Details for: ABCG8

Gene ID: 64241

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: ABCG8

Ensembl ID: ENSG00000143921

Description: ATP binding cassette subfamily G member 8

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • midzonal region hepatocyte CL0019028
    CSI 4.54
    rCSI 10.66%
    PRS 97.01
  • centrilobular region hepatocyte CL0019029
    CSI 3.13
    rCSI 8.16%
    PRS 96.53
  • hepatocyte CL0000182
    CSI 3.04
    rCSI 5.45%
    PRS 97.41
  • periportal region hepatocyte CL0019026
    CSI 2.77
    rCSI 10.78%
    PRS 96.81
  • BEST4+ enteroycte CL4030026
    CSI 2.39
    rCSI 2.97%
    PRS 98.15
  • colonocyte CL1000347
    CSI 2.29
    rCSI 3.29%
    PRS 98.28

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

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  • Node Color (Target Cell CSI, relative to current network):
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    • High
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  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [ABCG8](/details-gene/64241) (ATP Binding Cassette Subfamily G Member 8) is a protein-coding gene located on chromosome 2p21 that encodes a member of the ATP-binding cassette (ABC) transporter superfamily. This protein, also known as sterolin-2, functions as a half-transporter that forms an obligate heterodimer with ABCG5 (sterolin-1) to actively transport neutral sterols, including cholesterol and plant sterols (phytosterols), across cellular membranes ([Link](https://doi.org/10.1074/jbc.m310223200)). The expression of [ABCG8](/details-gene/64241) is highly prominent in cells critical for lipid homeostasis, such as [hepatocytes](/details-cell/CL0000182) and intestinal [enterocytes](/details-cell/CL0000066), where it plays a key role in limiting intestinal absorption and promoting biliary excretion of sterols. Mutations in this gene are causally linked to sitosterolemia ([210250](https://omim.org/entry/210250)), a rare autosomal recessive disorder characterized by the accumulation of dietary sterols in the blood and tissues ([Link](https://doi.org/10.1086/321294)). Furthermore, genetic variants in [ABCG8](/details-gene/64241) are associated with susceptibility to gallstone disease ([Link](https://doi.org/10.1038/ng2101)). ## Cellular Roles and Expression Landscape The expression profile of [ABCG8](/details-gene/64241) underscores its specialized function in cholesterol and sterol metabolism, primarily within the liver and intestine. **Overall**, the gene shows its highest significance in liver cells, particularly [midzonal region hepatocyte](/details-cell/CL0019028) (CSI: 4.54), followed by [centrilobular region hepatocyte](/details-cell/CL0019029) (CSI: 3.13), and [periportal region hepatocyte](/details-cell/CL0019026) (CSI: 2.77). This distinct zonal expression pattern within the liver lobule suggests that its activity may be regulated by the unique metabolic microenvironments of each zone and highlights its central role in hepatic sterol handling. Beyond the liver, [ABCG8](/details-gene/64241) is a significant marker in intestinal epithelial cells, including [BEST4+ enteroycte](/details-cell/CL4030026) (CSI: 2.39) and [colonocyte](/details-cell/CL1000347) (CSI: 2.29). This expression pattern is consistent with its established role in limiting the absorption of dietary sterols from the gut lumen. The co-expression in both the primary site of sterol excretion (liver) and absorption (intestine) establishes [ABCG8](/details-gene/64241) as a master regulator of systemic sterol balance. The highly specific expression in these metabolically active cell types suggests a tightly controlled function, rather than a ubiquitous cellular role. ## Pathways and Molecular Function The functional annotations for [ABCG8](/details-gene/64241) confirm its role as a key component of lipid transport machinery. It is principally involved in the biological processes of 'sterol transport' ([GO:0015918](https://www.ebi.ac.uk/QuickGO/term/GO:0015918)), 'cholesterol