key: cord-0006637-yw16be6k
authors: Litvinov, Dmitry Y.; Savushkin, Eugeny V.; Dergunov, Alexander D.
title: Analysis of Low Molecular Weight Substances and Related Processes Influencing Cellular Cholesterol Efflux
date: 2019-11-21
journal: Pharmaceut Med
DOI: 10.1007/s40290-019-00308-w
sha: deb6b60ccc8de9fe89df1b031de57f70c7cbdc53
doc_id: 6637
cord_uid: yw16be6k

Cholesterol efflux is the key process protecting the vascular system from the development of atherosclerotic lesions. Various extracellular and intracellular events affect the ability of the cell to efflux excess cholesterol. To explore the possible pathways and processes that promote or inhibit cholesterol efflux, we applied a combined cheminformatic and bioinformatic approach. We performed a comprehensive analysis of published data on the various substances influencing cholesterol efflux and found 153 low molecular weight substances that are included in the Chemical Entities of Biological Interest (ChEBI) database. Pathway enrichment was performed for substances identified within the Reactome database, and 45 substances were selected in 93 significant pathways. The most common pathways included the energy-dependent processes related to active cholesterol transport from the cell, lipoprotein metabolism and lipid transport, and signaling pathways. The activators and inhibitors of cholesterol efflux were non-uniformly distributed among the different pathways: the substances influencing ‘biological oxidations’ activate cholesterol efflux and the substances influencing ‘Signaling by GPCR and PTK6’ inhibit efflux. This analysis may be used in the search and design of efflux effectors for therapies targeting structural and functional high-density lipoprotein deficiency.

High-density lipoprotein (HDL) heterogeneity influences its atheroprotective effect via reverse cholesterol transport from macrophage to the liver [1] . Cholesterol efflux from a macrophage to the extracellular cholesterol acceptor is the first, and rate-limiting, step of reverse cholesterol transport [2, 3] . Four mechanisms of cholesterol efflux, namely aqueous diffusion, facilitated diffusion mediated by the scavenger receptor class B member 1 (SR-B1) receptor, and active unidirectional efflux mediated by the ATP binding cassette subfamily A member 1 (ABCA1) and the ATP binding cassette subfamily G member 1 (ABCG1) transporters are known [4] . ATP hydrolysis with concomitant conformational transition is required for cholesterol efflux by ABCA1 and ABCG1 transporters. The SR-B1 mediates cholesterol efflux by facilitated diffusion via hydrophobic tunnel within the molecule. Various HDL fractions and lipid-free apolipoprotein A1 (apoA-1) are able to accept cell-derived cholesterol with a different efficiency [2] . Cholesterol transport between intracellular compartments proceeds by both energy-dependent and energy-independent processes [5] . The energy-dependent vesicular traffic partly contributes to cholesterol flux between endoplasmic reticulum, plasma membrane (PM) and endocytic vesicles. The membrane contact sites and lipid transfer proteins are involved in nonvesicular lipid traffic [6] [7] [8] [9] [10] [11] . Importantly, the PM cholesterol is the cholesterol that participates in the efflux to the extracellular acceptors [12] .

Cholesterol efflux from the macrophage is clinically significant for two reasons. First, there is a significant relationship between the cholesterol efflux capacity (CEC) of apolipoprotein B (apoB)-depleted plasma and the manifestations of various cardiovascular events. The predictive significance of CEC for cardiovascular risk is stronger than for HDL cholesterol level [13] [14] [15] [16] . The second reason is the positive effect of efflux stimulation on the regression of atherosclerotic plaques [15, 17, 18] .

The molecular events in cellular cholesterol efflux, along with the contribution of various pathways, have been extensively studied; however, there is no systematic evaluation of the influence of various low molecular weight substances on cholesterol efflux as a process directed by both donor and acceptor participants. A combined cheminformatic and bioinformatic approach has been applied in the present review to classify and compare the known efflux effectors. Our work may be applicable in the targeted therapy of structural and functional HDL deficiency.

