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Review ArticleReview Article

Brothers in Arms: ABCA1- and ABCG1-Mediated Cholesterol Efflux as Promising Targets in Cardiovascular Disease Treatment

Sanne J. C. M. Frambach, Ria de Haas, Jan A. M. Smeitink, Gerard A. Rongen, Frans G. M. Russel and Tom J. J. Schirris
Martin C. Michel, ASSOCIATE EDITOR
Pharmacological Reviews January 2020, 72 (1) 152-190; DOI: https://doi.org/10.1124/pr.119.017897
Sanne J. C. M. Frambach
Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences (S.J.C.M.F., G.A.R., F.G.M.R., T.J.J.S.), Radboud Center for Mitochondrial Medicine (S.J.C.M.F., R.d.H., J.A.M.S., F.G.M.R., T.J.J.S.), Department of Pediatrics (R.d.H., J.A.M.S.), and Department of Internal Medicine, Radboud Institute for Health Sciences (G.A.R.), Radboud University Medical Center, Nijmegen, The Netherlands
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Ria de Haas
Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences (S.J.C.M.F., G.A.R., F.G.M.R., T.J.J.S.), Radboud Center for Mitochondrial Medicine (S.J.C.M.F., R.d.H., J.A.M.S., F.G.M.R., T.J.J.S.), Department of Pediatrics (R.d.H., J.A.M.S.), and Department of Internal Medicine, Radboud Institute for Health Sciences (G.A.R.), Radboud University Medical Center, Nijmegen, The Netherlands
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Jan A. M. Smeitink
Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences (S.J.C.M.F., G.A.R., F.G.M.R., T.J.J.S.), Radboud Center for Mitochondrial Medicine (S.J.C.M.F., R.d.H., J.A.M.S., F.G.M.R., T.J.J.S.), Department of Pediatrics (R.d.H., J.A.M.S.), and Department of Internal Medicine, Radboud Institute for Health Sciences (G.A.R.), Radboud University Medical Center, Nijmegen, The Netherlands
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Gerard A. Rongen
Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences (S.J.C.M.F., G.A.R., F.G.M.R., T.J.J.S.), Radboud Center for Mitochondrial Medicine (S.J.C.M.F., R.d.H., J.A.M.S., F.G.M.R., T.J.J.S.), Department of Pediatrics (R.d.H., J.A.M.S.), and Department of Internal Medicine, Radboud Institute for Health Sciences (G.A.R.), Radboud University Medical Center, Nijmegen, The Netherlands
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Frans G. M. Russel
Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences (S.J.C.M.F., G.A.R., F.G.M.R., T.J.J.S.), Radboud Center for Mitochondrial Medicine (S.J.C.M.F., R.d.H., J.A.M.S., F.G.M.R., T.J.J.S.), Department of Pediatrics (R.d.H., J.A.M.S.), and Department of Internal Medicine, Radboud Institute for Health Sciences (G.A.R.), Radboud University Medical Center, Nijmegen, The Netherlands
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  • For correspondence: frans.russel@radboudumc.nl
Tom J. J. Schirris
Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences (S.J.C.M.F., G.A.R., F.G.M.R., T.J.J.S.), Radboud Center for Mitochondrial Medicine (S.J.C.M.F., R.d.H., J.A.M.S., F.G.M.R., T.J.J.S.), Department of Pediatrics (R.d.H., J.A.M.S.), and Department of Internal Medicine, Radboud Institute for Health Sciences (G.A.R.), Radboud University Medical Center, Nijmegen, The Netherlands
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Martin C. Michel
Roles: ASSOCIATE EDITOR
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    Fig. 1.

    Cholesterol uptake, distribution, and peripheral utilization. (I) Schematic overview illustrating intestinal cholesterol (light yellow spheres) uptake by enterocytes, including cholesterol esterification and apoB-48 binding, which facilitates cholesterol efflux to the lymphatic system. (II) The resulting nascent chylomicrons are subsequently transported to the blood, where they collide with HDL particles that transfer apoE and apoC-II to chylomicrons, leading to their maturation. (III) Mature chylomicrons can be converted to chylomicron remnants by endothelial lipoprotein lipase (LPL) activated by apoC-II, which releases free fatty acids (yellow spheres) for uptake in peripheral tissues (e.g., muscles and fat) and apoC-II for translocation to HDL. (IV) Next, chylomicron remnants are imported into hepatocytes via the chylomicron remnant receptor (CRR), which releases the remaining cholesterol and apoE by lysosomal degradation. The resulting hepatic free cholesterol, which may also originate from de novo synthesis, can be exported as VLDL particles upon binding to apoB-100. (III) Removal of triglycerides by endothelial LPL converts VLDL particles into intermediate density lipoprotein (IDL) particles. They can collide with HDL to acquire apoE. (IV) Hepatic lipase (HL) subsequently hydrolyzes the remaining triglycerides in IDL, which forms LDL particles (III) that can also be formed by LPL (III) out of IDL particles, and that are able to release cholesterol to peripheral tissues via LDLR.

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    Fig. 2.

    Reverse cholesterol transport. Schematic overview of reverse cholesterol transport, (I) which is initiated by the efflux of cholesterol (yellow spheres) by ABCA1 and ABCG1 transporters. They are expressed on a variety of peripheral tissues, including macrophages that engulf cholesterol from atherosclerotic plaques (i.e., foam cells). ABCA1-mediated cholesterol efflux transfers cholesterol to lipid-poor apoA-I, leading to the formation of pre-βHDL. These particles can be converted by circulating lecithin:cholesterol acyltransferase (LCAT) into HDL particles, which function as cholesterol acceptor for ABCG1. Cholesterol efflux by ABCG1 is mediated via reorganization of cholesterol in the plasma membrane, which increases plasma membrane cholesterol concentrations. Subsequently, aqueous diffusion could increase the cholesterol efflux out of the cell to HDL without necessity of HDL to bind to the plasma membrane. (II) SR-BI mediates cholesterol influx into hepatocytes without whole HDL particle uptake, allowing unbound apoA-I to circulate and enter a new RCT cycle. Finally, hepatic free cholesterol can be directly removed to bile canaliculi by ABCG5 and ABCG8 transporters, or indirect via conversion by cytochrome P450 (CYP)7A1 into bile acids (green spheres) that can subsequently be transported into bile via the multidrug resistance protein (MRP)2/ABCC2 and bile salt export pump (BSEP/ABCB11) transporters, located on the canalicular membrane.

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    Fig. 3.

    Flow chart of systematic literature search strategy. Overview of the number of publications retrieved from all MEDLINE and EMBASE searches and exclusion criteria applied to these publications, including removal of duplicates and title- and abstract-based screenings conducted by two independent reviewers. For a detailed overview of the search strategies, see Supplemental Tables 1 and 2.

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    Fig. 4.