efflux' ([GO:0033344](https://www.ebi.ac.uk/QuickGO/term/GO:0033344)), and the 'negative regulation of intestinal cholesterol absorption' ([GO:0045796](https://www.ebi.ac.uk/QuickGO/term/GO:0045796)). Its molecular function is defined by 'Abc-type transporter activity' ([GO:0140359](https://www.ebi.ac.uk/QuickGO/term/GO:0140359)) and 'Atp binding' ([GO:0005524](https://www.ebi.ac.uk/QuickGO/term/GO:0005524)), as the ABCG5/G8 heterodimer utilizes energy from ATP hydrolysis to drive sterol transport ([Link](https://doi.org/10.1021/bi0608055)). Cellularly, the transporter complex is localized to the 'apical plasma membrane' ([GO:0016324](https://www.ebi.ac.uk/QuickGO/term/GO:0016324)) of [hepatocytes](/details-cell/CL0000182) and [enterocytes](/details-cell/CL0000066), which is the correct orientation for excreting sterols into bile or back into the intestinal lumen. Reactome pathway analysis further reinforces its clinical relevance, directly implicating it in 'Abc transporter disorders' ([R-HSA-5619084](https://reactome.org/content/detail/R-HSA-5619084)) and noting that defects cause sitosterolemia and gallstone disease ('Defective abcg8 causes gbd4 and sitosterolemia' [R-HSA-5679090](https://reactome.org/content/detail/R-HSA-5679090)). Its regulation is also highlighted through its involvement in pathways mediated by nuclear receptors, such as 'Nr1h2 and nr1h3-mediated signaling' ([R-HSA-9024446](https://reactome.org/content/detail/R-HSA-9024446)), which are known sensors of cellular lipid levels. ## Research Directions The well-defined role of [ABCG8](/details-gene/64241) in sterol transport and its association with metabolic diseases provide a strong foundation for further investigation into its regulation and therapeutic modulation. **Proposed Hypotheses:** 1. The observed gradient of [ABCG8](/details-gene/64241) expression across liver zones (midzonal > centrilobular > periportal) is actively maintained by metabolic gradients of bile acids or oxygen tension within the liver lobule. Disruption of this zonal regulation may be an early event in the pathogenesis of cholesterol-related liver diseases. 2. Dietary factors, particularly the ratio of saturated fats to polyunsaturated fats and fiber, directly modulate the transcriptional activity or post-translational stability of the ABCG5/G8 transporter complex in intestinal [enterocytes](/details-cell/CL0000066), thereby altering an individual's genetic predisposition to hypercholesterolemia and gallstone disease. **Experimental Approach:** To test the first hypothesis regarding zonal regulation in the liver, a combination of spatial transcriptomics and in vitro modeling could be employed. Spatial transcriptomics on human liver biopsies from healthy and diseased (e.g., non-alcoholic steatohepatitis) donors would allow for the precise mapping of [ABCG8](/details-gene/64241) mRNA levels relative to markers of hepatocyte zonation and key metabolic pathways. This could be complemented by studies using primary human [hepatocytes](/details-cell/CL0000182) cultured in microfluidic devices that mimic the oxygen and nutrient gradients of the liver lobule. Changes in [ABCG8](/details-gene/64241) expression and sterol efflux capacity in response to these gradients could be quantified using qPCR, Western blot, and mass spectrometry-based lipidomics. **Therapeutic Potential:** [ABCG8](/details-gene/64241) represents a compelling therapeutic target for metabolic disorders. Since loss-of-function variants lead to sterol accumulation and variants are associated with gallstone disease, a therapeutic strategy would likely focus on **activation** of the transporter. Small molecule agonists that enhance the ATP hydrolysis rate or improve the trafficking and stability of the ABCG5/G8 complex at the plasma membrane could increase biliary cholesterol excretion. Such a strategy could offer a non-surgical treatment for cholesterol gallstones and may also have applications in lowering plasma LDL-cholesterol by promoting a key pathway for its elimination from the body.