The PubMed database was initially searched using the term 'cholesterol efflux', and papers involving the use of low molecular weight substances were selected. This analysis of published data on the influence of low molecular weight substances on cholesterol efflux with various donors and acceptors revealed 191 substances with activating and inhibiting effects (Table 1) . These substances were grouped into the following classes by means of small-molecule highthroughput screening ( Fig. 1) : (1) inhibitors and activators of SR-B1 receptors or ABC transporters, including sulfonylureas (inhibitors of ATP-sensitive K+ channels); (2) cyclic nucleotides, nucleotide triphosphates, ligands of nucleotide-dependent protein kinases; (3) nuclear receptor ligands and their precursors; (4) cytokines and their receptors; (5) hormones, hormone receptor ligands (excluding ligands of nuclear receptors), hormone metabolism and growth factors; (6) lipid metabolism-intracellular and extracellular; (7) fatty acids and lipid membrane-disturbing agents; (8) protein kinase B, mammalian target of rapamycin, phosphatidylinositol-phospholipase C; (9) ceramide signaling; (10) mitogen-activated protein kinase and non-receptor tyrosine kinase signaling; (11) ion channels and Ca2+ regulation; (12) protein synthesis and degradation; (13) structural and trafficking proteins and their ligands; (14) DNA-dependent processes; (15) other factors; (16) vitamins, coenzymes and metabolites; and (17) extracts, components of plants, and other natural sources. Overall, 153 substances were present in the Chemical Entities of Biological Interest (ChEBI) database [220] .

The subsequent Reactome database search [221] identified 67 substances, and 9 substances were excluded due to dual activating and inhibiting properties. Pathway enrichment was then performed for the remaining 58 substances using the standard Reactome tools with a 'small molecules (chebi)' key. The significant (p < 0.05) 93 pathways were selected, including 45 from 58 substances. The number of significant pathways was reduced to 31 by the replacement of pathways of very low level with higher-level (parent) pathways (Table 2 ). These pathways included the Neuronal System (R-HSA-112316); transcriptional regulation of white adipocyte differentiation (R-HSA-381340); the citric acid (TCA) cycle and respiratory electron transport (R-HSA-1428517); integration of energy metabolism (R-HSA-163685); metabolism of vitamins and cofactors (R-HSA-196854); biological oxidations (R-HSA-211859); fatty acid metabolism (R-HSA-8978868); regulation of lipid metabolism by peroxisome proliferator-activated receptor-α (PPARα; R-HSA-400206); metabolism of steroids (R-HSA-8957322); metabolism of amino acids and derivatives (R-HSA-71291); cell junction organization (R-HSA-446728); signaling by nerve growth factor (R-HSA-166520); signaling by Wnt (R-HSA-195721); visual phototransduction (R-HSA-2187338); signaling by GPCR (R-HSA-372790); signaling by retinoic acid (R-HSA-5362517); death receptor signaling (R-HSA-73887); signaling by PTK6 (R-HSA-8848021); disorders of transmembrane transporters (R-HSA-5619115); diseases of signal transduction (R-HSA-5663202); metabolic disorders of biological oxidation enzymes (R-HSA-5579029); diseases of carbohydrate metabolism (R-HSA-5663084); immune system (R-HSA-168256); plasma lipoprotein assembly, remodeling, and clearance (R-HSA-174824); transport of bile salts and organic acids, metal ions, and amine compounds (R-HSA-425366); transport of vitamins, nucleosides, and related molecules (R-HSA-425397); metabolism of proteins (R-HSA-392499); circadian clock (R-HSA-400253); vesiclemediated transport (R-HSA-5653656); RNA polymerase II transcription (R-HSA-73857); and digestion and absorption (R-HSA-8963743). Importantly, the energy-dependent processes (R-HSA-1428517, R-HSA-163685, R-HSA-211859, R-HSA-5619115, R-HSA-5579029), lipoprotein metabolism and lipid transport (R-HSA-400206, R-HSA-8957322, R-HSA-174824, R-HSA-5653656) and signaling pathways (R-HSA-166520, R-HSA-195721, R-HSA-372790, R-HSA-5362517, R-HSA-73887, R-HSA-8848021, R-HSA-5663202) are included ( Table 2) . ApoA-I [197] Hesperetin One of the major citrus flavonoids THP-1

ApoA-I [198] Leoligin The major lignan from edelweiss (Leontopodium nivale subsp. alpinum)

