The Role of the ATP-Binding Cassette A1 (ABCA1) in Human Disease

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 pathophysiology of a broad array of diseases. This review describes evidence obtained from animal models, human studies and genetic variation explaining how ABCA1 is involved in dyslipidemia, coronary heart disease (CHD), type 2 diabetes (T2D), thrombosis, neurological disorders, age-related macular degeneration (AMD), glaucoma, viral infections and in cancer progression.

Keywords: ATP-binding cassette transporter A1 (ABCA1); HDL-C; cholesterol homeostasis; dyslipidemia; microparticles; reverse cholesterol transport; type 2 diabetes.

Figure 1

ATP-binding cassette transporter A1 (ABCA1) functions in different cell types and associated diseases. ABCA1 is widely expressed and participates in a broad array of physiological and pathological processes. ApoE: apolipoprotein E; HDL: high-density lipoproteins; apoAI: apolipoprotein I.

Figure 2

Effects of the viral negative factor (Nef) protein in human immunodeficiency virus (HIV)-infected cells. HIV enters cells by binding to the chemokine receptor 5 (CCR5) and chemokine receptor type 4 (CXCR4) and uses the host cell machinery to synthesize viral proteins such as Nef. Nef increases cholesterol biosynthesis and induces lipid raft formation, required to produce new virions. Nef also inhibits cholesterol efflux by suppressing ABCA1 activity, inducing structural and functional modifications of high-density lipoproteins (HDL). In addition, Nef blocks the interaction of the endoplasmic reticulum (ER) chaperon calnexin (CNX) with ABCA1, altering its folding and maturation. Nonfunctional and misfolded ABCA1 is retained in the ER and degraded in the proteasome, resulting in further accumulation of intracellular cholesterol, creating a favorable microenvironment for viral replication and release.

Figure 3

Proposed pathways of ABCA1 involvement in cancer. Downregulation of ABCA1 promotes cell growth and proliferation. a: ABCA1 downregulation avoids raft domain disruption and Akt pathway activation; b: ABCA1 downregulation causes cholesterol accumulation in the mitochondrial membrane inhibiting cytochrome c release and apoptosome formation; and c: ABCA1 downregulation activates the IL3-receptor, activating Janus kinase 2 (JAK2) and mitogen-activated protein kinase (MAPK) pathways. Upregulation of ABCA1 stabilizes caveolin-1 promoting epithelial-mesenchymal transition, and thus cell migration an invasion.