International Journal of Molecular Sciences Review The Role of the ATP-Binding Cassette A1 (ABCA1) in Human Disease Leonor Jacobo-Albavera 1,† , Mayra Domínguez-Pérez 1,† , Diana Jhoseline Medina-Leyte 1,2 , Antonia González-Garrido 1 and Teresa Villarreal-Molina 1,* 1 Laboratorio de Genómica de Enfermedades Cardiovasculares, Dirección de Investigación, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City CP14610, Mexico; [email protected] (L.J.-A.); [email protected] (M.D.-P.); [email protected] (D.J.M.-L.); [email protected] (A.G.-G.) 2 Posgrado en Ciencias Biológicas, Universidad Nacional Autónoma de México (UNAM), Coyoacán, Mexico City CP04510, Mexico * Correspondence: [email protected] † These authors contributed equally to this work. Abstract: Cholesterol homeostasis is essential in normal physiology of all cells. One of several proteins involved in cholesterol homeostasis is the ATP-binding cassette transporter A1 (ABCA1), a transmembrane protein widely expressed in many tissues. One of its main functions is the efflux of intracellular free cholesterol and phospholipids across the plasma membrane to combine with apolipoproteins, mainly apolipoprotein A-I (Apo A-I), forming nascent high-density lipoprotein- cholesterol (HDL-C) particles, the first step of reverse cholesterol transport (RCT). In addition, ABCA1 regulates cholesterol and phospholipid content in the plasma membrane affecting lipid rafts, microparticle (MP) formation and cell signaling. Thus, it is not surprising that impaired ABCA1 function and altered cholesterol homeostasis may affect many different organs and is involved in the Citation: Jacobo-Albavera, L.; pathophysiology of a broad array of diseases. This review describes evidence obtained from animal Domínguez-Pérez, M.; Medina-Leyte, models, human studies and genetic variation explaining how ABCA1 is involved in dyslipidemia, D.J.; González-Garrido, A.; Villarreal- coronary heart disease (CHD), type 2 diabetes (T2D), thrombosis, neurological disorders, age-related Molina, T. The Role of the ATP- macular degeneration (AMD), glaucoma, viral infections and in cancer progression. Binding Cassette A1 (ABCA1) in Human Disease. Int. J. Mol. Sci. 2021, Keywords: ATP-binding cassette transporter A1 (ABCA1); cholesterol homeostasis; reverse choles- 22, 1593. https://doi.org/10.3390/ ijms22041593 terol transport; HDL-C; dyslipidemia; type 2 diabetes; microparticles Academic Editor: Thomas Falguières Received: 31 December 2020 Accepted: 27 January 2021 1. Introduction Published: 5 February 2021 Cholesterol is an essential biomolecule, involved in a wide array of physiological and pathological processes. In the plasma membrane, changes in free cholesterol content Publisher’s Note: MDPI stays neutral and phospholipid species modulate signaling of multiple receptors [1]. A physiologi- with regard to jurisdictional claims in cal free cholesterol/phospholipid ratio in cellular membranes is necessary to maintain published maps and institutional affil- membrane fluidity [2], and altered membrane fluidity adversely affects the conformation iations. and function of certain integral membrane proteins that can be inhibited by a high free cholesterol/phospholipid ratio [3]. Excess plasma membrane cholesterol also disrupts the function of certain signaling molecules that normally reside in non-raft domains. In addition, excess intracellular cholesterol levels can also cause toxicity by mechanisms Copyright: © 2021 by the authors. including intracellular cholesterol crystallization, oxidation of cholesterol to oxysterols and Licensee MDPI, Basel, Switzerland. triggering of apoptotic signaling pathways [4]. This article is an open access article One of several proteins involved in cholesterol homeostasis is the ATP-binding cas- distributed under the terms and sette transporter A1 (ABCA1), a transmembrane protein widely expressed in many tissues conditions of the Creative Commons where it may have many different functions. Its most studied function is the efflux of Attribution (CC BY) license (https:// intracellular free cholesterol and phospholipids across the plasma membrane to combine creativecommons.org/licenses/by/ with apolipoproteins, mainly apolipoprotein A-I (ApoA-I), forming nascent high-density 4.0/). Int. J. Mol. Sci. 2021, 22, 1593. https://doi.org/10.3390/ijms22041593 https://www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 32 Int. J. Mol. Sci. 2021, 22, 1593 2 of 30 intracellular free cholesterol and phospholipids across the plasma membrane to combine with apolipoproteins, mainly apolipoprotein A-I (ApoA-I), forming nascent high-density lipoprotein particles (HDLs), the first step of reverse cholesterol transport (RCT) [5]. RCT lipoprotein particles (HDLs), the first step of reverse cholesterol transport (RCT) [5]. RCT is the process by which the body removes excess cholesterol from peripheral tissues and is the process by which the body removes excess cholesterol from peripheral tissues and delivers this cholesterol to the liver, where it is redistributed to other tissues or removed fromfrom the bodybody byby thethe gallbladder. gallbladder. HDL-cholesterol HDL-cholesterol (HDL-C) (HDL-C) particles particles are are the the main main lipopro- lipo- proteinsteins involved involved in thisin this process process [6 ].