ApoA-I, human plasma [199] Marrubium vulgare extract The plant is widely used in traditional medicine; extract is rich in phenolic compounds The distribution of activators and inhibitors between particular pathways is shown in Fig. 2 . Importantly, the substances are distributed non-uniformly among different pathways; the 'biological oxidations' pathway includes mostly substances with an activating effect on cholesterol efflux (all-trans retinoic acid, ethanol, 17β-estradiol, progesterone, hydrocortisone, resveratrol), while signaling by the G protein-coupled receptor and protein tyrosine kinase 6 pathways include substances with an inhibiting effect (oleic and eicosapentaenoic acids). 'Biological oxidations' include biotransformation of xenobiotics and endogenous compounds in the liver, kidneys, gut and lungs. As far as chemicals that undergo functionalization, the electrophilic or nucleophilic species can be detrimental to biological systems. Electrophiles can react with electron-rich macromolecules such as proteins, DNA and RNA by covalent interaction, while nucleophiles have the potential to interact with biological receptors [221] . Thus, in addition to nuclear receptor ligands and their precursors activating cholesterol efflux and lipoprotein metabolism, and widely used in clinics (bezafibrate and fenofibric acid [222] , pioglitazone [223] , telmisartan [224] ), targeting biological oxidation processes looks promising for the correction of inefficient reverse cholesterol transport in humans. For instance, the stimulating effect was described for chloroquine [225] , diosgenin [226] , 17β-estradiol [227] , all-trans retinoic acid [228] , ethanol [229] , spermidine [230, 231] , resveratrol [232] and 9-cis-retinoic acid [233] .

We performed a comprehensive analysis of the various substances influencing cholesterol efflux, with pathway enrichment using the Reactome database. The activators and inhibitors of cholesterol efflux are non-uniformly distributed among different pathways. The substances influencing biological oxidation activate cholesterol efflux, and the substances influencing signaling by GPCR and PTK6 inhibit efflux. This analysis may be useful in the targeted therapy of structural and functional HDL deficiency. 

Funding No funding has been received for the conduct of this analysis or the preparation of this article. 

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HIV-1 Nef mobilizes lipid rafts in macrophages through a pathway that competes with ABCA1-dependent cholesterol efflux

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Probucol inhibits ABCA1-mediated cellular lipid efflux

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Cholesterol efflux is differentially regulated in neurons and astrocytes: implications for brain cholesterol homeostasis

Probucol inactivates ABCA1 in the plasma membrane with respect to its mediation of apolipoprotein binding and high density lipoprotein assembly and to its proteolytic degradation

In vitro characterization and endocrine regulation of cholesterol and phospholipid transport in the mammary gland

Cyclosporine A and PSC833 inhibit ABCA1 function via direct binding

Cyclic AMP induces apolipoprotein E binding activity and promotes cholesterol efflux from a macrophage cell line to apolipoprotein acceptors

Ethanol induces cholesterol efflux and up-regulates ATPbinding cassette cholesterol transporters in fetal astrocytes

AMPK activates LXRalpha and ABCA1 expression in human macrophages

ABCA1 increases extracellular ATP to mediate cholesterol efflux to ApoA-I

Identification and characterization of rodent ABCA1 in isolated type II pneumocytes

Adenosine monophosphate-activated protein kinase induces cholesterol efflux from macrophage-derived foam cells and alleviates atherosclerosis in apolipoprotein E-deficient mice

Ht31, a protein kinase A anchoring inhibitor, induces robust cholesterol efflux and reverses macrophage foam cell formation through ATP-binding cassette transporter A1

Angiotensin-(1-7) upregulates (ATP-binding cassette transporter A1) ABCA1 expression through cyclic AMP signaling pathway in RAW 264.7 macrophages

Cholesterol efflux to apoA-I in ABCA1-expressing cells is regulated by Ca2+-dependent calcineurin signaling

Macrophage mitochondrial energy status regulates cholesterol efflux and is enhanced by anti-miR33 in atherosclerosis

Retinoic acid isomers up-regulate ATP binding cassette A1 and G1 and cholesterol efflux in rat astrocytes: implications for their therapeutic and teratogenic effects

13-hydroxy linoleic acid increases expression of the cholesterol transporters ABCA1, ABCG1 and SR-BI and stimulates apoA-Idependent cholesterol efflux in RAW264.7 macrophages

Epoxycholesterol impairs cholesteryl ester hydrolysis in macrophage foam cells, resulting in decreased cholesterol efflux

Polyunsaturated fatty acids and acetoacetate downregulate the expression of the ATP-binding cassette transporter A1

PAPP-A negatively regulates ABCA1, ABCG1 and SR-B1 expression by inhibiting LXRalpha through the IGF-I-mediated signaling pathway

A potent synthetic LXR agonist is more effective than cholesterol loading at inducing ABCA1 mRNA and stimulating cholesterol efflux

Impaired ATP-binding cassette transporter A1-mediated sterol efflux from oxidized LDL-loaded macrophages

Inhibitory effect of PCSK9 on Abca1 protein expression and cholesterol efflux in macrophages

