Enterocyte apical sterol uptake and efflux — NPC1L1 uptake opposed by ABCG5/ABCG8 export

Net absorption of dietary and biliary sterols across the small intestine is set at the enterocyte brush-border membrane by two opposing transport activities. Niemann-Pick C1-like 1 (NPC1L1) binds free cholesterol through its luminal N-terminal domain and takes it up into the cell by sterol-induced, clathrin/AP2-dependent endocytosis of NPC1L1 with cholesterol-enriched membrane; NPC1L1 favours cholesterol over plant sterols and is the target of the absorption inhibitor ezetimibe. The ATP-binding cassette heterodimer ABCG5/ABCG8 exports neutral sterols, especially plant sterols such as sitosterol and part of the absorbed cholesterol, from the apical membrane back into the lumen; the same transporter on the hepatocyte canalicular membrane secretes sterols into bile. The balance of uptake and efflux limits net sterol absorption and keeps plant sterols out of the circulation. NPC1L1 loss-of-function variants lower LDL cholesterol, whereas biallelic loss of ABCG5 or ABCG8 causes sitosterolaemia, with plant-sterol accumulation and premature atherosclerosis.

MODULE:intestinal_sterol_absorption_and_effluxDRAFTTransport Stepmodules/intestinal_sterol_absorption_and_efflux.yaml
intestinal cholesterol absorptionGO:0030299
GO:0030299
intestinal cholesterol absorption
The module is grounded in intestinal cholesterol absorption and its negative regulation by apical sterol efflux.
file:human/NPC1L1/NPC1L1-ai-review.yaml
NPC1L1 gene review (human)
The uptake step (UniProtKB:Q9UHC9, GO:0015485 cholesterol binding, directly involved in GO:0030299 and GO:0030301, apical plasma membrane) matches the completed human NPC1L1 review.
file:human/ABCG5/ABCG5-ai-review.yaml
ABCG5 gene review (human)
ABCG5 (UniProtKB:Q9H222) contributes to GO:0034041 ABC-type sterol transporter activity as part of the ABCG5/ABCG8 heterodimer at the apical plasma membrane, directly involved in GO:0045796 negative regulation of intestinal cholesterol absorption.
file:human/ABCG8/ABCG8-ai-review.yaml
ABCG8 gene review (human)
ABCG8 (UniProtKB:Q9H221) contributes to GO:0034041 ABC-type sterol transporter activity in the same heterodimer, directly involved in GO:0045796 and GO:0010949.

Concrete vertebrate (human-represented) module limited to the apical membrane transport steps that set net sterol absorption. GO terms follow the core_functions of the completed human NPC1L1, ABCG5 and ABCG8 reviews; PANTHER subfamily ids and labels are from interpro/panther/panther.obo and match each protein's PANTHER human classification. Trafficking partners of NPC1L1 (NUMB, LIMA1, the myosin Vb-Rab11a-Rab11-FIP2 recycling complex, clathrin/AP2) are NPC1L1 cargo machinery and are named only here. Downstream intracellular steps (sterol transfer to the ER, esterification by SOAT2/ACAT2, packaging into chylomicrons by MTTP and APOB-48) have no or partial reviews and are outside this boundary; basolateral efflux to HDL by ABCA1 is likewise not modelled. Hepatic canalicular secretion of sterols into bile by ABCG5/ABCG8 uses the same transporter and is mentioned in the role description rather than as a separate part. Human NPC1L1 is also expressed on the hepatocyte canalicular membrane, where it retrieves biliary cholesterol; that hepatic cycle is not modelled separately.

3Nodes
2Parts
0Variant Sets
0Variants
2Annotons
1Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:intestinal_sterol_absorption_and_efflux deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

1 gene-function check(s) reflected in core functions · 0 conflict(s) · 1 evidence or coverage gap(s) (3 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
npc1l1_cholesterol_uptake NPC1L1 (human)
UniProtKB:Q9UHC9
Family Representative 		cholesterol binding
GO:0015485 		Core Supported
The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
abcg5_abcg8_sterol_export PROTEIN_COMPLEX
Gene 		ABC-type sterol transporter activity
GO:0034041 		Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
npc1l1_cholesterol_uptake NPC1-like intracellular cholesterol transporter 1
PANTHER:PTHR45727:SF3
Family 		cholesterol binding
GO:0015485 		Family Review Missing
No supported structured family review is available for PANTHER:PTHR45727:SF3.

