Abstract
The cholesterol efflux protein ATP binding cassette protein A1 (ABCA) and apolipoprotein A1 (apo A1) are key constituents in the process of reverse-cholesterol transport (RCT), whereby excess cholesterol in the periphery is transported to the liver where it can be converted primarily to bile acids for either use in digestion or excreted. Due to their essential roles in RCT, numerous studies have been conducted in cells, mice, and humans to more thoroughly understand the pathways that regulate their expression and activity with the goal of developing therapeutics that enhance RCT to reduce the risk of cardiovascular disease. Many of the drugs and natural compounds examined target several transcription factors critical for ABCA1 expression in both macrophages and the liver. Likewise, several miRNAs target not only ABCA1 but also the same transcription factors that are critical for its high expression. However, after years of research and many preclinical and clinical trials, only a few leads have proven beneficial in this regard. In this review we discuss the various transcription factors that serve as drug targets for ABCA1 and provide an update on some important leads.
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1 Introduction
The ATP binding cassette A1 (ABCA1) efflux protein is a member of the ATP-dependent transport proteins. Upon binding to either lipid-free apolipoprotein (apo A1) or high-density lipoprotein (HDL), ABCA1 transports intracellular or membrane-associated cholesterol in a unidirectional manner out of the cell [1,2,3]. ABCA1 is expressed in many tissues and has been shown to be essential for the generation of nascent HDL and for cholesterol efflux in macrophage cells. Loss of ABCA1 in mice or in humans (as in Tangier’s disease) results in extremely low plasma HDL levels and increases susceptibility to atherosclerosis [4,5,6]. Therefore, ABCA1 is a key partner in the process of reverse-cholesterol transport (RCT) and numerous preclinical and clinical trials have been carried out to safely enhance its expression and activity. Regulation of the ABCA1 gene is complex. Several intracellular signaling pathways that sense intracellular sterol levels, lipid metabolites, and retinoids regulate ABCA1 promoter activity, as do inflammatory cytokines [7,8,9,10]. Furthermore, ABCA1 expression is negatively regulated post-transcriptionally by several micro RNAs and by proteasome-mediated degradation. This review focuses on mechanisms associated with transcriptional regulation of ABCA1 gene expression and describe potential therapeutic agents that target ABC1 gene expression.
2 The ABC Family of Lipid Transporters
The ABC family of proteins is involved in lipid transport to various compartments within and out of cells. Most of these transporters contain two trans-membrane domains each consisting of six hydrophobic helical bundles and two ATP binding domains that hydrolyze ATP, providing the energy required to transport its substrate against a concentration gradient (Fig. 1). Sequence alignments have indicated that this family of proteins can be classified into seven subfamilies. ABCA1 is a cholesterol and phospholipid efflux protein that is mutated in Tangier’s disease [4,5,6], while ATP binding cassette protein G1 (ABCG1) and ATP binding cassette protein B4 (ABCB4, also known as multidrug resistance 3) have been shown to transport cholesterol and phospholipids (ABCG1) and phosphatidylcholine (ABCB4). The human ABCA1 gene, the founding member of the ABCA family [11], encodes a 254 kDa protein and is located on chromosome 9q31. The human ABCA1 gene has 50 exons and spans nearly 150 kbp [12]. The ABCA1 gene encodes two mRNA species: type L, which is expressed in the liver only, and type P, which is expressed in liver and peripheral tissues [7]. Type P ABCA1 mRNA is liver-X-receptor (LXR) -responsive while the type L ABCA1 mRNA is regulated by sterol-responsive element binding protein 2 (SREBP2) [7]. The ABCA1 protein is localized to the cell surface and has been shown to interact with other proteins on its intracellular interface, including the oxysterol receptor liver-X-receptor β (LXRβ [13].
ABCA1 protein structure and topology. Alpha helices forming transmembrane domains 1-12, extracellular and intracellular helices, nucleotide binding domains (NBDs), and a PEST (Proline, Glutamic acid, Serine, Threonine) domain are indicated. The NBDs bind and hydrolyze ATP driving the transport of cholesterol while ABCA1 protein degradation (half-life) is mediated in part through the PEST domain
3 The ABCA1 Gene and Atherosclerosis
Numerous studies suggest that ABCA1 is a key component of reverse-cholesterol transport (RCT) [1,2,3] (Fig. 2) and HDL synthesis in both hepatocytes and intestinal cells [14]. It is noteworthy that the de novo-produced HDL is more likely to have cardioprotective properties than HDL that has accumulated because of reduced clearance [15]. The ABCA1 gene is mutated in Tangier’s disease and fibroblasts from these patients have reduced cholesterol efflux capacity, extremely low HDL levels, and a higher incidence of cardiovascular disease [4,5,6]. Genetic studies have also demonstrated that certain ABCA1 gene variants predict the development of ischemic heart disease [16,17,18,19]. Furthermore, Frikke-Schmidt [20] demonstrated that several ABCA1 allele variants were predictive of heart disease in subjects enrolled in the Copenhagen City Heart Study. The authors genotyped 9,259 individuals from the general Danish population, examining the presence of six nonsynonymous single nucleotide polymorphisms (SNPs), and found that three of them (V771M, I883M, and E1172D) were the most important predictors of ischemic heart disease.