LXR/RXR activation enhances basolateral efflux of cholesterol in CaCo-2 cells

9-cis beta-carotene increased cholesterol efflux to HDL in macrophages

Baicalin promotes cholesterol efflux by regulating the expression of SR-BI in macrophages

Simvastatin and bezafibrate increase cholesterol efflux in men with type 2 diabetes

E17110 promotes reverse cholesterol transport with liver X receptor beta agonist activity in vitro

Ethyl 2,4,6-trihydroxybenzoate is an agonistic ligand for liver X receptor that induces cholesterol efflux from macrophages without affecting lipid accumulation in HepG2 cells

The novel selective PPARalpha modulator (SPPARMalpha) pemafibrate improves dyslipidemia, enhances reverse cholesterol transport and decreases inflammation and atherosclerosis

Nicotinic acid receptor GPR109A is down-regulated in human macrophage-derived foam cells

Salvianolic acid B accelerated ABCA1-dependent cholesterol efflux by targeting PPARgamma and LXRalpha

Aspirin increases apolipoprotein-A-I-mediated cholesterol efflux via enhancing expression of ATP-binding cassette transporter A1

N-Acylthiadiazolines, a new class of liver X receptor agonists with selectivity for LXRbeta

Up-regulation of the ATP-binding cassette transporter A1 inhibits hepatitis C virus infection

LXR agonist treatment of blastic plasmacytoid dendritic cell neoplasm restores cholesterol efflux and triggers apoptosis

Walnut oil increases cholesterol efflux through inhibition of stearoyl CoA desaturase 1 in THP-1 macrophage-derived foam cells

Silymarin constituents enhance ABCA1 expression in THP-1 macrophages

Pioglitazone enhances cholesterol efflux from macrophages by increasing ABCA1/ABCG1 expressions via PPARgamma/ LXRalpha pathway: findings from in vitro and ex vivo studies

Telmisartan enhances cholesterol efflux from THP-1 macrophages by activating PPARgamma

Piperine inhibits ABCA1 degradation and promotes cholesterol efflux from THP-1-derived macrophages

PPAR-alpha and PPAR-gamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway

Anthocyanins induce cholesterol efflux from mouse peritoneal macrophages: the role of the peroxisome proliferator-activated receptor {gamma}-liver X receptor {alpha}-ABCA1 pathway

Saikosaponin-a attenuates oxidized LDL uptake and prompts cholesterol efflux in THP-1 cells

Chrysin inhibits foam cell formation through promoting cholesterol efflux from RAW264.7 macrophages

Tributyltin chloride induces ABCA1 expression and apolipoprotein A-I-mediated cellular cholesterol efflux by activating LXRalpha/RXR

Riccardin C: a natural product that functions as a liver X receptor (LXR)alpha agonist and an LXRbeta antagonist

Methyl protodioscin increases ABCA1 expression and cholesterol efflux while inhibiting gene expressions for synthesis of cholesterol and triglycerides by suppressing SREBP transcription and microRNA 33a/b levels

Promoter-specific roles for liver X receptor/corepressor complexes in the regulation of ABCA1 and SREBP1 gene expression

T-0901317, a synthetic liver X receptor ligand, inhibits development of atherosclerosis in LDL receptor-deficient mice

MiR-33 contributes to the regulation of cholesterol homeostasis

Pim-1L protects cell surfaceresident ABCA1 from lysosomal degradation in hepatocytes and thereby regulates plasma high-density lipoprotein level. Arterioscler

Cytomegalovirus restructures lipid rafts via a US28/CDC42-mediated pathway, enhancing cholesterol efflux from host cells

Activation of PPARgamma does not contribute to macrophage ABCA1 expression and ABCA1-mediated cholesterol efflux to apoAI

Apelin-13 increases expression of ATP-binding cassette transporter A1 via activating protein kinase C alpha signaling in THP-1 macrophage-derived foam cells

CXCL5 limits macrophage foam cell formation in atherosclerosis

Interleukin 8 inhibition enhanced cholesterol efflux in acetylated low-density lipoprotein-stimulated THP-1 macrophages

Interleukin-10 increases reverse cholesterol transport in macrophages through its bidirectional interaction with liver X receptor alpha

Interleukin-18 and interleukin-12 together downregulate ATP-binding cassette transporter A1 expression through the interleukin-18R/nuclear factor-kappaB signaling pathway in THP-1 macrophage-derived foam cells

Interleukin-27 inhibits foam cell formation by promoting macrophage ABCA1 expression through JAK2/STAT3 pathway

TGF-beta increases cholesterol efflux and ABC-1 expression in macrophage-derived foam cells: opposing the effects of IFN-gamma