Feedback loops (advisory, prose-driven: a regulator counts as "feedback" when its own description says so)

✓ every negative regulator described as feedback has an upstream edge closing the loop.

  • abcg5_abcg8_efflux ⊣ npc1l1_uptake [input]
    abcg5_abcg8_efflux is a negative regulator with no upstream edge (not described as feedback)

Gene-review completeness (3/3 grounded genes reviewed)

1 complete review(s) · 1 with deep research · 0 missing review · 2 reviewed but lacking deep research

Gene Review Complete Deep research
ABCG5 Q9H222 ✓ 47/53 ✗
ABCG8 Q9H221 ✓ 42/47 ✗
NPC1L1 Q9UHC9 ✓ ✓ ✓

Details

Context
Homo sapiensNCBITaxon:9606
apical plasma membraneGO:0016324
Enterocyte apical sterol uptake and effluxTransport Stepintestinal_sterol_absorption_and_efflux
intestinal cholesterol absorptionGO:0030299
Context
Homo sapiensNCBITaxon:9606
apical plasma membraneGO:0016324

Connections

abcg5_abcg8_efflux -> npc1l1_uptake Negatively Regulates
Apical ABCG5/ABCG8 efflux returns absorbed sterols (especially plant sterols) to the lumen, opposing NPC1L1-mediated uptake and lowering net sterol absorption.
Part 1: apical sterol uptake
NPC1L1 binds luminal cholesterol and internalizes it by sterol-induced endocytosisTransport Stepnpc1l1_uptake

Annotons

NPC1L1: apical cholesterol-uptake protein
npc1l1_cholesterol_uptake
Participant: Family: NPC1-like intracellular cholesterol transporter 1
Family:
NPC1-like intracellular cholesterol transporter 1PANTHER:PTHR45727:SF3
Representative Members: NPC1L1 (human)UniProtKB:Q9UHC9

Function

cholesterol bindingGO:0015485 The N-terminal domain binds cholesterol. GO has no current term that fits the uptake activity itself: GO:0015248 sterol transporter activity is obsolete, and the current GO:0120015 sterol transfer activity and GO:0120020 cholesterol transfer activity describe soluble carriers that ferry a sterol through the aqueous phase between membranes, whereas NPC1L1 stays in the apical membrane and moves the sterol through a channel inside itself. The transport role is therefore carried by the processes and role_description; the NPC1L1 review proposes a term for the activity.

Processes

intestinal cholesterol absorptionGO:0030299 cholesterol transportGO:0030301

Locations

apical plasma membraneGO:0016324

Required for most intestinal cholesterol absorption (NPC1L1-null mice) and the direct target of ezetimibe; also takes up alpha-tocopherol by the same mechanism.

Part 2: apical sterol efflux back to the lumen (and into bile)
ABCG5/ABCG8 heterodimer exports neutral sterols from the apical membraneTransport Stepabcg5_abcg8_efflux

Annotons

ABCG5/ABCG8: ATP-driven neutral sterol exporter
abcg5_abcg8_sterol_export
Participant: Protein Complex: ABCG5/ABCG8 sterol transporter heterodimer
Protein Complex:
ABCG5/ABCG8 sterol transporter heterodimerGO:0043190
Active units:
ABCG5 half-transporter
Participant: Family: ATP-binding cassette sub-family G member 5
Family:
ATP-binding cassette sub-family G member 5PANTHER:PTHR48041:SF113
Representative Members: ABCG5 (human)UniProtKB:Q9H222
Role: Contributes a transmembrane domain and the Walker motifs of the active composite ATPase site.
ABCG8 half-transporter
Participant: Family: ATP-binding cassette sub-family G member 8
Family:
ATP-binding cassette sub-family G member 8PANTHER:PTHR48041:SF71
Representative Members: ABCG8 (human)UniProtKB:Q9H221
Role: Contributes a transmembrane domain and the signature motif of the active composite ATPase site.

Function

ABC-type sterol transporter activityGO:0034041
Substrates: cholesterol plant sterols (sitosterol, campesterol)

Processes

negative regulation of intestinal cholesterol absorptionGO:0045796 negative regulation of intestinal phytosterol absorptionGO:0010949

Locations

apical plasma membraneGO:0016324

Obligate heterodimer; neither half-transporter is active alone. Biallelic loss of either subunit causes sitosterolaemia. The same transporter on the hepatocyte canalicular membrane drives biliary sterol secretion.