    Potential ABCA1- and ABCG1-driven cholesterol efflux modes. ABCA1-driven cholesterol efflux to lipid-poor apoA-I is hypothesized to occur either at the plasma membrane (upper left panel), or via endocytosis of the apoA-I–bound ABCA1 transporter, followed by intracellular lipid loading and exocytosis (upper right panel). ABCA1 is ubiquitously expressed, particularly at high levels in liver, small intestine, macrophages, adrenal glands, lungs, placenta, and fetal tissue. The transporter initiates cellular cholesterol efflux to the lymph and bloodstream via a specific interaction with apoA-I. Six different mechanisms have been proposed for the interaction between apoA-I and ABCA1 (small boxes), including the following: outward translocation of phosphatidylserine (PS) by ABCA1 floppase activity allowing apoA-I binding; direct binding of apoA-I to extracellular ABCA1 loop domains; ABCA1 floppase activity leading to the formation of protrusions facilitating apoA-I binding; ABCA1 floppase activity leading to the outward translocation of phosphatidylinositol 4,5-bisphosphate (PIP2), allowing apoA-I to bind and unfold, followed by microsolubilization of the membrane; low-affinity binding to ABCA1 and high-affinity binding to cholesterol; dimerization of ABCA1 transporter proteins is initiated by loading of the extracellular loop domains with cholesterol, followed by apoA-I binding to the dimerized cholesterol-loaded extracellular loop domains (ED). ABCG1-driven cholesterol efflux to HDL particles in the bloodstream or lymph is expected to be the result of a collision of these particles with cholesterol molecules that protrude from the plasma membrane (lower left panel), mediated either by a direct effect of the ABCG1 dimer on the membrane structure or by outward translocation via ABCG1 floppase activity (lower right panel). ABCG1 is expressed in many cell types, including macrophages, neurons, astrocytes, endothelial and epithelial cells, and many tissues (e.g., liver, intestine, kidney, spleen, lung, and brain), where it mediates basolateral cholesterol efflux.

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    Fig. 5.

    Cellular regulation of ABCA1 and ABCG1 transporter expression. Expression of ABCA1 and ABCG1 transporters is increased by stimulation of the nuclear PPAR, which upon dimerization with RXR (i.e., another nuclear factor) bind to the PPAR-responsive element (PPRE), leading to the transcription of the nuclear LXR and RAR, respectively (right upper panel). Next, dimerization of LXR or RAR with RXR enables binding to the LXRE, inducing the transcription of ABCA1 and ABCG1, respectively. Once transcribed, the stability of ABCA1 and ABCG1 mRNA can either be enhanced or decreased upon binding of miRNAs, of which an overview is provided in Table 4 (right middle panel). ABCA1 and ABCG1 plasma membrane expression is also mediated via modulation of its lysosomal (blue vesicle) or endosomal (orange vesicle) degradation. The latter is stimulated by phosphorylation of the PEST sequence by apelin-13 (AP-13) via PKCα (left lower panel). Upon phosphorylation, calpain (CALP) can bind and initiate proteolysis, a process that is stimulated by calpastatin (CPSTAT), and negatively affected by calmodulin (CM) or by the HO-1 axis. Finally, the ability of ABCA1 and ABCG1 to bind lipid poor apoA-I is stimulated upon transporter phosphorylation by PKA at Ser-1042 and Ser-2054, located in the nucleotide binding domain of ABCA1. PKA is positively regulated by cAMP levels that depend on the balance of cAMP breakdown by PDE, formation by adenosine receptor–stimulated AC, and efflux by multidrug resistance protein (MRP) 4 and 5 (right lower panel).

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    TABLE 1

    LXR-activating compounds

    Overview of compounds that activate LXR, including their primary pharmacological action, effects on ABCA1 and ABCG1 expression (arrows: mRNA, protein), and effects on cellular cholesterol efflux. Effects on ABCA1, ABCG1, and cholesterol efflux are presented as follows: (↓) decreased; (= ) no effect; (↑) increased. Italicized symbols indicate changes in ABCA1 and ABCG1 mRNA levels, whereas nonitalicized symbols indicate protein levels.