Tumor necrosis factor-alpha and lymphotoxin-alpha increase macrophage ABCA1 by gene expression and protein stabilization via different receptors

CC-chemokine ligand 2 (CCL2) suppresses high density lipoprotein (HDL) internalization and cholesterol efflux via CC-chemokine receptor 2 (CCR93) induction and p42/44 mitogen-activated protein kinase (MAPK) activation in human endothelial cells

Interferon-beta promotes macrophage foam cell formation by altering both cholesterol influx and efflux mechanisms

Inflammatory stress exacerbates lipid accumulation in hepatic cells and fatty livers of apolipoprotein E knockout mice

Effects of miR-33a-5P on ABCA1/G1-mediated cholesterol efflux under inflammatory stress in THP-1 macrophages

Interferon-gamma-mediated downregulation of cholesterol efflux and ABC1 expression is by the Stat1 pathway

IFN-gamma down-regulates ABCA1 expression by inhibiting LXRalpha in a JAK/STAT signaling pathwaydependent manner

The TNF-like protein 1A-death receptor 3 pathway promotes macrophage foam cell formation in vitro

Local TNF causes NFATc1-dependent cholesterol-mediated podocyte injury

Visfatin promotes foam cell formation by dysregulating CD36, SRA, ABCA1, and ABCG1 expression in Raw264.7 macrophages

17beta-estradiol promotes cholesterol efflux from vascular smooth muscle cells through a liver X receptor alphadependent pathway

Angiotensin-(1-7) upregulates expression of adenosine triphosphate-binding cassette transporter A1 and adenosine triphosphate-binding cassette transporter G1 through the Mas receptor through the liver X receptor alpha signalling pathway in THP-1 macrophages treated with angiotensin-II

Glucagon-like peptide 1 (GLP-1)-based therapy upregulates LXR-ABCA1/ABCG1 cascade in adipocytes

Fibroblast growth factor 21 enhances cholesterol efflux in THP-1 macrophage-derived foam cells

Ghrelin inhibits foam cell formation via simultaneously down-regulating the expression of acyl-coenzyme A:cholesterol acyltransferase 1 and up-regulating adenosine triphosphate-binding cassette transporter A1

Growth differentiation factor-15 induces expression of ATP-binding cassette transporter A1 through PI3-K/PKCzeta/SP1 pathway in THP-1 macrophages

Insulin-like growth factor 1 regulates the expression of ATP-binding cassette transporter A1 in pancreatic beta cells

Effect of vildagliptin and pravastatin combination on cholesterol efflux in adipocytes

Insulin promotes macrophage foam cell formation: potential implications in diabetes-related atherosclerosis

Corticotropin-releasing hormone (CRH) promotes macrophage foam cell formation via reduced expression of ATP binding cassette transporter-1 (ABCA1)

Glucocorticoid receptor regulates ATP-binding cassette transporter-A1 expression and apolipoprotein-mediated cholesterol efflux from macrophages

Inhibition of ERK1/2 and activation of liver X receptor synergistically induce macrophage ABCA1 expression and cholesterol efflux

Hydrocortisone directly promotes cholesterol accumulation in macrophages

Insulin down-regulates specific activity of ATP-binding cassette transporter A1 for high density lipoprotein biogenesis through its specific phosphorylation

Clinically used selective estrogen receptor modulators affect different steps of macrophage-specific reverse cholesterol transport

Ibrolipim increases ABCA1/G1 expression by the LXRalpha signaling pathway in THP-1 macrophage-derived foam cells

An inhibitor of acylCoA: cholesterol acyltransferase increases expression of ATP-binding cassette transporter A1 and thereby enhances the ApoA-I-mediated release of cholesterol from macrophages

SPTLC1 binds ABCA1 to negatively regulate trafficking and cholesterol efflux activity of the transporter

Effects of NTE-122, a novel acyl-CoA:cholesterol acyltransferase inhibitor, on cholesterol esterification and high-density lipoprotein-induced cholesterol efflux in macrophages

Phospholipid transfer protein interacts with and stabilizes ATP-binding cassette transporter A1 and enhances cholesterol efflux from cells

Pitavastatin increases ABCA1-mediated lipid efflux from Fu5AH rat hepatoma cells

Down-regulation of lipoprotein lipase increases ABCA1-mediated cholesterol efflux in THP-1 macrophages

Statin-induced decrease in ATP-binding cassette transporter A1 expression via microRNA33 induction may counteract cholesterol efflux to high-density lipoprotein