Reverse-cholesterol transport. Apolipoprotein A-I is synthesized in the liver (primary site) and small intestine and is lipidated by ATP binding cassette A1 (ABCA1) to generate pre-β-high-density lipoprotein (pre-β-HDL). Pre-β-HDL binds ABCA1 and free-cholesterol is transferred, forming HDL. Lecithin-cholesterol acyltransferase (LCAT) esterifies some of the free cholesterol and these cholesterol esters (CE) form the core of the mature HDL particle. Some of the cholesterol is removed from the mature HDL particle and transferred to low-density lipoprotein (LDL) by cholesteryl ester transfer protein (CETP) in exchange for triglyceride. The LDL binds the low-density lipoprotein receptor (LDLR) and the cholesterol is released. The mature HDL particle can also bind scavenger receptor class B type 1 (SRB1), a cholesterol transfer protein that transfers cholesterol (Chol) into the liver. The cholesterol may be converted to bile acids, however both bile acids and cholesterol are transported to the small intestine via the gall bladder
Obesity and metabolic syndrome are important risk factors for atherosclerosis [21, 22]. ABCA1 and ABCG1 are also expressed in white adipose tissue (WAT) and subcutaneous fat. Adipocytes contain more than 25% of the total cholesterol in the body [23], with 95% in the free form [24]. Obesity is associated with reduced HDL levels [25]. Furthermore, Choromanska et al. [26] demonstrated that plasma membrane-associated ABCA1 levels in WAT decreased significantly in obese individuals without metabolic syndrome whereas total ABCA1 levels were unchanged [26]. Plasma membrane-associated ABCG1 levels were also significantly decreased in obese women with metabolic syndrome, while total ABCG1 levels increased in WAT from obese individuals without metabolic syndrome [26]. These results suggest that obesity-associated adipocytes likely have decreased cholesterol efflux to HDL via ABCA1.
Intracellular cholesterol and triglyceride levels were higher in adipocytes of ABCA1-deficient mice on a high-fat, high-cholesterol diet [27]. As a result, the mice experienced decreased glucose tolerance and insulin sensitivity [27]. Furthermore, Umemoto et al. [28] demonstrated that ABCA1 was essential for the apo A-I and HDL-associated anti-inflammatory effects on adipocytes. Thus, in both mice and humans, ABCA1 is important in modulating adipocyte function.
4 Transcriptional Regulation of the ABCA1 Gene
Early studies indicated that ABCA1 protein levels increase when intracellular sterol and oxysterol levels are elevated. The sterol-responsive region in the ABCA1 gene promoter was mapped to a direct repeat 4 (DR4) element located 63 base pairs 5′ of the transcriptional start site and binds the liver-X- receptor α or β (LXRα, LXRβ)/retinoid- X- receptor α heterodimer [8, 9] (Fig. 3). LXRα is expressed primarily in liver, kidney, macrophage cells, endothelial cells, and intestine while LXRβ is expressed ubiquitously. LXRs bind to oxysterols stimulating LXR/RXR α dimer formation and binding to the DR4 element in the ABCA1 gene promoter. Several oxysterols, including the endogenous 20(S)-hydroxycholesterol, 22(R)-hydroxycholesterol, and 25-hydroxycholesterol, as well as several non-steroidal ligands bind to LXR and activate or repress expression of LXR-dependent genes. Other LXR ligands examined for their capacity to up-regulate ABCA1 gene expression and RCT are listed in Table 1. LXR-623 was the first LXR agonist examined in a clinical trial [59]. In a phase 2 escalating dose trial in normal healthy participants, LXR-623 was rapidly absorbed in a dose-dependent manner with peak concentrations achieved in 2 h [59]. The mean terminal disposition half-life was between 41 and 43 h independent of dose, and LXR-623 induced ABCA1 and ABCG1 levels, again in a dose-dependent manner with EC50 values of 526 ng/ml and 729 ng/ml, respectively [59]. Unfortunately, central nervous system-related adverse events were reported at the highest doses. Due to the presence of RXR in the activated LXR/RXR heterodimer, many LXR-dependent genes are also regulated by the RXR ligand 9-cis-retinoic acid and other retinoids (Table 2). Of the compounds listed in Tables 1 and 2, stigmasterol derivatives are the only agents for which subjects are being enrolled in clinical trials targeting cardiovascular disease (NCT03983603 and NCT02481466). Of note, all clinical trials identified in this review are currently enrolling subjects; we excluded all completed clinical trials. We also focused on trials listed on Clinicaltrials.gov.
