamp measurement of the human transporter gives 2:1 (a 3-fold drop in extracellular Na+ shifted the flux-voltage relationship by -52 mV, PMID:9856990) and UniProt''s curated RHEA reactions for both SLC10A1 and SLC10A2 (e.g. RHEA:71875) use two. GO:0008508 does not fix the stoichiometry, so the annotations stand either way. This is recorded here rather than as a knowledge gap because the quantity is settled experimentally; what differs is how two databases wrote it down, which a curator resolves and no experiment would. ABCB11 has two conflicting PANTHER assignments: PANTHER''s own classification file places it in PTHR24221:SF165 "BILE SALT EXPORT PUMP", which this module uses, while UniProt''s PANTHER cross-reference points to PTHR43394:SF23, in a family named for the mitochondrial MDL1 permease. The member index keeps both. A reasoned row in interpro/panther/panther-members-overrides.tsv would record the adjudication permanently; it has not been added because the disagreement is about family boundaries in the wider ABCB clade rather than about this module. That is a curator writing a row, not an open question about the biology, which is why it sits here and not in knowledge_gaps.' module: id: enterohepatic_bile_salt_cycling label: Enterohepatic bile salt cycling module_type: METABOLIC_PATHWAY description: Closed-loop transport relay that recirculates conjugated bile salts between liver and terminal ileum, modelled as five ordered transport/cargo-binding steps with a two-route variant set at the hepatic uptake step. concepts: - preferred_term: bile acid and bile salt transport term: id: GO:0015721 label: bile acid and bile salt transport description: The process the module implements; each part moves or carries bile salts across a membrane or compartment. - preferred_term: bile acid metabolic process term: id: GO:0008206 label: bile acid metabolic process description: 'Broader context: recirculation is the conservation arm of bile acid metabolism, limiting de novo synthesis from cholesterol.' context: taxa: - preferred_term: Mammalia term: id: NCBITaxon:40674 label: Mammalia description: The relay is described here for mammals, where all five steps and their loss-of-function phenotypes are established; the SLC10 and ABCB family members are vertebrate-wide. anatomical_locations: - preferred_term: liver description: Hepatocytes perform canalicular export and basolateral reuptake. - preferred_term: terminal ileum description: Ileal enterocytes perform apical reclamation and basolateral efflux. parts: - order: 1 role: ATP-driven bile salt export from hepatocyte into bile (canalicular) node: id: bsep_export_step label: bile salt export into bile by BSEP (ABCB11) module_type: TRANSPORT_STEP annotons: - id: bsep_activity label: 'ABCB11/BSEP: ATP-dependent bile salt export pump' participant: selector_type: FAMILY family: preferred_term: ABC transporter subfamily B, bile salt export pump branch term: id: PANTHER:PTHR24221:SF165 label: BILE SALT EXPORT PUMP description: PANTHER subfamily for the bile salt export pump, within family PTHR24221 (ATP-BINDING CASSETTE SUB-FAMILY B). Grounded at subfamily level because the family spans 168 subfamilies of unrelated ABCB activities. UniProt's PANTHER cross-reference for ABCB11 instead points to PTHR43394:SF23; the PANTHER classification is preferred here. representative_members: - preferred_term: ABCB11/BSEP (human) term: id: UniProtKB:O95342 label: Bile salt export pump function: preferred_term: ABC-type bile acid transporter activity term: id: GO:0015432 label: ABC-type bile acid transporter activity substrates: - preferred_term: conjugated bile salt (cytosolic) - preferred_term: ATP products: - preferred_term: conjugated bile salt (bile canaliculus) evidence: - source_id: PMID:33222321 statement: BSEP is the canalicular export pillar of the cycle; its loss causes progressive familial intrahepatic cholestasis type 2. processes: - preferred_term: bile acid and bile salt transport term: id: GO:0015721 label: bile acid and bile salt transport locations: - preferred_term: apical plasma membrane term: id: GO:0016324 label: apical plasma membrane description: The hepatocyte canalicular membrane is the apical pole of the hepatocyte. role_description: Rate-limiting, ATP-driven step that concentrates bile salts into bile against a steep gradient; it both drives bile flow and sets the luminal load that the ileal steps later reclaim. - order: 2 role: sodium-coupled reclamation across the ileal brush border (apical) node: id: asbt_uptake_step label: ileal bile salt uptake by ASBT (SLC10A2) module_type: TRANSPORT_STEP annotons: - id: asbt_activity label: 'SLC10A2/ASBT: apical sodium-dependent bile acid transporter' participant: selector_type: FAMILY family: preferred_term: SLC10 sodium/bile acid cotransporter family, apical ileal branch term: id: PANTHER:PTHR10361 label: SODIUM-BILE ACID COTRANSPORTER representative_members: - preferred_term: SLC10A2/ASBT (human) term: id: UniProtKB:Q12908 label: Ileal sodium/bile acid cotransporter ancestral_nodes: - preferred_term: apical SLC10 sub-branch node term: id: PANTHER:PTN002570923 label: PTN002570923 description: PAINT node carrying apical plasma membrane localization for the ileal branch, from the GO_REF:0000033 WITH/FROM evidence on GO:0016324 for UniProtKB:Q12908. evidence: - source_id: GO_REF:0000033 statement: 'PAINT ancestral node assertion: GO:0016324 apical plasma membrane, IBD seeded by MGI:MGI:1201406 and RGD:3682 (mouse and rat Slc10a2) per interpro/panther/PTHR10361/PTHR10361-paint.tsv' - preferred_term: SLC10 sodium/bile acid symport node term: id: PANTHER:PTN000040761 label: PTN000040761 description: PAINT node carrying sodium-coupled bile acid symport, shared with the hepatic branch. evidence: - source_id: GO_REF:0000033 statement: 'PAINT ancestral node assertion: GO:0008508 bile acid:sodium symporter activity and GO:0015721 bile acid and bile salt transport, IBD seeded by RGD:3681 and RGD:3682 (rat Slc10a1 and Slc10a2) per interpro/panther/PTHR10361/PTHR10361-paint.tsv' function: preferred_term: bile acid:sodium symporter activity term: id: GO:0008508 label: bile acid:sodium symporter activity substrates: - preferred_term: conjugated bile salt (intestinal lumen) - preferred_term: sodium(1+) term: id: CHEBI:29101 label: sodium(1+) products: - preferred_term: conjugated bile salt (enterocyte cytosol) evidence: - source_id: Reactome:R-HSA-194187 statement: Reactome models ileal uptake of bile salts with sodium by SLC10A2 at the apical membrane. - source_id: PMID:9458785 statement: The ileal/renal sodium-dependent bile acid transporter retains a narrow specificity for reclamation of bile acids, in contrast to the multispecific liver transporter. processes: - preferred_term: bile acid and bile salt transport term: id: GO:0015721 label: bile acid and bile salt transport locations: - preferred_term: apical plasma membrane term: id: GO:0016324 label: apical plasma membrane role_description: Reclaims conjugated bile salts from the ileal lumen using the inward sodium gradient; the committed step of recovery, and the target of pharmacological ASBT inhibitors used to divert bile salts into the colon. - order: 3 role: cytosolic traversal of the enterocyte by a soluble carrier node: id: fabp6_shuttle_step label: cytosolic bile salt binding by FABP6 (ileal bile acid binding protein) module_type: TRANSPORT_STEP annotons: - id: fabp6_activity label: 'FABP6/I-BABP: ileal bile acid binding protein (gastrotropin)' participant: selector_type: FAMILY family: preferred_term: Intracellular lipid-binding protein (FABP) family term: id: PANTHER:PTHR11955:SF69 label: GASTROTROPIN description: PANTHER subfamily for the ileal bile acid binding protein, within the FATTY ACID BINDING PROTEIN family (PTHR11955); the family itself spans lipid-binding proteins with unrelated ligands, so the bile-acid-binding role is a subfamily-level claim. representative_members: - preferred_term: FABP6 (human) term: id: UniProtKB:P51161 label: Gastrotropin (ileal bile acid binding protein) function: preferred_term: bile acid binding term: id: GO:0032052 label: bile acid binding substrates: - preferred_term: conjugated bile salt (enterocyte cytosol) products: - preferred_term: FABP6-bound bile salt evidence: - source_id: Reactome:R-HSA-159418 statement: Reactome names traversal of the enterocyte cytosol as mediated by ileal bile acid binding protein (I-BABP, FABP6). locations: - preferred_term: cytosol term: id: GO:0005829 label: cytosol role_description: Binds the imported bile salt in the enterocyte cytosol, keeping free detergent concentrations low and delivering cargo to the basolateral efflux step. A cargo-binding rather than membrane-transport role; it is included because the relay has no other mechanism for crossing the cell. - order: 4 role: basolateral efflux from the enterocyte into portal blood node: id: ost_efflux_step label: basolateral bile salt efflux by the OSTalpha/OSTbeta heteromer module_type: PROTEIN_COMPLEX description: 'OSTalpha and OSTbeta are an obligate heteromer: neither subunit traffics to the plasma membrane or transports on its own, so the activity is modelled on the complex with both subunits visible as active units.' annotons: - id: osta_activity label: 'SLC51A/OSTalpha: organic solute transporter subunit alpha' participant: selector_type: FAMILY family: preferred_term: Organic solute transporter alpha family term: id: PANTHER:PTHR23423:SF11 label: ORGANIC SOLUTE TRANSPORTER SUBUNIT ALPHA description: PANTHER subfamily for OSTalpha within PTHR23423 (ORGANIC SOLUTE TRANSPORTER-RELATED). representative_members: - preferred_term: SLC51A/OSTalpha (human) term: id: UniProtKB:Q86UW1 label: Organic solute transporter subunit alpha function: preferred_term: bile acid transmembrane transporter activity term: id: GO:0015125 label: bile acid transmembrane transporter activity substrates: - preferred_term: conjugated bile salt (enterocyte cytosol) products: - preferred_term: conjugated bile salt (portal blood) evidence: - source_id: PMID:33222321 statement: OSTalpha/OSTbeta is the basolateral efflux pillar of enterohepatic cycling. processes: - preferred_term: bile acid and bile salt transport term: id: GO:0015721 label: bile acid and bile salt transport locations: - preferred_term: basolateral plasma membrane term: id: GO:0016323 label: basolateral plasma membrane role_description: Multi-pass subunit that forms the translocation pathway; requires OSTbeta for maturation and surface delivery. - id: ostb_activity label: 'SLC51B/OSTbeta: organic solute transporter subunit beta' participant: selector_type: FAMILY family: preferred_term: Organic solute transporter beta family term: id: PANTHER:PTHR36129 label: ORGANIC SOLUTE TRANSPORTER SUBUNIT BETA-RELATED representative_members: - preferred_term: SLC51B/OSTbeta (human) term: id: UniProtKB:Q86UW2 label: Organic solute transporter subunit beta function: preferred_term: bile acid transmembrane transporter activity term: id: GO:0015125 label: bile acid transmembrane transporter activity evidence: - source_id: PMID:33222321 statement: The beta subunit is required for the transport function of the OST heteromer; human SLC51B deficiency causes congenital chronic diarrhoea with cholestasis. locations: - preferred_term: basolateral plasma membrane term: id: GO:0016323 label: basolateral plasma membrane role_description: Small ancillary subunit required for OSTalpha folding, trafficking and activity; it contributes to, rather than independently possessing, the transport activity. - order: 5 role: hepatocyte basolateral reuptake from portal blood, closing the cycle node: id: hepatic_uptake_step label: hepatic sinusoidal bile salt uptake module_type: TRANSPORT_STEP description: Two parallel routes implement this step; they differ in sodium dependence and in which bile salt species they prefer, and are modelled as a variant set rather than as alternative modules. variant_sets: - id: hepatic_uptake_routes label: hepatic uptake route axis: coupling ion and substrate conjugation state variants: - id: ntcp_route label: sodium-dependent uptake by NTCP (SLC10A1) module_type: TRANSPORT_STEP annotons: - id: ntcp_activity label: 'SLC10A1/NTCP: sodium/taurocholate cotransporting polypeptide' participant: selector_type: FAMILY family: preferred_term: SLC10 sodium/bile acid cotransporter family, basolateral hepatic branch term: id: PANTHER:PTHR10361 label: SODIUM-BILE ACID COTRANSPORTER representative_members: - preferred_term: SLC10A1/NTCP (human) term: id: UniProtKB:Q14973 label: Hepatic sodium/bile acid cotransporter - preferred_term: Slc10a1/Ntcp (rat) term: id: UniProtKB:P26435 label: Hepatic sodium/bile acid cotransporter ancestral_nodes: - preferred_term: basolateral SLC10 sub-branch node term: id: PANTHER:PTN002570905 label: PTN002570905 description: PAINT node carrying basolateral plasma membrane localization for the hepatic branch, from the GO_REF:0000033 WITH/FROM evidence on GO:0016323 for UniProtKB:Q14973. Distinct from the apical node PTN002570923 used by the ileal branch. evidence: - source_id: GO_REF:0000033 statement: 'PAINT ancestral node assertion: GO:0016323 basolateral plasma membrane, IBD seeded by RGD:3681 (rat Slc10a1) per interpro/panther/PTHR10361/PTHR10361-paint.tsv' - preferred_term: SLC10 sodium/bile acid symport node term: id: PANTHER:PTN000040761 label: PTN000040761 description: PAINT node carrying sodium-coupled bile acid symport, shared with the apical ileal branch. evidence: - source_id: GO_REF:0000033 statement: 'PAINT ancestral node assertion: GO:0008508 bile acid:sodium symporter activity and GO:0015721 bile acid and bile salt transport, IBD seeded by RGD:3681 and RGD:3682 (rat Slc10a1 and Slc10a2) per interpro/panther/PTHR10361/PTHR10361-paint.tsv' function: preferred_term: bile acid:sodium symporter activity term: id: GO:0008508 label: bile acid:sodium symporter activity substrates: - preferred_term: conjugated bile salt (portal blood) - preferred_term: sodium(1+) term: id: CHEBI:29101 label: sodium(1+) products: - preferred_term: conjugated bile salt (hepatocyte cytosol) evidence: - source_id: PMID:35545671 statement: Human NTCP is the main bile salt uptake system in liver and operates by a gated-pore mechanism coupled to sodium. - source_id: file:human/SLC10A1/SLC10A1-ai-review.yaml statement: 'Core function of the completed human SLC10A1 review: sodium-coupled bile salt import at the hepatocyte basolateral plasma membrane.' processes: - preferred_term: bile acid and bile salt transport term: id: GO:0015721 label: bile acid and bile salt transport locations: - preferred_term: basolateral plasma membrane term: id: GO:0016323 label: basolateral plasma membrane role_description: Dominant route for conjugated bile salts; also the entry receptor for hepatitis B and D virus, a function unrelated to this module and not part of the relay. - id: oatp_route label: sodium-independent uptake by OATP1B1 (SLCO1B1) module_type: TRANSPORT_STEP annotons: - id: oatp1b1_activity label: 'SLCO1B1/OATP1B1: organic anion transporting polypeptide 1B1' participant: selector_type: FAMILY family: preferred_term: Organic anion transporting polypeptide (SLCO/OATP) family term: id: PANTHER:PTHR11388:SF82 label: SOLUTE CARRIER ORGANIC ANION TRANSPORTER FAMILY MEMBER 1B1 description: PANTHER subfamily for OATP1B1 within PTHR11388 (ORGANIC ANION TRANSPORTER); the family spans OATPs with very different substrate preferences, so the bile-salt-uptake role is a subfamily-level claim. representative_members: - preferred_term: SLCO1B1/OATP1B1 (human) term: id: UniProtKB:Q9Y6L6 label: Solute carrier organic anion transporter family member 1B1 function: preferred_term: bile acid transmembrane transporter activity term: id: GO:0015125 label: bile acid transmembrane transporter activity substrates: - preferred_term: bile salt (portal blood) products: - preferred_term: bile salt (hepatocyte cytosol) evidence: - source_id: Reactome:R-HSA-159418 statement: Reactome assigns hepatocyte uptake to NTCP (SLC10A1) and, to a lesser extent, to the organic anion transporting proteins. processes: - preferred_term: bile acid and bile salt transport term: id: GO:0015721 label: bile acid and bile salt transport locations: - preferred_term: basolateral plasma membrane term: id: GO:0016323 label: basolateral plasma membrane role_description: Sodium-independent, broad-specificity