HMG-CoA reductase inhibitors, simvastatin and atorvastatin, downregulate ABCG1-mediated cholesterol efflux in human macrophages

Modulation of microRNA expression in subjects with metabolic syndrome and decrease of cholesterol efflux from macrophages via microRNA-33-mediated attenuation of ATPbinding cassette transporter A1 expression by statins

The effect of statins on ABCA1 and ABCG1 expression in human macrophages is influenced by cellular cholesterol levels and extent of differentiation

Pitavastatin effect on ATP binding cassette A1-mediated lipid efflux from macrophages: evidence for liver X receptor (LXR)-dependent and LXR-independent mechanisms of activation by cAMP

Efflux of lipid from fibroblasts to apolipoproteins: dependence on elevated levels of cellular unesterified cholesterol

Expression of ABCG1, but not ABCA1, correlates with cholesterol release by cerebellar astroglia

Antitumoral alkylphospholipids induce cholesterol efflux from the plasma membrane in HepG2 cells

ABCA1-mediated cholesterol efflux is defective in free cholesterol-loaded macrophages. Mechanism involves enhanced ABCA1 degradation in a process requiring full NPC1 activity

Delton-Vandenbroucke I. Bis(monoacylglycero)phosphate accumulation in macrophages induces intracellular cholesterol redistribution, attenuates liver-X receptor/ATP-Binding cassette transporter A1/ATP-binding cassette transporter G1 pathway, and impairs cholesterol efflux

Pleiotropic effects of antitumour alkylphospholipids on cholesterol transport and metabolism

Eicosapentaenoic acid reduces ABCA1 serine phosphorylation and impairs ABCA1-dependent cholesterol efflux through cyclic AMP/protein kinase A signaling pathway in THP-1 macrophage-derived foam cells

Linoleic acid suppresses cholesterol efflux and ATP-binding cassette transporters in murine bone marrowderived macrophages

Acyl-CoA synthetase 1 is required for oleate and linoleate mediated inhibition of cholesterol efflux through ATP-binding cassette transporter A1 in macrophages

Akt inhibition promotes ABCA1-mediated cholesterol efflux to ApoA-I through suppressing mTORC1

PI(4,5)P2 is translocated by ABCA1 to the cell surface where it mediates apolipoprotein A1 binding and nascent HDL assembly

Ceramide enhances cholesterol efflux to apolipoprotein A-I by increasing the cell surface presence of ATP-binding cassette transporter A1

Cathepsin D, a lysosomal protease, regulates ABCA1-mediated lipid efflux

MEK1/2 inhibitors activate macrophage ABCG1 expression and reverse cholesterol transport-An anti-atherogenic function of ERK1/2 inhibition

Lck inhibits heat shock protein 65-mediated reverse cholesterol transport in T cells

Digoxin and ouabain induce the efflux of cholesterol via liver X receptor signalling and the synthesis of ATP in cardiomyocytes

Nifedipine enhances cholesterol efflux in RAW264.7 macrophages. Cardiovasc Drugs Ther

Effect of apolipoprotein A-I on ATP binding cassette transporter A1 degradation and cholesterol efflux in THP-1 macrophage-derived foam cells

Proteasomal inhibition promotes ATP-binding cassette transporter A1 (ABCA1) and ABCG1 expression and cholesterol efflux from macrophages in vitro and in vivo

Monensin and brefeldin A inhibit high density lipoprotein-mediated cholesterol efflux from cholesterol-enriched cells. Implications for intracellular cholesterol transport

Evidence for the separation of albumin-and apo A-I-dependent mechanisms of cholesterol efflux from cultured fibroblasts into human plasma

Expression of caveolin-1 enhances cholesterol efflux in hepatic cells

Targeting mitochondrial 18 kDa translocator protein (TSPO) regulates macrophage cholesterol efflux and lipid phenotype

Targeting GGTase-I activates RHOA, increases macrophage reverse cholesterol transport, and reduces atherosclerosis in mice

DNA topoisomerase II inhibitors induce macrophage ABCA1 expression and cholesterol efflux-an LXR-dependent mechanism

A novel gene regulator, pyrrole-imidazole polyamide targeting ABCA1 gene increases cholesterol efflux from macrophages and plasma HDL concentration

A novel function of apolipoprotein E: upregulation of ATP-binding cassette transporter A1 expression

CD36-mediated cholesterol efflux is associated with PPARgamma activation via a MAPK-dependent COX-2 pathway in macrophages

IRAK regulates macrophage foam cell formation by modulating genes involved in cholesterol uptake and efflux