The ATP binding cassette A1 (ABCA1) gene promoter. The ABCA1 gene promoter is regulated by several tissue-specific, hormonal, and metabolic cues to generate two ABCA1 mRNA species (arrows). Binding sites for hepatocyte nuclear factor 1 (HNF1), liver-X-receptor (LXR), peroxisome proliferator-activated receptor (PPAR), retinoic acid receptor (RAR), retinoid-X-receptor (RXR), sterol-responsive element binding protein (SREBP), specificity protein 1/3 (SP1/3), TATA binding activating factors (TAF’s), and upstream stimulatory factor 1/2 (USF1/2) are indicated. Binding sites for these factors include two GC boxes, an E box, a direct-repeat 4 (DR4) element, a TATA box, and an intragenic sterol-responsive element (SRE). Drugs that induce ABCA1 gene expression include agonists for several nuclear receptors (LXR, PPAR, RXR, and RAR) and SREBPs. ABCA1 inhibitors include epigenetic changes (especially cytosine methylation), TNFα, endotoxin, and several siRNAs that promote ABCA1 mRNA degradation
Oxysterol binding proteins (OSBPs) have also been shown to alter cholesterol efflux, HDL levels, and ABCA1 expression. The OSBP and OSBP-related protein (ORPs) families form the largest family of lipid transfer proteins [72]. The OSBPs transfer cholesterol and phosphatidylserine against concentration gradients, transferring phosphoinositide in the opposite direction. These proteins possess lipid-binding and membrane-interacting domains [72]. When late endosomal (LE) lysosomal cholesterol levels are high, ORP1L and ORP1S participate in the transfer of cholesterol from the late endosomal vesicle to the endoplasmic reticulum (ER) where it is esterified [73]. When LE lysosomal cholesterol levels are low, ORP1L transfers cholesterol from the ER to the LE lysosome in a microtubule-guided process and driven by the molecular motor dynein [74]. Interestingly, ORP1S has also been shown to translocate to the nucleus and upregulate apolipoprotein E expression via LXR activation [75]. Whether or not it upregulates ABCA1 gene expression is not known.
The OSBPs and ORPs are also involved in dyslipidemia and atherosclerosis. A heterozygous loss-of-function ORP1L allele (C38X) produces a truncated protein and is associated with hypoalphalipoproteinemia [76]. Cultured fibroblasts from these individuals have reduced cholesterol efflux capacity to apo A-1 [76]. These results suggest that a defect in LE lysosomal trafficking can promote dyslipidemia. Activation of ORP7 by 5-arylnicotinamide in kidney podocytes increased ABCA1 protein levels by prolonging its half-life and enhanced cholesterol efflux to HDL [77]. In mouse kidney disease model, 5-arylnicotinamide treatment normalized proteinuria and prevented the decline in renal function [76].
The retinoic acid receptor (RAR), which binds the ligand all-trans-retinoic acid, has also been shown to upregulate ABCA1 gene expression. The specific RAR agonist 4-[(E)-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtalenyl)-1-propenyl]benzoic acid (TTNPB) (Table 2) increased ABCA1 expression in both mouse and human macrophages [78, 79]. Other retinoids, including 9-cis-retinoic acid, also increased ABCA1 gene expression. Manna et al. [55] and Zhou et al. [78] independently demonstrated that 9-cis-retinoic acid increased ABCA1 expression in macrophage cells by stimulating the LXRα/RXR heterodimer. The synthetic RXR agonist stimulated ABCA1 expression and cholesterol efflux also through the LXRα/RXR heterodimer while HX630 stimulated ABCA1 gene through the peroxisome proliferator-activated receptor γ (PPARγ/RXR heterodimer in RAW264 cells [64]. Since RXR is an important factor involved in the activity of all class II nuclear hormone receptors including PPARs, thyroid hormone receptor (THR), RAR, vitamin D receptor (VDR), and farnesoid-X-receptor (FXR), use of retinoids targeting this receptor induces a wide spectrum of adverse effects, especially hypertriglyceridemia, limiting their use for reverse cholesterol transport [79].
Located immediately 5′ to the DR4 element is a GC-box containing binding sites for the specificity protein 1 (SP1) family of transcription factors. SP1 has been shown to interact with several nuclear receptors including RXR [80], the VDR [81], and the estrogen receptor (ER) [82]. Thymiakou et al. [83] demonstrated that induction of ABCA1 promoter activity by LXRα ligands required SP1, and that the SP1 transactivation domain and DNA binding domain were required to interact with the LXRα transactivation/DNA binding domain. Chen et al. [67] demonstrated that low-density lipoprotein (LDL) treatment of mouse macrophage cells induces SP1 binding to a GC box located in the mouse ABCA1 gene promoter (which is conserved in the human gene promoter). Treatment of mouse macrophage cells with LDL increased intracellular phosphatidylinositol-3 (PI-3) kinase and protein kinase t activity, resulting in Sp1 phosphorylation and increased binding to the ABCA1 gene promoter in vivo. Mutation of either the SP1 or LXR element in the ABCA1 gene promoter decreased the capacity of LDL to induce ABCA1 gene expression, while mutation of both elements completely abolished the effect, suggesting that there is cross-talk between the DR4 and SP1 elements.