route contributing a minority of bile salt uptake; its persistence explains the residual enterohepatic cycling and the mild phenotype of human NTCP deficiency. notes: The sodium-dependent SLC10A1 route carries the bulk of conjugated bile salts; the sodium-independent OATP route carries unconjugated and some conjugated species and provides the residual cycling seen in human NTCP deficiency. connections: - source: bsep_export_step target: asbt_uptake_step connection_type: PRECEDES description: Canalicular export sets the luminal bile salt load that the ileal brush border later reclaims; the two steps are separated by bile storage, meal-triggered gallbladder contraction and intestinal transit. chaining_status: NOT_APPLICABLE chaining_note: Transport relay, not an acyl-CoA reaction chain; the shared entity is the bile salt itself in successive compartments, so CoA-continuity checking does not apply. - source: asbt_uptake_step target: fabp6_shuttle_step connection_type: PRECEDES description: Imported bile salt is handed to the cytosolic binding protein. chaining_status: NOT_APPLICABLE chaining_note: Transport relay; no CoA intermediate. - source: fabp6_shuttle_step target: ost_efflux_step connection_type: PRECEDES description: FABP6-bound bile salt is delivered to the basolateral membrane for efflux into portal blood. chaining_status: NOT_APPLICABLE chaining_note: Transport relay; no CoA intermediate. - source: ost_efflux_step target: hepatic_uptake_step connection_type: PRECEDES description: Bile salts effluxed into portal blood travel bound to albumin and are extracted by the hepatocyte sinusoidal membrane. chaining_status: NOT_APPLICABLE chaining_note: Transport relay; no CoA intermediate. - source: hepatic_uptake_step target: bsep_export_step connection_type: PRECEDES description: Reuptake returns bile salts to the hepatocyte cytosol, where they are available for canalicular export again; this edge closes the cycle, so the parts list is a loop rather than a linear chain. chaining_status: NOT_APPLICABLE chaining_note: Cycle-closing edge of a transport relay; no CoA intermediate, and the loop is intended rather than an ordering error. knowledge_gaps: - gap_statement: The quantitative split between the sodium-dependent and sodium-independent hepatic uptake routes is not settled. Human NTCP deficiency shows the OATP route is sufficient to sustain residual cycling, but the fraction each route carries in healthy liver, and whether it shifts with conjugation state or meal state, is unresolved. boundary: Firmly established are that NTCP is the main import system for conjugated bile salts into the hepatocyte, that the OATPs carry a sodium-independent share of the same step, and that the OATP route alone sustains enterohepatic cycling when NTCP is absent. What is not established is the fraction each route carries when both are present. gap_kind: - BIOLOGY status: OPEN provenance: - reference_id: PMID:24867799 supporting_text: The identification of NTCP deficiency confirms that this transporter is the main import system for conjugated bile salts into the liver but also indicates that auxiliary transporters are able to sustain the enterohepatic cycle in its absence. reference_section_type: ABSTRACT - gap_statement: FABP6 is modelled as a required cytosolic step because Reactome names it, but whether enterocyte traversal strictly depends on it, or whether free diffusion of bile salts can substitute, is not established; a FABP6-null phenotype in the relay would settle it. boundary: Firmly established are that FABP6 binds bile acids, that it is expressed in ileal enterocytes, and the order of the enterocyte leg (ASBT uptake, cytosolic traversal, basolateral export by OSTalpha/beta). What is not established is whether the cytosolic carrier step is obligatory, which is the sense in which this module marks it required. gap_kind: - BIOLOGY status: OPEN provenance: - reference_id: Reactome:R-HSA-159418 supporting_text: traversal of the enterocyte cytosol mediated by ileal bile acid binding protein (I-BABP - FABP6) reference_section_type: DATABASE_ENTRY