Lactobacillus acidophilus K301 inhibits atherogenesis via induction of 24 (S), 25-epoxycholesterol-mediated ABCA1 and ABCG1 production and cholesterol efflux in macrophages

Purified human paraoxonase-1 interacts with plasma membrane lipid rafts and mediates cholesterol efflux from macrophages

Arsenic trioxide suppresses liver X receptor beta and enhances cholesteryl ester transfer protein expression without affecting the liver X receptor alpha in HepG2 cells

COX-2-dependent and independent effects of COX-2 inhibitors and NSAIDs on proatherogenic changes in human monocytes/macrophages

Chlamydia pneumoniae negatively regulates ABCA1 expression via TLR2-Nuclear factorkappa B and miR-33 pathways in THP-1 macrophage-derived foam cells

C-reactive protein inhibits cholesterol efflux from human macrophage-derived foam cells

Necrotic cell sensor Clec4e promotes a proatherogenic macrophage phenotype through activation of the unfolded protein response

The novel anticancer agent JNJ-26854165 induces cell death through inhibition of cholesterol transport and degradation of ABCA1

Acidic extracellular environments strongly impair ABCA1-mediated cholesterol efflux from human macrophage foam cells

Human serum albumin and its structural variants mediate cholesterol efflux from cultured endothelial cells

Differential regulation of ATP binding cassette protein A1 expression and ApoA-I lipidation by Niemann-Pick type C1 in murine hepatocytes and macrophages

Antagonism of betulinic acid on LPS-mediated inhibition of ABCA1 and cholesterol efflux through inhibiting nuclear factor-kappaB signaling pathway and miR-33 expression

Human immunodeficiency virus protease inhibitor ritonavir inhibits cholesterol efflux from human macrophage-derived foam cells

Urotensin II increases foam cell formation by repressing ABCA1 expression through the ERK/NF-kappaB pathway in THP-1 macrophages

Nitro-oleic acid reduces J774A.1 macrophage oxidative status and triglyceride mass: involvement of paraoxonase2 and triglyceride metabolizing enzymes

Vitamin D protects against atherosclerosis via regulation of cholesterol efflux and macrophage polarization in hypercholesterolemic swine

Citrulline increases cholesterol efflux from macrophages in vitro and ex vivo via ATP-binding cassette transporters

Coenzyme Q10 consumption promotes ABCG1-mediated macrophage cholesterol efflux: a randomized, double-blind, placebo-controlled, cross-over study in healthy volunteers

Coenzyme Q10 promotes macrophage cholesterol efflux by regulation of the activator protein-1/miR-378/ATP-binding cassette transporter G1-signaling pathway

Effect of ethanol on cell growth and cholesterol metabolism in cultured Hep G2 cells

Reduced glutathione increases quercetin stimulatory effects on HDL-or apoA1-mediated cholesterol efflux from J774A.1 macrophages

Nicotinic acid inhibits progression of atherosclerosis in mice through its receptor GPR109A expressed by immune cells

Niacin promotes cholesterol efflux through stimulation of the PPARgamma-LXRalpha-ABCA1 pathway in 3T3-L1 adipocytes

Spermidine reduces lipid accumulation and necrotic core formation in atherosclerotic plaques via induction of autophagy

Inhibition of cholesterol efflux by 7-ketocholesterol: comparison between cells, plasma membrane vesicles, and liposomes as cholesterol donors

In vitro effects of exogenous carbon monoxide on oxidative stress and lipid metabolism in macrophages

Exendin-4 ameliorates lipotoxicity-induced glomerular endothelial cell injury by improving ABC transporter A1-mediated cholesterol efflux in diabetic apoE knockout mice

Neopterin negatively regulates expression of ABCA1 and ABCG1 by the LXRalpha signaling pathway in THP-1 macrophage-derived foam cells

Alpinetin enhances cholesterol efflux and inhibits lipid accumulation in oxidized lowdensity lipoprotein-loaded human macrophages

Arctigenin promotes cholesterol efflux from THP-1 macrophages through PPAR-gamma/LXR-alpha signaling pathway

Purple perilla extracts with alpha-asarone enhance cholesterol efflux from oxidized LDL-exposed macrophages

Astaxanthin enhances ATP-binding cassette transporter A1/G1 expressions and cholesterol efflux from macrophages

Optimization of rutaecarpine as ABCA1 up-regulator for treating atherosclerosis

Betulin attenuates atherosclerosis in apoE−/− mice by up-regulating ABCA1 and ABCG1