The DR4 element is also required for induction of ABCA1 promoter activity by niacin. Niacin increases plasma HDL levels significantly and is used therapeutically to manage dyslipidemia [84, 85] but does not reduce the risk of cardiovascular events [86]. Previous studies suggested that niacin increases apo A-I levels by decreasing its catabolic rate [87, 88], while other studies in cell cultures suggest that niacin may increase apo A-I synthesis [89, 90]. Zhang et al. [91] demonstrated that niacin-treatment of HepG2 cells increases ABCA1 expression and increases HDL synthesis by promoting lipidation of nascent apo A-I. Niacin treatment increased LXRα expression and mutation of the LXR binding DR4 element abolished the effect of niacin on ABCA1 promoter activity. It is not clear, however, if niacin mediates these effects through a receptor-mediated mechanism or if LXRα expression and activity is induced by niacin-induced intracellular accumulation of oxidized cholesterol.
The adipocyte-derived bioactive peptide adiponectin has also been shown to regulate hepatic HDL and ABCA1 synthesis [92] and ABCA1 expression in RAW 264.7 macrophage cells [93]. Though the former study did not investigate the molecular mechanisms involved in regulating HDL and ABCA1 synthesis, in the latter study the authors showed adiponectin induced LXRα expression in RAW 264.7 macrophages, which was inhibited by addition of an LXRα-specific small interfering RNA [93]. Likewise, Oku et al. [94] demonstrated that ABCA1 expression and apo A-I synthesis in the liver is dramatically reduced in adiponectin-deficient mice. In most studies, high plasma adiponectin levels are directly correlated with elevated plasma high-density lipoprotein cholesterol (HDLc) levels [95, 96], while hypoadiponectinemia is associated with several risk factor for cardiovascular disease including visceral adiposity, hypertension, impaired glucose tolerance, and low HDLc levels [96]. Adiponectin has been shown to possess anti-inflammatory and anti-atherogenic properties [97, 98], though mechanisms related to their effects remain to be elucidated.
PPAR ligands, commonly used to treat dyslipidemia and diabetes have been shown to impact ABCA1 gene expression (Table 3), though their effects are complex. Mogilenko et al. [103] showed that the peroxisome proliferator activated receptor γ (PPARγ) induces ABCA1 gene transcription; however, it reduced ABCA1 protein levels on the surface of HepG2 liver cells. Cells treated with GW1929, a potent and specific PPARγ agonist, induced LXRβ binding to the ABCA1 gene promoter and increased ABCA1 mRNA levels. GW1929 treatment also led to a disruption in formation of the ABCA1/LXRβ complex, destabilizing the ABCA1 component and leading to its degradation [103]. Interestingly, inhibition of the protein kinases mitogen-activated protein kinase kinase 1/2 (MEK1/2) partially prevented the GW1929-mediated disruption of the ABCA1/LXRβ complex at the cell surface. Since GW1929 is a PPARγ agonist and not a LXR agonist, the authors speculated that GW1929 enhances cytochrome P450-Cyp27 activity increasing the production of 27-hydroxycholesterol, a weak LXR agonist [123].
There are many randomized clinical trials examining the effects of pioglitazone (PPARγ agonist) on various components that mediate RCT. Yoshi et al. [124] performed a randomized multicenter open-label comparative study in 522 patients with diabetes. Each patient was randomly assigned to receive pioglitazone (n = 254) or not (n = 268) and observed for a medium of 672 days [124]. The primary outcome was the time to first occurrence of a composite all-cause death, nonfatal cerebral infarction, and nonfatal myocardial infarction. Pioglitazone treatment reduced HbA1c levels, diastolic blood pressure, LDL-cholesterol levels, and importantly increased HDL-cholesterol levels. However, there was no difference in the cumulative incidence of the primary outcomes (nine in the pioglitazone group and ten in the non-pioglitazone group) [124]. In the Diabetes Atherosclerosis Intervention Study, the effect of fenofibrate (PPARα agonist) on HDL and cardiovascular disease was examined [125]. Those who were assigned to 200 mg of fenofibrate had higher HDL α-2 and α-3 levels. Fenofibrate treatment had no effect on total LDLc and small dense LDLc but decreased triglyceride and remnant-like particle cholesterol [125]. Also, a randomized, placebo-controlled, cross-over study (three 8-week treatment periods with 40 mg daily simvastatin, 400 mg daily bezafibrate (pan-PPAR agonist), alone and in combination) was carried out in 14 men with type 2 diabetes and cholesterol efflux was measured in THP-1 macrophage cells and pre- β -HDL was measured using crossed immunoelectrophoresis [126]. Pre- β -HDL levels were increased in all three treatment groups, as was cholesterol efflux capacity [126].