    CompoundPrimary ActionABCA1ABCG1Cholesterol EffluxReference
    Acetyl-podocarpic dimerSelective LXR agonist↑THP-1↑Caco-2THP-1Sparrow et al., 2002
    ↑Caco-2↑Primary hepatocytesa↑ apoA-I
    ↑Primary hepatocytesa↑Caco-2
    ↑Monocytesa
    Primary fibroblastsa:
    ↑ apoA-I
    BaclofenGABAB receptor agonist——MDMYang et al., 2014
    = apoA-I
    = HDL
    DigoxinNa+-K+-ATPase inhibitor↑H9c2—↑H9c2Campia et al., 2012
    Disodium ascorbyl phytostanol phosphate (FM-VP4)MDR1 antagonist↑Liverb——Méndez-González et al., 2010
    =Small intestineb
    DaunorubicinAnthracycline antibiotic=HL-1=HL-1—Monzel et al., 2017
    DMHCALXRα agonist↑THP-1↑BREC↑THP-1Quinet et al., 2004; Kratzer et al., 2009; Hammer et al., 2017
    ↑J774↑PMc
    ↑HepG2↑Livera,d
    ↑↑BREC↑Ileumd
    ↑PMb,c↑Aortad
    ↑Livera
    =Liverd
    ↑Ileumd
    ↑Aortad
    DoxorubicinAnthracycline antibiotic↑HL-1↑HL-1HL-1Monzel et al., 2017
    ↑ apoA-I
    ↑ HDL
    E17110Benzofuran-2-carboxylate analog↑↑RAW264.7↑↑RAW264.7RAW264.7Li et al., 2016
    ↑ apoA-I
    ↑ HDL
    (E)-1-(e,4-diisopropoxyphenyl)-3-(4-isopropoxy-3-methoxyphenyl-2-en-1-oneChalcone derivative↑↑THP-1↑THP-1—Teng et al., 2018
    Ergosterol derivativesErgosterol analog↑U937Marinozzi et al., 2017
    EtoposideDNA topoisomerase II inhibitor↑RAW264.7↑PMb↑PM Zhang et al., 2013a
    ↑↑PMb↑RCTb
    ↑THP-1
    Blood monocytea
    EXEL-04286651/BMS-779788LXR partial agonist↑Murine blood cells↑Murine blood cells—Kick et al., 2015; Kirchgessner et al., 2015
    ↑Blood cellse
    FTY720-PSphingosine-1-phosphate analog↑Monocytesa—↑MonocytesaBlom et al., 2010
    G004Unknown (synthetic sulfonylurea compound)↑↑RAW264.7↑↑RAW264.7↑RAW264.7Qian et al., 2017
    ↑Liverc↑↑Liverc↑RCTc
    GW3965LXRα agonist↑THP-1↑haSMCa↑THP-1Miao et al., 2004; Quinet et al., 2004, 2006; Brunham et al., 2006; Naik et al., 2006; Delvecchio et al., 2007; DiBlasio-Smith et al., 2008; Kannisto et al., 2014
    ↑J774↑=Liverb↑RCTb
    ↑HepG2↑Peripheral bloodf
    ↑haSMCa↑Spleenf
    ↑BMM↑Prox small intestineb,g
    ↑PMb,h,i
    ↑↑Livera,h
    ↑=Livera,h
    ↑Peripheral bloodf
    ↑Spleenf
    ↑↑Prox small intestineb
    =Prox small intestineg
    ↑Kidneyb,h
    ↑Duodenumb,h
    IbandronateOsteoclast inhibitor↑MM6—↑MM6Strobach and Lorenz, 2003
    ↑PBMCsa
    Ibrolipim (NO-1886)Lipoprotein lipase activator↑↑THP-1↑↑THP-1↑THP-1Zhang et al., 2006; Ma et al., 2009; Chen et al., 2010
    ↑↑Liverj
    ↑↑Adipose tissuej
    ↑↑Aortaj
    IdarubicinAnthracycline antibiotic↑HL-1↑HL-1Monzel et al., 2017
    IMB-151Unknown↑↑RAW264.7↑↑RAW264.7↑RAW264.7Li et al., 2014
    InfliximabAnti–TNF-α mAb↑↑THP-1==THP-1↑THP-1 (restores effect of TNF-α)Voloshyna et al., 2014
    LansoprazoleProton pump inhibitor↑H4 neuroglioma cellsa——Cronican et al., 2010
    ↑U-87 astrocytoma
    ↑↑CCF astrocytoma
    ↑U-118 astrocytoma
    ↑Primary astrocytesb
    LXR-623Synthetic LXR agonist↑Duodenumg↑Duodenumg—DiBlasio-Smith et al., 2008; Katz et al., 2009; Quinet et al., 2009
    =Liverg=Liverg
    ↑Spleenf↑Spleenf
    ↑Peripheral blooda,b,f↑Peripheral blooda,b,f
    ↑↑PBMCsa↑↑PBMCsa
    ↑Whole blooda,e↑Whole blooda,e
    Methyl-3β-hydroxy-5α,6α-epoxycholanateLXRα agonist↑THP-1——Yan et al., 2010
    ↑Aortac
    OmeprazoleProton pump inhibitor↑H4 neuroglioma cellsa——Cronican et al., 2010
    PantoprazoleProton pump inhibitor↑H4 neuroglioma cella——Cronican et al., 2010
    OuabainNa+-K+-ATPase inhibitor↑H9c2—↑H9c2Campia et al., 2012
    RitonavirViral proteinase inhibitor↑↑THP-1=THP-1—Pou et al., 2008
    SirolimusFK-binding protein-12 inhibitor↑hVSMC=hVSMC=hVSMCMa et al., 2007
    (24S)-stigmasta-5,28-diene-3β,24- olLXR agonist↑U937Castro Navas et al., 2018
    (24S)-stigmasta-5-ene-3β,24-olLXR agonist↑U937Castro Navas et al., 2018
    Stigmasterol derivativesLXR agonist↑U937Marinozzi et al., 2017
    T0901317LXR agonist↑↑THP-1↑THP-1↑THP-1Fukumoto et al., 2002; Murthy et al., 2002; Terasaka et al., 2003; Thomas et al., 2003; Beyer et al., 2004; Miao et al., 2004; Quinet et al., 2004, 2006; Wu et al., 2004; Panzenboeck et al., 2006; Wang et al., 2006; Delvecchio et al., 2007, 2008; Fujiyoshi et al., 2007; Sprecher et al., 2007; Dai et al., 2008; DiBlasio-Sato et al., 2008; Smith et al., 2008; Zanotti et al., 2008; Larrede et al., 2009; Verschuren et al., 2009; Mogilenko et al., 2010; Morrow et al., 2010; Yan et al., 2010; Maejima et al., 2011; Honzumi et al., 2011; Chen et al., 2012; Di et al., 2012; El Roz et al., 2012; Elali and Hermann, 2012; Jiang et al., 2012; Ma et al., 2014; Kaneko et al., 2015; Kirchgessner et al., 2015; Manna et al., 2015; Tamehiro et al., 2015; Li et al., 2016; Carter et al., 2017; Jiang and Li, 2017; Marinozzi et al., 2017; Monzel et al., 2017; Kaseda et al., 2018
    ↑↑RAW264.7↑↑RAW264.7↑ HDL
    ↑J774↑MCF-7↑J774
    ↑U937↑↑Caco-1↑Caco-1
    ↑↑HepG2↑HL-1HL-1
    ↑↑Caco-1↑TR-CSFB3↑ apoA-I
    ↑HL-1↑↑haSMCa↑ HDL
    ↑↑pBCECs↑Cerebral endothelial cells↑SAS
    ↑TR-CSFB3↑↑Blood-derived macrophagesa↑Jurkat
    ↑↑SAS↑Aorta endothelial cellsc↑Fu5AH
    ↑↑haSMC↑Liverb,k↑COS-7
    ↑↑McARH7777↑Aortai,o↑pBCECs
    ↑↑CD4+ T cellsa↑Peripheral bloode,f↑Monocyte-derived macrophagesa
    ↑↑Jurkat↑CD4+ T cellsa
    ↑Cerebral endothelial cells↑HSKMca
    ↑Murine immortal macrop.haSMCa
    ↑Murine neuro2A= apoA-I
    ↑Murine BV-2↑ HDL
    ↑Rat C6MCF-7
    ↑↑Blood-derived macropg= apoA-I
    ↑Aorta endothelial cellsc↑ HDL
    ↑Renal glomerular mesangial cellsi↑Murine primary macrop.
    ↑↑PMb,d,g,h↑PMb,d,g,h
    ↑↑Liver b,c,h,i,l,k↑Murine immortal macrop.
    ↑↑Aortab,c,i,k,o↑Renal glomerular mesangial cellsi
    ↑Small intestinec
    ↑Kidneyb,h
    ↑Duodenumb,h
    ↑Peripheral bloodf
    ↑Proximal intestinek
    ↑Distal intestinek
    ↑↑Brainm,n
    TacrolimusFK-binding protein-12 inhibitor↑=THP-1——Jin et al., 2004
    TeniposideDNA topoisomerase II inhibitor↑RAW264.7↑PMb↑PMbZhang et al., 2013a
    ↑↑PMb↑RCT
    ↑THP-1
    ↑Blood monocyte
    TopiramateGABA-A receptor agonist↑↑MDM↑↑MDMMDMYang et al., 2014
    ↑ apoA-I
    ↑ HDL
    YC-1Soluble guanylyl cyclase activator↑↑J774A.1=J774A.1↑J774A.1Tsou et al., 2014
    ↑Aortac=Aortac
    • BMM, bone marrow– derived macrophage; BREC, bovine retinal endothelial cells; haSMC, human airway smooth muscle cells; HSKM, human skeletal muscle cells; hVSMC, human vascular smooth muscle cells; macrop, macrophage; MCF-7, Michigan Cancer Foundation-7; MDM, monocyte-derived macrophage; pBCECs, procine brain capillary endothelial cells; PBMC, peripheral blood mononuclear cell; PM, peritoneal macrophages; prox, proximal; SAS, human squamous cell carcinoma cell line.

    • ↵a Human.

    • ↵b C75BL/6 mice.

    • ↵c apoE−/− C57BL/6 mice.

    • ↵d LXRβ−/− C75BL/6 mice.

    • ↵e Cynomolgus monkeys.

    • ↵f Male long Evans rats.