Genular Protein ID: 3859500697

Symbol: ABCG8_HUMAN

Name: N/A

UniProtKB Accession Codes:

Q9H221 Q53QN8

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CORUM 1 CTD 1 ChEBI 13 DIP 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 2 EMBL 16 EMDB 6 Ensembl 1 ExpressionAtlas 1 GO 24 Gene3D 1 GeneCards 1 GeneReviews 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 6 KEGG 1 MANE-Select 1 MIM 5 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 2 OrthoDB 1 PANTHER 2 PDB 8 PDBsum 8 PRO 1 PROSITE 2 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 3 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 RNAct 1 Reactome 4 RefSeq 2 Rhea 4 SIGNOR 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TCDB 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 11099417

Title: Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters.

PubMed ID: 11099417

DOI: 10.1126/science.290.5497.1771

PubMed ID: 11452359

Title: Two genes that map to the STSL locus cause sitosterolemia: genomic structure and spectrum of mutations involving sterolin-1 and sterolin-2, encoded by ABCG5 and ABCG8, respectively.

PubMed ID: 11452359

DOI: 10.1086/321294

PubMed ID: 15815621

Title: Generation and annotation of the DNA sequences of human chromosomes 2 and 4.

PubMed ID: 15815621

DOI: 10.1038/nature03466

PubMed ID: 11590207

Title: Role of ABCG1 and other ABCG family members in lipid metabolism.

PubMed ID: 11590207

PubMed ID: 14504269

Title: ABCG5 and ABCG8 are obligate heterodimers for protein trafficking and biliary cholesterol excretion.

PubMed ID: 14504269

DOI: 10.1074/jbc.m310223200

PubMed ID: 16893193

Title: Purification and ATP hydrolysis of the putative cholesterol transporters ABCG5 and ABCG8.

PubMed ID: 16893193

DOI: 10.1021/bi0608055

PubMed ID: 20210363

Title: Bile acids stimulate ATP hydrolysis in the purified cholesterol transporter ABCG5/G8.

PubMed ID: 20210363

DOI: 10.1021/bi902064g

PubMed ID: 24275569

Title: An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome.

PubMed ID: 24275569

DOI: 10.1016/j.jprot.2013.11.014

PubMed ID: 27144356

Title: Crystal structure of the human sterol transporter ABCG5/ABCG8.

PubMed ID: 27144356

DOI: 10.1038/nature17666

PubMed ID: 11668628

Title: Mutations in ATP-cassette binding proteins G5 (ABCG5) and G8 (ABCG8) causing sitosterolemia.

PubMed ID: 11668628

DOI: 10.1002/humu.1206

PubMed ID: 12111378

Title: Catalog of 605 single-nucleotide polymorphisms (SNPs) among 13 genes encoding human ATP-binding cassette transporters: ABCA4, ABCA7, ABCA8, ABCD1, ABCD3, ABCD4, ABCE1, ABCF1, ABCG1, ABCG2, ABCG4, ABCG5, and ABCG8.

PubMed ID: 12111378

DOI: 10.1007/s100380200041

PubMed ID: 15054092

Title: Missense mutations in ABCG5 and ABCG8 disrupt heterodimerization and trafficking.

PubMed ID: 15054092

DOI: 10.1074/jbc.m402634200

PubMed ID: 17632509

Title: A genome-wide association scan identifies the hepatic cholesterol transporter ABCG8 as a susceptibility factor for human gallstone disease.

PubMed ID: 17632509

DOI: 10.1038/ng2101

Sequence Information:

  • Length: 673
  • Mass: 75679
  • Checksum: 594AFD1D6C1BB50F
  • Sequence:
    • MAGKAAEERG LPKGATPQDT SGLQDRLFSS ESDNSLYFTY SGQPNTLEVR DLNYQVDLAS 
QVPWFEQLAQ FKMPWTSPSC QNSCELGIQN LSFKVRSGQM LAIIGSSGCG RASLLDVITG 
RGHGGKIKSG QIWINGQPSS PQLVRKCVAH VRQHNQLLPN LTVRETLAFI AQMRLPRTFS 
QAQRDKRVED VIAELRLRQC ADTRVGNMYV RGLSGGERRR VSIGVQLLWN PGILILDEPT 
SGLDSFTAHN LVKTLSRLAK GNRLVLISLH QPRSDIFRLF DLVLLMTSGT PIYLGAAQHM 
VQYFTAIGYP CPRYSNPADF YVDLTSIDRR SREQELATRE KAQSLAALFL EKVRDLDDFL 
WKAETKDLDE DTCVESSVTP LDTNCLPSPT KMPGAVQQFT TLIRRQISND FRDLPTLLIH 
GAEACLMSMT IGFLYFGHGS IQLSFMDTAA LLFMIGALIP FNVILDVISK CYSERAMLYY 
ELEDGLYTTG PYFFAKILGE LPEHCAYIII YGMPTYWLAN LRPGLQPFLL HFLLVWLVVF 
CCRIMALAAA ALLPTFHMAS FFSNALYNSF YLAGGFMINL SSLWTVPAWI SKVSFLRWCF 
EGLMKIQFSR RTYKMPLGNL TIAVSGDKIL SVMELDSYPL YAIYLIVIGL SGGFMVLYYV 
SLRFIKQKPS QDW