Of all the compounds listed in Table 3, there are only two pioglitazone trials targeting cardiovascular disease (NCT04123067 and NCT04419337) and one atherosclerosis trial (NCT04392557). There are four fenofibrate trials targeting cardiovascular disease (NCT04907084, NCT04661358, NCT01320345, and NCT04748965) and one clinical trial looking at atherosclerosis (NCT00965315)
3-Hydroxy-3-methyl-glutaryl coenzyme A (HMG-CoA) reductase inhibitors have also been shown to increase ABCA1 mRNA levels in liver cells in vitro [127, 128]. Maejima et al. [50] showed that pitavastatin, atorvastatin, and simvastatin, but not pravastatin, induced ABCA1 expression in rat McARH7777 hepatoma cells. Surprisingly, treatment with pitavastatin repressed P-type ABCA1 mRNA but increased the amount of ABCA1 L-type mRNA. Pitavastatin treatment also increased PPARα receptor (as well as its target genes), inhibiting LXR activity and enhanced ABCA1 protein stability [50]. In another study, ABCA1 mRNA levels in pravastatin-treated murine RAW264.7 cells decreased when cells were cultured in lipoprotein-deficient conditions [129]. Interestingly, this inhibition was blunted when cells were treated with mevalonic acid and cholesterol, or treated with LXR agonist 22(R)-hydroxycholesterol. Pravastatin had no effect on ABCA1 mRNA and protein levels in HepG2 cells. In mice administered pravastatin (0.1% in drinking water) for 2 weeks, hepatic and leukocyte LXRα levels increased but there was no change in ABCA1 gene expression. It is not clear why pravastatin does not decrease ABCA1 in HepG2 cells as observed in macrophage cells. HMG-CoA reductase inhibitors activate PPARα [130] and PPARγ [131], elevating LXRα levels and ABCA1 expression [66, 110]. Another factor may be related to the level of endogenous LXR agonists in HepG2 cells relative to macrophage cells. High endogenous LXR agonist levels may compensate for the mevalonic acid-related inhibition of LXRα activity in hepatocytes where oxysterol levels are much higher than in macrophage cells.
Many clinical trials have examined the effects of various statins on HDLc and apo A-I. Lee et al. [132] examined the effects of atorvastatin (20 mg; n = 11), or atorvastatin plus ezetimibe (10 mg; n = 10) combination in randomized patients for 8 weeks. Cholesterol efflux capacity increased to similar extents in both treatment groups, as did apo A-I, apo A-II, and HDL levels.
Insulin has been shown to induce apo A-I gene expression through a GC-rich insulin-responsive core element (IRCE) in the apo A-I gene promoter following phosphorylation and binding of SP1 to the element [133, 134]. Insulin treatment decreases ABCA1 levels by increasing ABCA1 tyrosine phosphorylation (1206) promoting its degradation and efflux capacity [135]. In the latter study, insulin-mediated decreases in ABCA1 were associated with lower HDLc and HDL phospholipid levels but had no effect on ABCA1 mRNA expression. Furthermore, inhibition of calpain and proteasome activity with calpeptin/N-[N-(N-acetyl-l-leucyl)-l-leucyl]-l-norleucine (ALLN) and MG-132, respectively, reversed most of the decrease in ABCA1 protein levels in insulin-treated cells [135]. Similar results were observed in vivo in male Crl:CD rats fed a high-fructose diet to promote insulin resistance/hyperinsulinemia [135].
Epigenetics, in particular DNA methylation, has also been shown to play an important role in regulating ABCA1 gene expression. Cytosine methylation in the context of a CpG dinucleotide is generally associated with gene repression and is believed to influence DNA structure and/or binding of methylation-specific trans-acting factors that repress gene transcription [136, 137]. Tobi et al. [138] demonstrated that the ABCA1 gene promoter is more methylated in adults prenatally exposed to starvation decades prior, and also demonstrated that there is considerable inter-individual variation in ABCA1 gene promoter methylation status [139]. However, they did not determine if the methylation status was associated with altered lipid levels or elevated risk for coronary artery disease. To address these issues, Guay et al. [140] determined whether or not ABCA1 promoter methylation was associated with changes in HDL particle size and concentration as well as coronary artery disease in patients with familial hypercholesterolemia (FH) and carrying the W66G mutation in the LDL receptor and not under lipid-lowering treatment. Changes in the epigenome may account for the variability in the presentation of FH in each patient [141] as well as the observation that maternal transmission of FH has an influence on lipid metabolism in the offspring [142]. ABCA1 promoter methylation was negatively correlated with plasma HDLc and HDL2-phospholipid levels, and correlated with the prior risk of coronary artery disease [140] in the 97 FH patients. Furthermore, many of the methylated CpGs identified in the study mapped to a CpG island in the proximal promoter of the ABCA1 gene containing consensus binding sites for the transcription factors SP1, signal transducer and activator of transcription (STAT), activator protein -1 (AP-1), activator protein-2 (AP-2), activator protein-4 (AP-4), ETS1, and sex-determining region Y (SRY) [140]. A critical caveat of these studies is that they were all performed with leukocytes, not with hepatocytes, macrophages, or intestinal cells; there may be important tissue-specific differences in ABCA1 promoter methylation status. However, if epigenetic control of ABCA1 gene expression is conserved between leukocytes, hepatocytes, and macrophage cells, it is likely that the observations made in leukocytes are also applicable to the other cell types. All of the key transcription factors are expressed in leukocytes, hepatocytes, and macrophage cells. Regardless, leukocyte proliferation and differentiation is suppressed by HDL (through its anti-inflammatory effects) in response to ABCA1/apo A1 binding, potentially suppressing atherosclerosis [19].
5 Regulation of ABCA1 Gene Expression by Natural Compounds
The search for natural therapeutics that target and increase ABCA1 expression and RCT has yielded several important leads. A thorough review was recently published on this topic [143]. Natural compounds upregulate ABCA1 expression in three ways; (1) by preventing ABCA1 degradation, (2) by increasing ABCA1 mRNA stability, and (3) by increasing ABCA1 gene transcription (the most commonly employed mechanism) (Table 4).