    • ↵g LDLR−/− C75BL/6 mice.

    • ↵h LXRα−/− C75BL/6 mice.

    • ↵i New Zealand White rabbits.

    • ↵j Male chine Bama minipigs.

    • ↵k Male SD rats.

    • ↵l 129Sv mice.

    • ↵m APP/PS1∆9/APOE4+/+/ABCA1+/− C57 BL/6 mice.

    • ↵n APP/PS1∆9/APOE3+/+/ABCA1+/− C57 BL/6 mice.

    • ↵o E3L mice.

    • View popup
    TABLE 2

    PPAR-activating compounds

    Overview of compounds that activate PPARs, including their primary pharmacological action, effects on ABCA1 and ABCG1 expression (arrows: mRNA, protein), and effects on cellular cholesterol efflux. Effects on ABCA1, ABCG1, and cholesterol efflux are presented as follows: (↓) decreased; (= ) no effect; (↑) increased. Italicized symbols indicate changes in ABCA1 and ABCG1 mRNA levels, whereas nonitalicized symbols indicate protein levels.

    CompoundPrimary ActionABCA1ABCG1Cholesterol EffluxReference
    PPARγ-activating compounds
    15d-PGJ2Prostanoid-specific receptor inhibitor↑THP-1↑PMaLipid-loaded HMCRuan et al., 2003; Jiang and Li, 2017
    ↑HMC↑ apoA-I
    ↓↓PMaPMa
    ↓ apoA-I
    ↑ HDL
    4010B-30Benzamide analog↑RAW264.7—RAW264.7Du et al., 2015b
    ↑HepG2↑ apoA-I
    CiglitazonePPARγ agonist↑=THP-1↑THP-1↑THP-1Argmann et al., 2003, 2005
    E3317PPARγ agonistRAW264.7RAW264.7Wang et al., 2018
    ↑↑LO2↑ apoA-I
    GQ-11PPARγ/α agonist↑LiverbSilva et al., 2018
    GW1929PPARγ agonist↑↑HepG2——Mogilenko et al., 2010
    GW7845PPARγ agonist↑THP-1—↑THP-1Chawla et al., 2001; Oliver et al., 2001
    PropofolGABAB receptor agonist↑↑THP-1↑↑THP-1↑THP-1Ma et al., 2015; Hsu et al., 2018
    ↑RAECsRAECs
    ↑ HDL
    LysophosphatidylcholineUnknown↑↑PMa—↑PMaHou et al., 2007
    Mycophenolic acidInosine-5′-monophosphate dehydrogenase inhibitor↑↑HepG2——Xu et al., 2011
    PioglitazonePPARγ agonist↑↑THP-1↑↑THP-1THP-1Panzenboeck et al., 2006; Nakaya et al., 2007; Tanabe et al., 2008; Ogata et al., 2009; Cocks et al., 2010; Ozasa et al., 2011; Wang et al., 2014b, 2015b; Jiang and Li, 2017; Silva et al., 2018
    ↑HepG2↑Monocyte-derived macrop↑ apoA-I
    ↑↑pBCECs↑PMa↑ HDL
    ↑gBECs↑Diabetic patientsc↓pBCECs
    ↑↑WI38 fibroblasts↑Rat cortical neurons↑gBECs
    ↑Monocyte-derived macropc↑WI38 fibroblasts
    ↓↓PMaPMa
    =Liverb↓ apoA-I
    ↑Diabetic patientsc↑ HDL
    ↑Rat cortical neurons↑Diabetic patientsc
    RosiglitazonePPARγ agonist↑↑THP-1↑↑THP-1↑THPChawla et al., 2001; Chinetti et al., 2001; Claudel et al., 2001; Li et al., 2004, 2015; Llaverias et al., 2006
    ↑RAW264.7↑macropd↑RAW264.7
    ↑HepG2↑Aortad↑macropd
    ==macropd↑PMe
    ↑PMe↑Hepatocytese
    ↑=Hepatocytese
    =Aortad
    Aorta lesione
    TelmisartanAngiotensin receptor 1 antagonist↑↑THP-1↑↑THP-1↑THP-1Nakaya et al., 2007
    ↑Monocyte-derived macropc↑Monocyte-derived macropc
    TroglitazonePPARγ agonist↑THP-1↑PMa↑pBCECsCabrero et al., 2003; Panzenboeck et al., 2006; Lee et al., 2008; Jiang and Li, 2017
    ↓↑pBCECsPMa
    ↑↑gBECs↓ apoA-I
    =Monocyte-derived macropc↑ HDL
    ↓↓PMa
    PPARα-activating compounds
    AspirinCOX-1/2 inhibitor↑THP-1—RAW264.7Viñals et al., 2005; Wang et al., 2010
    ↑↑RAW264.7↑apoA-I
    AtorvastatinHMG-CoA reductase inhibitor↑THP-1↑THP-1THP-1Argmann et al., 2005; Maejima et al., 2011; Nicholls et al., 2015, 2017
    ↑McARH7777↑ apoA-I
    ↑ HDL
    BezafibratePan-PPAR agonist↑↑THP-1—↑THP-1Cabrero et al., 2003; Ruan et al., 2003; Panzenboeck et al., 2006; Hossain et al., 2008; Inaba et al., 2008; Ogata et al., 2009
    ↑↑HepG2↑HepG2
    ==pBCECs=pBCECs
    ↑↑W138 fibroblast↑W138 fibroblast
    ↑HMCLipid-loaded HMC
    ↑↑Primary hepatocytes↑ apoA-I
    =Monocyte-derived macropc↑Primary hepatocytes
    =aortab
    ClofibratePPARα agonist↑=HepG2——Guan et al., 2003; Kobayashi et al., 2011
    =Primary hepatocytesf
    ↑Liverf
    FenofibratePPARα agonist↑↑THP-1↑Liverg↑THP-1Forcheron et al., 2002; Lin and Bornfeldt, 2002; Cabrero et al., 2003; Thomas et al., 2003; Arakawa et al., 2005; Kooistra et al., 2006; Hossain et al., 2008; Tanabe et al., 2008; Ogata et al., 2009; Jiang and Li, 2017
    ↑↑RAW264.7↑RAW264.7
    ↑↑HepG2↑HepG2
    =↑pBCECs=pBCECs
    ↑↑Balb/3T3=Balb/3T3
    ↑↑W138 fibroblast↑W138 fibroblast
    ↑↑Primary hepatocytes↑Primary hepatocytes
    =Monocyte-derived macropc
    ↑PMa
    ↑Liverh
    ↑Diabetic patientsc
    ↑Aortai
    GemfibrozilPPARα agonist↑↑THP-1—↑THP-1Hossain et al., 2008; Ogata et al., 2009
    ↑↑HepG2↑HepG2
    ↑↑W138 fibroblast↑W138 fibroblast
    ↑↑Primary hepatocytes↑Primary hepatocytes
    GW7647PPARα agonist↑THP-1=macropd=THP-1Oliver et al., 2001; Li et al., 2004; Wang et al., 2010; Nakaya et al., 2011
    ↑↑RAW264.7=AortadRAW264.7
    ==macropd↑↑BMMa↑ apoA-I
    ==Atherosclerotic lesiond=macropd
    ↑↑BMMa↑BMMa
    LY518674PPARα agonist↑↑THP-1—↑THP-1Hossain et al., 2008; Ogata et al., 2009
    ↑↑HepG2↑HepG2
    ↑↑W138 fibroblast↑W138 fibroblast
    ↑↑Primary hepatocytes↑Primary hepatocytes
    PitavastatinHMG-CoA reductase inhibitor↓J774—↓J774Zanotti et al., 2004, 2006; Kobayashi et al., 2011; Maejima et al., 2011
    ↑HepG2↑Fu5AH
    ↑↑McARH7777↓PMa,b,d
    ↑Liverf=LXR−/− mice
    PravastatinHMG-CoA reductase inhibitor↑↑3T3-L1↓↓3T3-L1↓3T3-L1Maejima et al., 2011; Mostafa et al., 2016
    =McARH7777
    RosuvastatinHMG-CoA reductase inhibitor=Hepatocytesa↑J774Shimizu et al., 2014; Mostafa et al., 2016
    ↑BMMa
    ↑RCTa
    SimvastatinHMG-CoA reductase inhibitor↑McARH7777==PMiTHP-1Argmann et al., 2005; Guan et al., 2008; Maejima et al., 2011; Song et al., 2011; Ying et al., 2013; Gong et al., 2014
    ↑Diabetic patients with hyperlipidemia==Liveri↑ apoA-I
    ==PMd= HDL
    ↑↑Liveri↑RAW264.7
    WY14643PPARα agonist↑↑THP-1↑THP-1↑THP-1Chinetti et al., 2001; Ruan et al., 2003; Beyer et al., 2004; Arakawa et al., 2005; Lee et al., 2008; Maejima et al., 2011
    ↑↑RAW264.7↑RAW264.7
    ↑↑gBECs=Balb/3T3
    ↑↑Balb/3T3Lipid-loaded HMC
    =McARH7777↑ apoA-I
    ↑Livera
    Wy,14,563PPARα agonist——↑THP-1Chawla et al., 2001
    PPARδ/β-activating compounds
    Carbaprostacyclin (cPGI)PPARδ agonist——↑THP-1Chawla et al., 2001
    GW0742PPARδ agonist=Livera=Livera↑BMMaLi et al., 2004; Briand et al., 2009
    =Small intestinea=Small intestinea=macropa
    ==macropd=macropd
    =Atherosclerotic lesiond=Aortad
    GW501515PPARδ agonist↑↑THP-1=HSKM↑THP-1Oliver et al., 2001; Sprecher et al., 2007; Ogata et al., 2009
    ↑↑W138 fibroblast↑W138 fibroblast
    ↑1BR3N fibroblast↑1BR3N fibroblast
    ↑Intestinal FHS74↑Intestinal
    ↑HSKMHSKM
    • BMM, bone marrow– derived macrophage; gBECS, gallbladder epithelial cells; HMC, human mast cell; HSKM, human skeletal muscle cell; macrop, macrophage; pBCECs, porcine brain capillary endothelial cells; PM, peritoneal macrophages; RAECs, rat aortic endothelial cells.