Dihydrocapsaicin attenuates plaque formation through a PPARgamma/LXRalpha pathway in apoE(−/−) mice fed a high-fat/high-cholesterol diet

Curcumin promotes cholesterol efflux from adipocytes related to PPARgamma-LXRalpha-ABCA1 passway

Identification of dehydroxytrichostatin A as a novel up-regulator of the ATP-binding cassette transporter A1 (ABCA1)

Diosgenin inhibits atherosclerosis via suppressing the MiR-19b-induced downregulation of ATP-binding cassette transporter A1

Emodin enhances cholesterol efflux by activating peroxisome proliferator-activated receptor-gamma in oxidized low density lipoproteinloaded THP1 macrophages

Ethanolic extracts of Brazilian red propolis increase ABCA1 expression and promote cholesterol efflux from THP-1 macrophages

Hesperetin upregulates ABCA1 expression and promotes cholesterol efflux from THP-1 macrophages

Leoligin, the Major Lignan from Edelweiss (Leontopodium nivale subsp. alpinum), Promotes Cholesterol Efflux from THP-1 Macrophages

Marrubium vulgare extract inhibits human-LDL oxidation and enhances HDLmediated cholesterol efflux in THP-1 macrophage

A novel small molecule liver X receptor transcriptional regulator, nagilactone B, suppresses atherosclerosis in apoE-deficient mice

Novel effect of paeonol on the formation of foam cells: promotion of LXRalpha-ABCA1-dependent cholesterol efflux in macrophages

The effects of phellinus linteus polysaccharide extracts on cholesterol efflux in oxidized low-density lipoprotein-loaded THP-1 macrophages

Pomegranate peel polyphenols inhibit lipid accumulation and enhance cholesterol efflux in raw264.7 macrophages

Gut microbiota metabolism of anthocyanin promotes reverse cholesterol transport in mice via repressing miRNA-10b

Rutaecarpine suppresses atherosclerosis in ApoE−/− mice through upregulating ABCA1 and SR-BI within RCT

Quercetin increases macrophage cholesterol efflux to inhibit foam cell formation through activating PPARgamma-ABCA1 pathway

Synthesis and cardiovascular protective efects of quercetin 7-O-sialic acid

Resveratrol counters systemic lupus erythematosus-associated atherogenicity by normalizing cholesterol efflux

Sage weed (Salvia plebeia) extract antagonizes foam cell formation and promotes cholesterol efflux in murine macrophages

Sesamol and sesame (Sesamum indicum) oil enhance macrophage cholesterol efflux via up-regulation of PPARgamma1 and LXRalpha transcriptional activity in a MAPK-dependent manner

Sesamin enhances cholesterol efflux in RAW264.7 macrophages

Tanshinone IIA suppresses cholesterol accumulation in human macrophages: role of heme oxygenase-1

Phenolic-extract from argan oil (Argania spinosa L.) inhibits human low-density lipoprotein (LDL) oxidation and enhances cholesterol efflux from human THP-1 macrophages

Wogonin promotes cholesterol efflux by increasing protein phosphatase 2B-dependent dephosphorylation at ATP-binding cassette transporter-A1 in macrophages

Zerumbone, a natural cyclic sesquiterpene, promotes ABCA1-dependent cholesterol efflux from human THP-1 macrophages

Paraoxsonase2 (PON2) and oxidative stress involvement in pomegranate juice protection against cigarette smoke-induced macrophage cholesterol accumulation

Regulation of macrophage cholesterol efflux and liver X receptor alpha activation by nicotine

Molecular mechanisms underlying the effects of statins in the central nervous system

The ChEBI reference database and ontology for biologically relevant chemistry: enhancements for

The reactome pathway knowledgebase

Balanced pan-PPAR activator bezafibrate in combination with statin: comprehensive lipids control and diabetes prevention?

Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis

Efficacy and tolerability of telmisartan/amlodipine and rosuvastatin coadministration in hypertensive patients with hyperlipidemia: a phase III, multicenter, randomized, double-blind study

Cardiovascular risk factors in inflammatory arthritis

An update on the biological and pharmacological activities of diosgenin

Sex differences in lipid and lipoprotein metabolism

Retinoic acid and liver X receptor agonist synergistically inhibit HIV infection in CD4+ T cells by up-regulating ABCA1-mediated cholesterol efflux

Moderate beer intake and cardiovascular health in overweight individuals

Target acquired: selective autophagy in cardiometabolic disease

Spermidine in health and disease

Transintestinal cholesterol excretion in humans

Liver X receptor: a cardinal target for atherosclerosis and beyond