Two compounds, 6-dihydroparadol (from the ginger species Zingiber officinale) [144] and paeonol (from Paeonia suffruticosa) [154, 155] increased ABCA1 protein levels by inhibiting proteasomal ABCA1 degradation and calpain-mediated ABCA1 degradation in THP-1 and RAW264.7 macrophages and apoE−/− knockout mice. Three compounds, betulinic acid (a terpenoid from the bark of Tetracera potatoria) [147], diosgenin (a steroid from Dioscorea nippionica) [152], and protocatechuic acid (a polyphenol from the medicinal herb danshen) [156] increased ABCA1 gene expression by downregulating miR-33a and b, miR-10b, and miR-19b expression, respectively. These microRNAs down regulate ABCA1 gene expression by targeting its mRNA for degradation (see below). These effects were observed in THP-1 and murine peritoneal macrophage (MPM) cells in vitro and apoE−/− mice in vivo.
By far the largest number of natural compounds enhance ABCA1 gene expression by targeting signaling pathways and transcription factors that enhance ABCA1 gene transcription. Kuwanon G (a flavonoid from root bark of Morus alba) induced ABCA1 gene expression by directly stimulating LXRα and LXRβ activity [153]. Puerarin (a flavonoid from Pueraria lobate root) enhanced ABCA1 gene expression by stimulating PPARγ and LXRα via AMPK [157], while alpinetin (a ginger flavonoid from Alpinia katsumadai) induced PPARγ and LXRα activity directly [145]. Quercetin (a flavonoid from numerous fruits and vegetables) enhanced ABCA1 gene expression by stimulating LXRα and SP1 via tachykinin precursor 1 (TAK1), mitogen-activated protein kinase kinase 3/6 (MKK3/6), and p38 mitogen-activated protein (MAP) kinase [158, 159]. In a randomized, double-blinded, placebo-controlled, cross-over study (n = 93) where the subjects received 150 mg/day quercetin for 6 weeks followed by a 5-week washout period, quercetin treatment had beneficial effect on diastolic blood pressure but HDLc levels decreased [162]. Total plasma cholesterol and triglyceride levels did not change with quercetin treatment [162]. Currently, there are three clinical trials examining the effect of quercetin on cardiovascular disease (NCT03943459 and NCT04907253) and atherosclerosis (NCT02998918). Likewise, curcumin (a non-flavonoid from Curuma longa) induced ABCA1 gene expression by stimulating LXRα and PPARγ activity via AMP-activated protein kinase (AMPK) [149,150,151]. A recent double-blinded, placebo-controlled, clinical trial in men (n = 22) examined the effect of enhanced bioavailable curcumin versus placebo on obesity-related cardiovascular risk factors after 12 weeks of treatment [163]. Curcumin treatment increased HDLc and reduced homocysteine levels; however, there were no differences in plasma insulin, glucose, leptin, or adiponectin levels between the two groups [163]. There are currently two clinical trials examining the effect of curcumin on cardiovascular disease (NCT02998918 and NCT04458116). Betulinic acid (a terpenoid from Tetracera potatoria bark) also elevated ABCA1 gene expression by stimulating SREBP activity [147]. Tanshindiol IIA (a terpenoid from the Salvia miltiorrhiza rhizome) induced ABCA1 gene expression via heme oxygenase (HO-1), requiring both ERK and nuclear factor erythroid 2-related factor 2 (Nrf2) [160, 161]. There is one clinical trial currently under way (NCT02524964) examining the effect of Tashinone IIA on cardiovascular disease. Finally, all-trans-retinoic acid [57, 81, 146] and β -carotene (both from vitamin A-rich vegetables) [148] increased ABCA1 gene expression by stimulating RAR and RXR activity, respectively. In total, these effects were observed in vitro (THP-1, RAW264.7, MPMs, human monocyte-derived macrophages (HMDM), and J77A.1 cells) and in vivo (apo E−/− mice and Sprague Dawley rats on a high-fat diet). Unfortunately, none of these observations have led to the development of therapeutics to enhance RCT in humans. Indeed, a recent meta-analysis comparing the results of clinical trials examining the effects of β -carotene supplementation on cardiovascular disease risk failed to show any benefit [164]. In fact, there was a slight increase in risk associated with β -carotene use [164].
6 Inhibition of ABCA1 Gene Expression by Endotoxin and Pro-Inflammatory Cytokines
Several studies indicate that atherosclerosis is associated with chronic sub-clinical endotoxemia. In contrast to high-dose lipopolysaccharide (LPS) (> 10 ng/ml), which is associated with septic shock and cytokine storms, chronic subclinical endotoxemia (< 100 pg/ml) induces only a mild but persistent increase in inflammatory mediators, potentially enhancing atherosclerosis. Indeed, currently available cardioprotective drugs have anti-inflammatory properties and reduce proinflammatory cytokine secretion from human coronary artery endothelial cells [165]. Maitra and Li [166] demonstrated that subclinical amounts of endotoxin suppressed ABCA1 expression, as well as expression of ABCG1 and SR-B1 in macrophages.