    • ↵a C75BL/6 mice.

    • ↵b LDLR−/− C75BL/6 mice.

    • ↵c Human.

    • ↵d LDLR−/− C75BL/6 hypercholesterolemic mice.

    • ↵e New Zealand White rabbits.

    • ↵f Male Wistar rats.

    • ↵g Male Zucker diabetic fatty rats.

    • ↵h 129SV mice.

    • ↵i Female E3L transgenic mice.

    • View popup
    TABLE 3

    Synthetic retinoid nuclear receptor agonists

    Overview of retinoid nuclear receptor agonists, including their primary pharmacological action, effects on ABCA1 and ABCG1 expression (arrows: mRNA, protein), and effects on cellular cholesterol efflux. Effects on ABCA1, ABCG1, and cholesterol efflux are presented as follows: (↓) decreased; (= ) no effect; (↑) increased. Italicized symbols indicate changes in ABCA1 and ABCG1 mRNA levels, whereas nonitalicized symbols indicate protein levels.

    CompoundPrimary ActionABCA1ABCG1Cholesterol EffluxReference
    RXR agonists
     Bexarotenepan-RXR agonist↑↑BLECs—↑BLECsLaClair et al., 2013; Kuntz et al., 2015; Tachibana et al., 2016
    ↑Cortexa
    ↑Cortexb
    ↑Cortexc
     HX630RXR agonist↑THP-1↑THP-1↑THP-1Nishimaki-Mogami et al., 2008
    ↑RAW264.7
     LG101305RXR agonist↑RAW264.7—↑RAW264.7Claudel et al., 2001
     LG268RXR agonist↑Small intestined—↑THP-1Chawla et al., 2001
    ↑PM
     MethopreneRXR agonist↑Astrocyte↑AstrocyteAstrocyteRepa et al., 2000; Chen et al., 2011b
    ↑ apoA-I
    ↑ HDL
     PA024RXR agonist↑THP-1↑THP-1↑THP-1Nishimaki-Mogami et al., 2008
    ↑RAW264.7
    Tri-butylin  chlorideRXRα agonist↑↑RAW264.7↑↑Primary mouse astrocyte cells↑RAW264.7Cui et al., 2011; Sun et al., 2015
    ↑↑Primary mouse astrocyte cells↑↑Cortexc
    ↑↑Cortexc
    RAR agonists
     AM580RARα agonist—↑THP-1—Ayaori et al., 2012
     TTNPBSynthetic RAR agonist↑THP-1↑THP-1↑RAW264.7Costet et al., 2003; Chen et al., 2011b; Ayaori et al., 2012
    ↑HEK293↓Astrocytes↓Astrocytes
    ↓Astrocytes=Liverd
    =Liverd
    ↑PMd
    • BLEC, bovine lens epithelial cells; PM, peritoneal macrophages.

    • ↵a Lrp1flox/flox; αCamKII-Cre−/− mice.

    • ↵b Lrp1flox/flox; αCamKII-Cre+/− mice.

    • ↵c APPSWE/PSE1∆E mice.

    • ↵d C75BL/6/A129Sv mice.

    • View popup
    TABLE 4

    Overview of microRNAs enhancing or reducing ABCA1 and ABCG1 mRNA

    Overview of microRNAs, including their effects on ABCA1 and ABCG1 expression. Effects on ABCA1, ABCG1, and cholesterol efflux are presented as follows: (↓) decreased; (= ) no effect; (↑) increased.

