3.A.1.211.14
cAMP-dependent and sulfonylurea-sensitive anion transporter, ABCA1 (ABCAI) of 2261 aas and possibly 8 TMSs in a 1 + 2 + 4 + 1 TMS arrangement. It is a key gatekeeper catalyzing intracellular phospholipid and cholesterol transport (Orlowski et al. 2007).  It interacts with the MEGF10 protein and is 95% identical to the mouse orthologue, 3.A.1.211.1.  Cholesterol efflux from THP-1 macrophages decreases in the presence of plasma obtained from humans and rats with mild hyperbilirubinemia. A direct effect of unconjugated bilirubin on cholesterol efflux was demonstrated and is associated with decreased ABCA1 protein expression (Wang et al. 2017). A cryoEM structure (4.1 Å) revealed that the two transmembrane domains contact each other through a narrow interface in the intracellular leaflet of the membrane, and two extracellular domains of ABCA1 enclose an elongated hydrophobic tunnel. Structural mapping of dozens of disease-related mutations allowed potential interpretation of their diverse pathogenic mechanisms. Structure-based analyses suggested a plausible "lateral access" mechanism for ABCA1-mediated lipid export that may be distinct from the conventional alternating-access paradigm. ABCA1 acts in concert with ABCB1, ABCG2 and ABCG4 to efflux amyloid-β peptide (Aβ) from the brain across the blood-brain barrier (BBB) (Kuai et al. 2018). One substrate of systems ABCA1, ABCB1 and ABCC1 is arsenate, where ABCC1 is most effective while ABCA1 and ABCB1 are less effective (Zhou et al. 2018). ABCA1 transports lipids and cholesterol to apolipoprotein E (APOE) (Castranio et al. 2018). Cholesterol binding to ABCA1 may interfere with ATP binding in both nucleotide-binding domains of the ABCA1 structure (Dergunov et al. 2018).  Adiponectin, possibly acting through AdipoR1 and AdipoR2, plays a key role in promoting ABCA1-dependent cholesterol efflux (Hafiane et al. 2019). Reverse cholesterol transport or cholesterol efflux is part of an extensive plasma membranes remodelling process in spermatozoa that induces hyperactivated motility and is imperative for fertilization. Cholesterol efflux depends on high density lipoproteins (HDLs) that interact with transmembrane cholesterol transporters, such as ABCA1 and scavenger receptor class B, type I (SR-BI; TC# 9.B.39.1.3) (Bernecic et al. 2021). Smoking can influence the expression of the ABCA1 gene, thereby modulating lipid transport processes in macrophages, which are part of the mechanisms of inflammation development (Kotlyarov and Kotlyarova 2021). The cavity enclosed within the ATP-unbound form of ABCA1 is narrow at the distal ends of the TMD as well as the ECD region, substantiating the "lateral access" theory (Sunidhi et al. 2021). Curcumin ameliorates lipid metabolic disorder and cognitive dysfunction via ABCA1 (Tian et al. 2021). Insulin downregulates the expression of ABC A-I in human hepatoma cell line HepG2 in a FOXO1 and LXR-dependent manner (Shavva et al. 2022). Loss of function of the ABCA1 gene results in low levels of HDL as well as a concomitant reduction in plasma HexCer levels (Iqbal et al. 2022). Inflammation and immunomodulatory therapies influence the relationship between the ABCA1 transporter-mediated cholesterol efflux capacity and coronary atherosclerosis in rheumatoid arthritis (Karpouzas et al. 2023). Macrophage cholesterol efflux is mediated by ABCA1 and constitutes the initial and rate-limiting step of reverse cholesterol transport, displaying a negative correlation with the development of atherosclerosis.  Macrophage allosterically activate AMPK (see TC# 8.A.104) to enhance ABCA1 stability by retarding the calpain-mediated degradation pathway (Li et al. 2023). CE9A215 (inotodiol), a lanostane-type oxysterol, mitigates LPS-induced sepsis through multifaceted mechanisms (Nguyet Nguyen et al. 2024).  Aberrant cholesterol homeostasis is a hallmark of cancer and is implicated in metastasis as well as chemotherapeutic resistance. Liver X receptors (LXRs) are the key transcription factors that induce cholesterol efflux via enhancing the expression of ABCA1 and ABCG1 (Taank et al. 2024). Ergosterol and its metabolites are agonists of Liver X receptor and their anticancer potential in colorectal cancer.