Patients with Crohn’s disease have persistently low HDL levels as well as accelerated atherosclerosis [167]. In addition, patients with sepsis can have transient dyslipidemia mimicking the plasma lipid profile of Tangier disease [168]. Field et al. [10] hypothesized that the potent pro-inflammatory cytokine TNFα, which has been shown to play a major role in Crohn’s disease [169] may promote atherogenic dyslipidemia in part by repressing ABCA1 gene expression leading to lower HDL levels. Treatment of Caco-2 intestinal cells with TNFα down-regulated basolateral cholesterol efflux to apo A-I and also diminished ABCA1 promoter activity. TNFα treatment had no effect on expression of LXRα or LXRβ, or on the expression of other genes involved in cholesterol transport including ABCG1, ABCG8, or SR-B1, but did enhance the rate of ABCA1 degradation. Furthermore, inhibition of nuclear factor-κB activity, a pathway known to be activated by TNFα, partially prevented these effects [10].
Extracellular-signal regulated kinase 1/2 (ERK1/2) activity is important in regulating cellular growth and differentiation, especially in cardiac development and hypertrophy [170]. ERK1/2 is a Ser/Thr protein kinase that functions through the RAS-RAF-mitogen-activated protein kinase (MEK)-ERK1/2 signaling cascade and is activated by several growth factors [171] as well as TNFα [172]. Zhou et al. [173] demonstrated that inhibiting ERK1/2 activity by treatment with the ERK1/2 inhibitors PD98059 and U0126 inhibited cholesterol efflux in macrophage cells. In contrast, inhibition of protein kinase C (PKC), protein kinase A (PKA), p38 MAP kinase, and c-jun-N-terminal kinase (JNK) had no effect on cholesterol efflux to apo A-I or HDL [173]. Furthermore, addition of both PD98059 and U0126 induced ABCA1 protein and mRNA expression, as did treatment with siRNA specific for ERK1/2 [173]. ABCA1 protein levels were enhanced by ERK1/2 inhibitor treatment by elevating its mRNA and prolonging the proteins half-life, however treatment with the ERK1/2 inhibitors had no effect on LXRα and LXRβ expression. Furthermore, treatment with the ERK1/2 inhibitors and the LXR agonist T0901317 had synergistic effects on ABCA1 expression [173]. Thus, elevated ABCA1 levels (protein or mRNA) are not necessarily associated with increased cholesterol efflux.
7 Regulation of ABCA1 Expression by MicroRNAs
MicroRNAs (miRNA) are important modulators of ABCA1 expression and HDL metabolism. MicroRNAs are small (~ 22 nucleotides), non-coding RNA molecules that regulate gene expression by base pairing with a partially complementary RNA sequence on the target RNA (usually within the 3′ untranslated region), either inhibiting its translation or initiating its degradation via the RNA-induced silencing complex (RISC) [174]. miRNAs are encoded in both intergenic and intronic regions of the genome [175] and in most cases miRNAs suppress gene expression. However, there are instances where miRNAs act on a target gene in a positive manner enhancing its expression. Since the inhibitory effect of a single miRNA is small (10–30%), two or more miRNAs function primarily to control the output of gene networks, partially inhibiting the expression of numerous genes within each pathway, culminating in robust pathway inhibition [176]. miRNAs not only function in the cell in which they are produced but several have been shown to be transported by lipoproteins in the plasma [177] and by small extracellular vesicles (sEVs) [178]. Several excellent reviews on the role of miRNAs in HDL metabolism and atherosclerosis have been published [179,180,181,182].
Several miRNAs have been implicated in regulating ABCA1 mRNA and protein levels (Table 5). As discussed above, LXRα is a key regulator of ABCA1 gene transcription. Adding more complexity, microRNA-206 was shown to regulate LXRα activity differently in hepatocytes and macrophage cells [193]. In hepatocytes, miR-206 suppressed LXRα expression and activity, and down-regulated LXRα target genes without altering LXRβ expression and activity. In macrophage cells however, miR-206 enhanced LXRα activity and expression, enhanced the expression of LXRα genes and increased cholesterol efflux. In macrophage cells, treatment with LXRα agonists suppressed miR-206 expression while treatment with TNF α or LPS enhanced miR-206 expression. The ABCG1 expression and possibly cholesterol efflux was increased with miR-206. It is not entirely clear why miR-206 has opposite effects in hepatocytes and macrophage cells. The miR-206 is localized to both the cytoplasm and nucleus [196] and in the cytoplasm, miR-206 interacts with the 3′-untranslated region of the LXRα mRNA {193] which may enhance its translation [197]. In silico studies indicate that there may be miR-206 interacting sites in the ABCA1 (907 bp 5′ of the transcriptional start site) and the ABCG1 gene promoter (4809 bp 5′ of the transcriptional start site) [193]. After promoter binding, mrR-206 enhances transcription of these target genes as well as others through an unknown mechanism. Much work remains to examine these possibilities. These observations taken together suggest that miR206 regulates ABCA1 gene expression in a tissue-specific fashion.
