ABCA1 (ATP-Binding Cassette Subfamily A Member 1 Cholesterol Efflux Gene)
ABCA1 (ATP binding cassette subfamily A member 1; HGNC:29, NCBI Gene ID 19) is a human locus mapped to chromosome band 9q31.1 that encodes full-transporter ATP-binding cassette sterol/phospholipid floppase ABCA1 (2,261 aa). ABCA1 acts in nascent HDL biogenesis, macrophage reverse cholesterol transport & brain ApoE lipidation, together with ABCG1 (Macrophage HDL Cholesterol Efflux Gene), APOA1 (Apolipoprotein A-I Gene), and APOE (Apolipoprotein E Gene). Encodes the ATP-binding cassette transporter ABCA1 that exports cellular cholesterol and phospholipids onto lipid-poor ApoA-I and ApoE.
Genomic Organization & Cytogenetic Locus: 50-exon gene spanning 149 kb on chromosome 9q31.1 with a proximal promoter strongly activated by oxysterol-sensing liver X receptors (LXR-alpha/beta heterodimerized with RXRA) and post-transcriptionally repressed by intron-encoded miR-33a/miR-33b.
Cellular & Tissue Expression Profile: Widely expressed across hepatic hepatocytes (which generate ~70–80% of plasma nascent HDL), arterial wall macrophages (foam cells), small intestinal enterocytes, and central nervous system astrocytes and microglia.
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Uses ATP hydrolysis across two cytoplasmic nucleotide-binding domains to flop phosphatidylcholine and unesterified cholesterol across two 6-helix transmembrane bundles into two large extracellular domains, transferring lipids directly onto lipid-free apolipoprotein A-I (APOA1) in periphery/liver and apolipoprotein E (APOE) in the brain.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Biallelic loss-of-function mutations cause Tangier disease, an autosomal recessive disorder characterized by near-complete absence of plasma HDL-cholesterol (<5 mg/dL), rapid catabolism of unlipidated ApoA-I, cholesteryl ester-laden macrophages producing enlarged orange-yellow tonsils, hepatosplenomegaly, and peripheral demyelinating neuropathy, while loss-of-function variants also increase Alzheimer disease risk via impaired brain ApoE lipidation.
Therapeutic & Clinical Pharmacology: Up-regulated transcriptionally by LXR agonists and anti-miR-33a/b oligonucleotides to promote macrophage reverse cholesterol transport, atherosclerotic plaque regression, and enhanced APOE4 lipidation in Alzheimer disease models.