    MicroRNAABCA1ABCG1Reference
    miR-10b↓↓Hazen and Smith, 2012; Wang et al., 2012; Dávalos and Fernandez-Hernando, 2013; Goedeke et al., 2014; Rayner and Moore, 2014; Rotllan et al., 2016; Aryal et al., 2017
    miR-17↓He et al., 2015
    miR-19b↓Lv et al., 2014, 2015; DiMarco and Fernandez, 2015
    miR-20a/b↓Liang et al., 2017
    miR-21↓↓Canfrán-Duque et al., 2017
    miR-26↓↓ (Indirect via LXR)Sun et al., 2012; Dávalos and Fernandez-Hernando, 2013; Canfrán-Duque et al., 2014; Goedeke et al., 2014; Rayner and Moore, 2014; DiMarco and Fernandez, 2015; Yang et al., 2015; Feinberg and Moore, 2016; Rotllan et al., 2016
    miR-27a/b↓= (↓ Indirect)Kang et al., 2013; Canfrán-Duque et al., 2014; Goedeke et al., 2014, 2015b; Zhang et al., 2014; DiMarco and Fernandez, 2015; Yang et al., 2015; Rotllan et al., 2016
    miR-33a/33b↓↓Moore et al., 2010, 2011; Fernandez-Hernando et al., 2011; Fernández-Hernando and Moore, 2011; Rayner et al., 2011, 2012; Iatan et al., 2012; Rotllan and Fernandez-Hernando, 2012; Dávalos and Fernandez-Hernando, 2013; Kang et al., 2013; Canfrán-Duque et al., 2014; Goedeke et al., 2014; Mao et al., 2014; Rayner and Moore, 2014; DiMarco and Fernandez, 2015; He et al., 2015; Mandolini et al., 2015; Yang et al., 2015; Feinberg and Moore, 2016; Ono, 2016; Rotllan et al., 2016; Aryal et al., 2017
    miR-93↓He et al., 2015
    miR-96↓Moazzeni et al., 2017
    miR-101↓Zhang et al., 2015a; Aryal et al., 2017
    miR-106b↓Kim et al., 2012; Rotllan and Fernandez-Hernando, 2012; Dávalos and Fernandez-Hernando, 2013; Goedeke et al., 2014; Rayner and Moore, 2014; Feinberg and Moore, 2016
    miR-128-1↓Wagschal et al., 2015; Feinberg and Moore, 2016; Rotllan et al., 2016; Aryal et al., 2017
    miR-128-2↓↓Adlakha et al., 2013; DiMarco and Fernandez, 2015
    miR-130b↓Wagschal et al., 2015; Feinberg and Moore, 2016
    miR-144↓↓ (Indirect via RXR)de Aguiar Vallim et al., 2013; Kang et al., 2013; Ramírez et al., 2013; Canfrán-Duque et al., 2014; Goedeke et al., 2014; Rayner and Moore, 2014; DiMarco and Fernandez, 2015; Feinberg and Moore, 2016; Rotllan et al., 2016; Aryal et al., 2017
    miR-145↓Kang et al., 2013; Canfrán-Duque et al., 2014; Goedeke et al., 2014; Sala et al., 2014; DiMarco and Fernandez, 2015
    miR-148a↓Kang et al., 2013; Goedeke et al., 2015a; Wagschal et al., 2015; Feinberg and Moore, 2016; Rotllan et al., 2016; Aryal et al., 2017
    miR-223↑DiMarco and Fernandez, 2015; Rotllan et al., 2016
    miR-301b↓Wagschal et al., 2015; Feinberg and Moore, 2016
    miR-302a↓DiMarco and Fernandez, 2015; Meiler et al., 2015; Rotllan et al., 2016; Aryal et al., 2017
    miR-378↓ (Indirect)Wang et al., 2014a; DiMarco and Fernandez, 2015; Yang et al., 2015
    miR-613↓Zhao et al., 2014; DiMarco and Fernandez, 2015
    miR-758↓Ramirez et al., 2011; Kim et al., 2012; Rayner et al., 2012; Rotllan and Fernandez-Hernando, 2012; Dávalos and Fernandez-Hernando, 2013; Canfrán-Duque et al., 2014; Goedeke et al., 2014; Rayner and Moore, 2014; DiMarco and Fernandez, 2015; Mandolini et al., 2015; Yang et al., 2015; Feinberg and Moore, 2016
    • miR, microRNA.

    • View popup
    TABLE 5

    Compounds enhancing ABCA1 and ABCG1 mRNA stability

    Overview of compounds that enhance ABCA1 and ABCG1 mRNA stability, including their primary pharmacological action, effects on ABCA1 and ABCG1 expression (arrows: mRNA, protein), and effects on cellular cholesterol efflux. Effects on ABCA1, ABCG1, and cholesterol efflux are presented as follows: (↓) decreased; (= ) no effect; (↑) increased. Italicized symbols indicate changes in ABCA1 and ABCG1 mRNA levels, whereas nonitalicized symbols indicate protein levels.

    CompoundPrimary ActionABCA1ABCG1Cholesterol EffluxReference
    AICARAMPK agonist==J774.A1↑↑J774.A1J774.A1Li et al., 2010; Kemmerer et al., 2016
    ↑THP-1↑↑PMa↑ HDL
    A769662Allosteric AMPK agonist↑↑THP-1↑J774.A1↑THP-1Li et al., 2010; Kemmerer et al., 2016
    SalicylateAllosteric AMPK agonist↑THP-1——Kemmerer et al., 2016
    • ↵a apoE−/− C75BL/6 mice.

    • PM, peritoneal macrophages.

    • View popup
    TABLE 6

    Inhibitors of ABCA1 and ABCG1 protein breakdown

    Overview of compounds that inhibit ABCA1 and ABCG1 protein breakdown, including their primary pharmacological action, effects on ABCA1 and ABCG1 expression (arrows: mRNA, protein), and effects on cellular cholesterol efflux. Effects on ABCA1, ABCG1, and cholesterol efflux are presented as follows: (↓) decreased; (= ) no effect; (↑) increased. Italicized symbols indicate changes in ABCA1 and ABCG1 mRNA levels, whereas nonitalicized symbols indicate protein levels.