[6]. In In addition addition to to HDL-C HDL-C formation,formation, ABCA1ABCA1 regulates cholesterol andand phospholipidphospholipid content content in in the the plasma plasma membrane membrane and and is involvedis involved in micropar-in micro- particleticle formation formation and and thus thus in in cell cell signaling. signaling. For For all all these these reasons, reasons, it it isis notnot surprisingsurprising that altered cholesterol homeostasis may may affect many different organs and is involved in the pathophysiology ofof aa broadbroad array array of of diseases diseases (Figure (Figure1). 1). The The present present review review focuses focuses on the on therole role of the of the ABCA1 ABCA1 cholesterol cholesterol transporter transporter in human in human disease. disease. Figure 1. ATP-binding cassettecassette transportertransporter A1A1 (ABCA1) (ABCA1) functions functions in in different different cell cell types types and and associated associated diseases. diseases. ABCA1 ABCA1 is widelyis widely expressed expressed and and participates participates in in a broada broad array array of physiologicalof physiological and and pathological pathological processes. processes. ApoE: ApoE: apolipoprotein apolipoprotein E; HDL:E; HDL: high-density high-density lipoproteins; lipoprotein apoAI:s; apoAI: apolipoprotein apolipoprotein I. I. 2. Global Global ABCA1 ABCA1 Deficiency: Deficiency: Tangier Disease Tangier disease (TD) (TD) is is a a rare rare autosomal autosomal recessive recessive disease disease caused caused by by homozygous homozygous or compoundor compound heterozygous heterozygous loss loss of offunction function variants variants in in both both alleles alleles of of the the ABCA1 gene (OMIM #205400). TD isis characterizedcharacterized byby severesevere deficiency deficiency or or absence absence of of circulating circulating HDL-C HDL- Cparticles particles and and accumulation accumulation of cholesteryl-estersof cholesteryl-esters in cellsin cells throughout throughout the the body, body, particularly particu- larlyin the in reticuloendothelial the reticuloendothelial system system [7,8]. The[7,8]. major The clinicalmajor clinical signs of signs TD are of veryTD are low very HDL-C low HDL-Clevels (<5 levels mg/dL), (<5 mg/dL), hyperplastic hyperplastic yellow yellow orange orange tonsils tonsils and hepatosplenomegaly; and hepatosplenomegaly; while whileperipheral peripheral neuropathy neuropathy occurs occurs in approximately in approximately 50%, and 50%, premature and premature coronary coronary heart disease heart disease(CHD), (CHD), occurs inoccurs 30 to in 50% 30 to of 50% TD patientsof TD patients [9–11]. [9–11]. Carriers Carriers of a single of a singleABCA1 ABCA1mutation mu- tation(heterozygotes) (heterozygotes) have variable have variable reductions reductions in plasma in HDL-Cplasma levelsHDL-C and levels a variable and a increased variable increasedrisk for CHD risk [ 12for]. CHD Other [12]. less frequentOther less symptoms frequent includesymptoms corneal include opacity corneal and hematologicopacity and hematologicmanifestations, manifestations, such as thrombocytopenia, such as thromb alteredocytopenia, platelet altered morphology platelet and morphology function, mildand function,bleeding tendency,mild bleeding reticulocytosis, tendency, stomatocytosisreticulocytosis, andstomatocytosis hemolytic anemia and hemolytic [13]. anemia [13]. Macrophages and other cells from TD patients are overloaded with cholesterol (foam cells) because the ABCA1-mediated efflux of cellular free (unesterified) cholesterol and phospholipids to ApoA-I is defective [14]. These foam cells play a crucial role in the pathogenesis of atherosclerosis and CHD. However, it is not clear why not all TD patients Int. J. Mol. Sci. 2021, 22, 1593 3 of 30 develop premature CHD. A review of 185 TD cases reported that 51% of patients aged 40 to 65 years had premature CHD and suggested that reduced low-density lipoprotein- cholesterol (LDL-C) levels in TD patients provide cardiovascular protection, while TD patients with normal LDL-C levels are likely to develop premature CHD [10]. A more recent review reported angina in 24.8%,