The miRNA-328-5P also effects ABCA1 gene expression, however by a different mechanism (194). The miRNA-328-5P inhibits histone deacetylase 3 levels by targeting the 3′-untranslated region of its mRNA, leading to higher ABCA1 levels. Consequently, in THP-1 macrophage foam cells, a miRNA-328-5P mimic increased cholesterol efflux, decreased total and free cholesterol, cholesteryl ester, and reduced lipid droplet formation. Though it is likely that mi328-5P-mediated histone deacetylase 3 expression alters the expression of many genes, there were no changes in scavenger receptor-A, thrombospondin receptor (CD36), and ABCG1 expression [194].
8 Conclusions
Numerous preclinical studies in animals and human trials have revealed that ABCA1 is an important therapeutic target for treating cardiovascular disease by specifically enhancing RCT. Several limitations to this strategy remain due to the protein’s short half-life on the cell surface. Considering the fact that the ABCA1 mRNA is targeted by several inhibitory siRNAs is also of concern. Likewise, long-term protease inhibitor use to inhibit ABCA1 degradation will likely have significant side effects. While several lines of drugs targeting LXR, PPAR, RXR, and RAR in animal studies and clinical trials in humans have been tested, none have proven safe and effective at enhancing ABCA1 expression and/or activity. Likewise, numerous natural compounds have not proven useful in this regard, and siRNA-based therapeutics seem unlikely due to the fact that ABCA1 is targeted by multiple inhibitory miRNAs. Therefore, a drug combination that specifically and significantly increases ABCA1 gene transcription and extends the half-life of the ABCA1 protein may be more effective for enhancing RCT. A variety of technologies may be employed to address these goals, including small-molecule inducers and inhibitors, siRNA- or antisense oligonucleotide-based therapeutics, or genetically engineered adeno-associated virus-gene or lentivirus-based gene therapies. However, since ABCA1 is expressed in most tissues in the body, local regulation of ABCA1 gene expression should be the goal. Since hepatocytes and macrophage cells would be the primary cells to target with each therapy, the means to target each therapeutic modality may be important to limit side effects. Targeting the asialoglycoprotein receptor, which is expressed only in the liver, by conjugating galactose to various therapeutics may prove effective in targeting the liver. Other macrophage-specific cell surface receptors that are internalized after ligand binding may be used to specifically target this cell population.
Other therapeutic targets remain to be discovered. The observation that elevated ABCA1 levels are not always associated with increased cholesterol efflux indicates that there are cellular and/or environmental factors that regulate ABCA1 cholesterol transport. A range of mechanisms can be envisioned to account for this, including post-translational modifications, steric hinderance due to intracellular binding to other membrane-associated or cytoplasmic proteins, or decreases in OSBP and/or ORP expression/activity affecting the delivery of cholesterol to the plasma membrane. Once these targets are identified, therapeutic agents may be available or developed to increase ABCA1 expression and activity.
Another therapeutic modality that may bypass the need to enhance ABCA1 gene expression is HDL or apo A-I mimetic infusion. In a double-blind, randomized, multicenter trial evaluating ten weekly injections of CER-100, a pre- β HDL mimetic containing apo A-I and sphingomyelin (3 mg/kg; n = 135), or placebo (n = 137) had no effect on coronary atherosclerosis (measured by intravascular ultrasonography) in statin-treated patients with acute coronary syndrome and high plaque burden [198]. In a recent trial using CER-100 and targeting 30 patients with familial hypoalphalipoproteinemia due to ABCA1 and/or apo A-I loss-of-function variants [199], Patients were randomized to treatment (8 mg/kg CER-100) or placebo (2:1 ratio) with nine weekly infusions followed by infusions every 2 weeks for a total of 24 weeks. Mean vessel wall area was measured by 3T-MRI and arterial wall inflammation was measured by 18F-FDG/CT. Unfortunately, there were no differences in mean vessel wall area or arterial wall inflammation between the treatment group and those given placebo. Another HDL mimetic containing recombinant apo A-I Milano (MDCO-216) did not promote plaque regression in patients with acute coronary artery syndrome taking a statin [200]. This double-blind, randomized, multicenter trial treated patients with 20 mg/kg MDCO-216 (n = 59) or placebo (n = 67) weekly for 5 weeks. The primary outcome, percent atheroma volume, was measured by intravascular ultrasound. Another clinical trial phase 1/II trial examining the safety/tolerability, pharmacokinetics, and pharmacodynamics of the apo A-I mimetic peptide D-4F [201]. The compound was well tolerated and importantly, rendered the patients HDL less inflammatory. Unfortunately, ABCA1-mediated cholesterol efflux was not assessed in any of the studies described above. Future studies will have to address the effect of various therapeutic agents on cholesterol efflux.
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Haas, M.J., Mooradian, A.D. Potential Therapeutic Agents That Target ATP Binding Cassette A1 (ABCA1) Gene Expression. Drugs 82, 1055–1075 (2022). https://doi.org/10.1007/s40265-022-01743-x
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DOI: https://doi.org/10.1007/s40265-022-01743-x