    CompoundPrimary ActionABCA1ABCG1Cholesterol EffluxReference
    AcifranGPR109A agonist———Gaidarov et al., 2013
    AcipimoxGPR109A agonist———Gaidarov et al., 2013
    ALLNThiol-protease inhibitor=↑THP-1—↑THP-1Arakawa and Yokoyama, 2002; Yokoyama, 2004
    Calphostin CPKC inhibitor——↓CHO-K1 ABCG1(+12)Gelissen et al., 2012
    ↓CHO-K1 ABCG1(−12)
    DiphenoquinoneUnknown, probucol metabolite↑THP-1↑RAW264.7↑THP-1Arakawa et al., 2009; Lu et al., 2016; Yakushiji et al., 2016
    ↑RAW264.7RAW264.7
    ↑HEK293↑ apoA-I
    ↑Balb/3T3↑ HDL
    ↑MEFs↑Hek293
    =↑Livera↑MEFs
    Exendin-4GLP-1R agonist↑↑3T3-L1 adipocytes↑↑3T3-L1 adipocytes↑3T3-L1 adipocytesMostafa et al., 2015; Yin et al., 2016
    ↑↑glomerulib↑glomerulib
    EzetimibeNPC1L1 inhibitor↑VSCMs——Gong et al., 2014; Kannisto et al., 2014
    ↓↓Liverc
    ↓↓Proximal small intestinec
    Gö6976PKC inhibitor↑↑THP-1—↑THP-1Iwamoto et al., 2008
    Gö6983PKC inhibitor↑↑ ↑↑THP-1—↑THP-1Iwamoto et al., 2008
    Liverc
    IMM-H007AMPK agonist↑THP-1—↑J774Huang et al., 2015
    ↑Liverd↑THP-1
    ↑RCTc
    LD211MC1-R agonist↑BMDMd↑BMDMdBMDMdRinne et al., 2017
    ↑ apoA-I
    ↑ HDL
    LeupeptinThiol-protease inhibitor=↑THP-1——Arakawa and Yokoyama, 2002
    MK-0354GPR109A agonist=MDMd=MDMd=MDMdGaidarov et al., 2013
    MK-1903GPR109A agonist↑MDMd↑MDMd↑MDMdGaidarov et al., 2013
    MSG606MC1-R agonist↑BMDMd↑BMDMdBMDMdRinne et al., 2017
    =Aortad=Aortad↑ apoA-I
    ↑Liverd↑Liverd↑ HDL
    N-acetyl cysteineGlutathione synthase stimulator↓J774↑J774J774Machado et al., 2014
    ↓ apoA-I
    ↑ HDL
    NiacinGPR109A agonist↑↑HepG2↑MDMd↑THP-1Rubic et al., 2004; Siripurkpong and Na-Bangchang, 2009; Wu and Zhao, 2009; Yvan-Charvet et al., 2010a; Zhang et al., 2012; Gaidarov et al., 2013
    ↑↑3T3-L1 adipocytes↑HepG2
    ↑MM6sr↑3T3-L1 adipocytes
    ↑MDMd↑MM6sr
    ↑Monocyted↑MDMd
    ↑↑Livere
    NicardipineCalcium channel blocker——↑THP-1Suzuki et al., 2004
    ↑RAW264.7
    NifedipineCalcium channel blocker↑↑RAW264.7↑↑RAW264.7↑THP-1Suzuki et al., 2004; Ishii et al., 2010; Zhang et al., 2013b
    ↑↑Aorta sinusfRAW264.7
    ↑↑PMa↑ apoA-I
    ↑ HDL
    PD98059MEK1/2 inhibitor↑THP-1↑THP-1↓CHOZhou et al., 2010; Mulay et al., 2013; Zhang et al., 2016
    ↑↑RAW264.7↑↑RAW264.7PMd
    ↓HuH7↓CHO↑ HDL
    ↓CHO↓HEK293
    ↑↑Mouse primary macrop
    ↑PMd
    PKC19-36PKC inhibitor——↓CHO-K1 ABCG1(+12)Gelissen et al., 2012
    ↓CHO-K1 ABCG1(−12)
    RottlerinPKC inhibitor↑↑THP-1—=THP-1Iwamoto et al., 2008
    SpiroquinoneUnknown, probucol metabolite↑THP-1↑RAW264.7↑THP-1Yokoyama, 2004; Arakawa et al., 2009; Lu et al., 2016; Yakushiji et al., 2016
    ↑RAW264.7RAW264.7
    ↑HEK293↑ apoA-I
    ↑Balb/3T3= HDL
    ↑MEFs↑Hek293
    =↑Livera↑MEFs
    Tert-butylhydroquinoneSynthetic phenolic antioxidant↑↑THP-1—↑THP-1Lu et al., 2013
    U0126MEK1/2 inhibitor↑↑RAW264.7↑THP-1RAW264.7Mogilenko et al., 2010; Zhou et al., 2010; Mulay et al., 2013; Xue et al., 2016; Zhang et al., 2016; Liu et al., 2019
    ↑↑HepG2↑↑RAW264.7↑ apoA-I
    ↑↑PMb↑↑Mouse primary macrop↑ HDL
    ↑↑Jurkat↑PMdPM
    ↑↑PMg↑ apoA-I
    ↑↑Jurkat↑ HDL
    Jurkat
    ↑ apoA-I
    VerapamilCalcium channel blocker↑↑RAW264.7↓RAW264.7↑THP-1Suzuki et al., 2004
    ↑RAW264.7
    VildagliptinGLP-1R agonist↑↑3T3-L1 adipocytes↑↑3T3-L1 adipocytes↑3T3-L1 adipocytesMostafa et al., 2015, 2016
    • ALLN, N-acetyl-leu-leu-norleucinal; GLP-1R, glucagon-like peptide-1 receptor; MDM, monocyte-derived macrophage; MEF, murine embryonic fibroblast; MEK, mitogen-activated protein kinase kinase; NPC1L1, Niemann-Pick C1-like 1; PM, peritoneal macrophages.

    • ↵a New Zealand White rabbits.

    • ↵b apoE−/− C75BL/6 diabetic mice.

    • ↵c apoE−/− C75BL/6 mice.

    • ↵d C75BL/6 mice.

    • ↵e Golden Syrian Hamster.

    • ↵f C3H/He mice.

    • ↵g Sprague Dawley rats.

    • View popup
    TABLE 7

    Compounds increasing cAMP levels

    Overview of compounds that increase intracellular cAMP levels, including their primary pharmacological action, effects on ABCA1 and ABCG1 expression (arrows: mRNA, protein), and effects on cellular cholesterol efflux. Effects on ABCA1, ABCG1, and cholesterol efflux are presented as follows: (↓) decreased; (= ) no effect; (↑) increased. Italicized symbols indicate changes in ABCA1 and ABCG1 mRNA levels, whereas nonitalicized symbols indicate protein levels.

    CompoundPrimary ActionABCA1ABCG1Cholesterol EffluxReference
    6-Benz-cAMPPKA agonist↑THP-1—↑THP-1Bingham et al., 2010
    8-Bromo-cAMPcAMP analog=↑Skin fibroblastsa—↑THP-1Haidar et al., 2002; Lin and Bornfeldt, 2002
    ↑PM↑Skin fibroblastsa
    8-(4-Chlorophenylthio)adenosine-cAMPcAMP analog↑J774.A1—=THP-1Sakr et al., 1999; Kellner-Weibel et al., 2003
    ↑J774.A1
    ↑L cells
    =CHO
    =Fu5AH
    =Skin fibroblastsa
    ↑Mouse PM
    8-pcPT-2′-O-Me-cAMPEpac agonist↑THP-1—↑THP-1Bingham et al., 2010
    ATL313A2AR agonist↑↑THP-1↑↑THP-1—Voloshyna et al., 2013
    (Bu)2cAMPcAMP analog↑RAW264.7—↑RAW264.7Manna et al., 2015
    CGS-21680A2AR agonist↑↑THP-1↑↑THP-1↑THP-1Bingham et al., 2010; Voloshyna et al., 2013
    CilomastPDE4 inhibitor↑THP-1—↑THP-1Lin and Bornfeldt, 2002
    ↑J774.A1↑J774.A1
    CilostazolPDE3 inhibitor↑↑THP-1↑↑THP-1↑THP-1Nakaya et al., 2010
    ↑↑RAW264.7↑↑RAW264.7↑RAW264.7
    ↑MDMa↑MDMa↑MDMa
    ↑PMb↑RCTb
    =Liverb
    =Small intestineb
    Dibutyrl cyclic AMPcAMP analog↑RAW264↑Monocyte-derived macropa↑RAW264.7Abe-Dohmae et al., 2000; Gaidarov et al., 2013
    ↑Monocyte-derived macropa↑Monocyte-derived macropa
    Doxazosinα-A1 adrenergic receptor antagonist↑↑THP-1—↑THP-1Iwamoto et al., 2007; Tsunemi et al., 2014
    ↑↑RAW264.7↑RAW264.7
    ↑NCTC clone 1469
    ↑CHO-K1
    ↑↑Liverb
    ForskolinAdenylyl cyclase activator↑Skin fibroblastsa—↑THP-1Haidar et al., 2002; Lin and Bornfeldt, 2002
    ↑Skin fibroblastsa
    H89PKA inhibitor—↑CHO-K1 ABCG1(+12)↑CHO-K1 ABCG1(+12)Gelissen et al., 2012
    =CHO-K1 ABCG1(−12)=CHO-K1 ABCG1(−12)
    IBMXNonselective PDE inhibitor——↑THP-1Haidar et al., 2002; Lin and Bornfeldt, 2002
    ↑Skin fibroblastsa
    KT5720PKA inhibitor——↑CHO-K1 ABCG1(+12)Gelissen et al., 2012
    =CHO-K1 ABCG1(−12)
    MethotrexateDihydrofolate reductase inhibitor↑PBMCsa—Chen et al., 2011a
    RolipramPDE4-selective inhibitor↑↑THP-1—↑THP-1Lin and Bornfeldt, 2002
    ↑J774.A1↑J774.A1
    • IBMX, 3-isobutyl-1-methylxanthine; macrop, macrophage; MDM, monocyte-derived macrophage; PBMC, peripheral blood mononuclear cell; PM, peritoneal macrophages.

    • ↵a Human.

    • ↵b C57BL/6 mice.

    • View popup
    TABLE 8

    Compounds increasing ABCA1/G1 expression or function by an unknown mechanism

    Overview of compounds that increase ABCA1 or ABCG1 expression or function by a yet unknown mechanism, including their primary pharmacological action, effects on ABCA1 and ABCG1 expression (arrows: mRNA, protein), and effects on cellular cholesterol efflux. Effects on ABCA1, ABCG1, and cholesterol efflux are presented as follows: (↓) decreased; (= ) no effect; (↑) increased. Italicized symbols indicate changes in ABCA1 and ABCG1 mRNA levels, whereas nonitalicized symbols indicate protein levels.

    CompoundPrimary ActionABCA1ABCG1Cholesterol EffluxReference
    1-Phenyl-2-Decanoylamino-3-morpholino-1-propanolGlycosylceramide transferase inhibitor↑↑Skin fibroblastsa—↑Skin fibroblastsaGlaros et al., 2005
    ↑MDMa
    AclarubicinTopoisomerase I and II inhibitor↑↑HepG2——Gao et al., 2008
    AnacetrapibCETP inhibitor——↑THP-1Yvan-Charvet et al., 2010a; Brodeur et al., 2017
    ↑BHK
    ↑ABCA1-expressing BHK
    DaidzeinMitochondrial aldehyde dehydrogenase inhibitor↑↑HepG2——Gao et al., 2008
    DalcetrapibCETP inhibitor——↑BHKBrodeur et al., 2017
    ↑ABCA1-expressing BHK
    IbrutinibNLRP3 inflammasome inhibitor↑THP-1=THP-1THP-1Chen et al., 2018
    = apoA-I
    ↑ HDL
    IMB2026791Unknown——↑THP-1Liu et al., 2012
    ↑CHO-ABCA1
    ↑CHO
    MCC950NLRP3 inflammasome inhibitor↑THP-1=THP-1THP-1Chen et al., 2018
    = apoA-I
    ↑ HDL
    MetforminAntihyperglycemic agent==RAW264.7↑↑RAW264.7RAW264.7He et al., 2019
    = apoA-I
    ↑ HDL
    N-butyldeoxynojirimycinGlycosylceramide transferase inhibitor——=Skin fibroblastsaGlaros et al., 2005
    PratenseinUnknown↑↑HepG2——Gao et al., 2008
    PyrromycinMicrobial protein synthesis inhbitor↑↑HepG2——Gao et al., 2008
    t-AUCBSoluble epoxide hydrolase inhibitor↑↑Liverb==Liverb↑3T3-L1 adipocytesShen et al., 2015
    ↑Epididymal fatc
    ↑ RCTb
    TorcetrapibCEPT inhibitor↑THP-1↑THP-1Yvan-Charvet et al., 2007
    • BHK, baby hamster kidney cell; fatc., fat cell; MDM, monocyte-derived macrophage; NLRP3, nucleotide binding oligomerization domain receptor family, pyrin domain-containing protein 3; t-AUCB, trans-4-[4-(3-Adamanthan-1-yl-uneido)-cyclonexyloxy]-benzoic acid.

    • ↵a Human.

    • ↵b LXRα−/− C75BL/6 mice.

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In this issue

Pharmacological Reviews: 72 (1)
Pharmacological Reviews
Vol. 72, Issue 1
1 Jan 2020
  • Table of Contents
  • Table of Contents (PDF)
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Brothers in Arms: ABCA1- and ABCG1-Mediated Cholesterol Efflux as Promising Targets in Cardiovascular Disease Treatment
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Review ArticleReview Article

Increased Cholesterol Efflux To Treat Cardiovascular Disease

Sanne J. C. M. Frambach, Ria de Haas, Jan A. M. Smeitink, Gerard A. Rongen, Frans G. M. Russel and Tom J. J. Schirris
Pharmacological Reviews January 1, 2020, 72 (1) 152-190; DOI: https://doi.org/10.1124/pr.119.017897

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Review ArticleReview Article

Increased Cholesterol Efflux To Treat Cardiovascular Disease

Sanne J. C. M. Frambach, Ria de Haas, Jan A. M. Smeitink, Gerard A. Rongen, Frans G. M. Russel and Tom J. J. Schirris
Pharmacological Reviews January 1, 2020, 72 (1) 152-190; DOI: https://doi.org/10.1124/pr.119.017897
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  • Article
    • Visual Overview
    • Abstract
    • I. Introduction
    • II. Reverse Cholesterol Transport Pathway
    • III. Apolipoprotein A-I and Apolipoprotein E Mimetics
    • IV. Regulation and Pharmacological Manipulation of Nuclear Receptor–Mediated ATP-Binding Cassette A1 and ATP-Binding Cassette G1 Expression
    • V. ATP-Binding Cassette A1 and ATP-Binding Cassette G1 mRNA Stability
    • VI. ATP-Binding Cassette A1 and ATP-Binding Cassette G1 Protein Degradation as a Target to Increase Cholesterol Efflux
    • VII. ATP-Binding Cassette A1 Function and Cyclic Adenosine Monophosphate
    • VIII. Increasing Cellular Cholesterol Efflux via Unknown Mechanisms
    • IX. Conclusions and Future Directions
    • Authorship Contributions
    • Footnotes
    • Abbreviations
    • References
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