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Regulation of Cholesterol Transporters by Nuclear Receptors

Department of Food and Nutrition, Faculty of Home Economics, Kyoto Women’s University, Kyoto 605-8501, Japan
Receptors 2023, 2(4), 204-219;
Submission received: 19 June 2023 / Revised: 22 August 2023 / Accepted: 7 October 2023 / Published: 9 October 2023


Atherosclerosis is a pathological condition characterized by the accumulation of plaques in the arteries, leading to cardiovascular diseases. The deposition of cholesterol in peripheral cells increases the risk of atherosclerosis. Reverse cholesterol transport (RCT) is essential to reduce the risk of atherosclerosis because it removes excessive cholesterol from the peripheral tissues. ATP-binding cassette transporters such as ABCA1, ABCG1, ABCG5, and ABCG8 are involved in the efflux of cholesterol. The upregulation of these ABC transporters enhances RCT, thereby promoting the removal of excess cholesterol from the body. The expression and activity of ABC transporters are regulated by transcriptional and post-transcriptional mechanisms, as well as by post-translational modifications. In this review, the regulation of ABC transporters by nuclear receptors such as farnesoid X receptor, liver X receptor, retinoid X receptor, retinoic acid receptor, and peroxisome proliferator-activated receptors is discussed. Pharmacological and natural compounds serving as agonists for the nuclear receptors have been identified to elevate the mRNA levels of the transporters. Consequently, it is anticipated that these compounds will attenuate the development of atherosclerosis through stimulation of the ABC transporters, thereby enhancing RCT and fecal cholesterol excretion. Understanding these regulatory processes can aid in the development of therapeutic approaches to prevent atherosclerosis.

1. Atherosclerosis

Atherosclerosis is a pathological condition characterized by plaques within arterial walls, which are formed through the accumulation of lipids, inflammatory cells, and other substances [1,2]. Over time, plaques consisting of cholesterol, triglyceride, calcium, and other components grow, causing arteries to narrow and harden. This process can result in various cardiovascular diseases, including coronary heart disease and stroke.
Cholesterol is essential for the proper functioning of the body because it is a constituent of cellular membranes and precursors of steroid hormones and bile acids. Cholesterol is mainly synthesized in the liver and can also be obtained from foods. Lipoproteins, such as low-density lipoprotein (LDL) and high-density lipoprotein (HDL), transport cholesterol in the blood. Cholesterol, particularly LDL cholesterol, plays a key role in the development of atherosclerosis. Studies have shown that high levels of LDL cholesterol in the blood are associated with an increased risk of developing atherosclerosis and cardiovascular diseases [3] because it contributes to plaque formation in the arteries. Conversely, higher levels of HDL cholesterol are associated with a lower risk of cardiovascular disease [4,5] because HDL helps remove excess cholesterol from the peripheral cells and prevents plaque formation.
Lifestyle changes, such as a healthy diet, regular exercise, and smoking cessation, can effectively lower LDL cholesterol levels and increase HDL cholesterol levels, thereby reducing the risk of atherosclerosis and related diseases. A previous study showed that a Mediterranean-style diet, which is high in fruits, vegetables, whole grains, and healthy fats, can reduce the risk of cardiovascular disease by lowering LDL cholesterol levels [6]. In some cases, medications such as statins may be prescribed to lower cholesterol levels and reduce the risk of cardiovascular disease. Statins inhibit cholesterol production in the liver, thereby reducing LDL cholesterol levels and decreasing the risk of atherosclerosis and related diseases [3]. Regular physical activity has been shown to increase HDL cholesterol levels and reduce the risk of cardiovascular disease [7]. Additionally, the removal of accumulated cholesterol from cells is inversely associated with atherosclerotic events [8,9,10].

2. Reverse Cholesterol Transport

Reverse cholesterol transport (RCT) is a process by which excess cholesterol is removed from peripheral tissues, such as the arterial wall, and transported back to the liver for excretion to the bile and ultimately the feces [11]. The RCT pathway involves multiple steps and several different cell types, including macrophages, which play critical roles in this process (Figure 1). Excess cholesterol in cells is excreted by ATP-binding cassette (ABC) transporters, ABCA1 and ABCG1, and HDL is formed [12,13,14]. Subsequently, HDL is delivered to the liver, where it is taken up by hepatocytes through scavenger receptor class B type I (SR-BI), and cholesterol can either be excreted in the bile or used for bile acid synthesis. Cholesterol in the liver is excreted into the bile duct by ABC transporters, ABCG5 and ABCG8 [15,16].
Impaired RCT has been implicated in the development of atherosclerosis, thereby increasing the risk of coronary heart disease and stroke [11]. Conversely, promoting RCT by exercise and dietary changes, as well as through pharmacological interventions, has been shown to prevent the progression of atherosclerosis [6,10,17,18]. Overall, RCT is an important physiological process for maintaining cholesterol homeostasis and preventing the development of cardiovascular diseases.

3. ABC Transporters Involved in Reverse Cholesterol Transport

ABC transporters are membrane proteins that consist of transmembrane domains (TMDs) and nucleotide-binding domains (NBDs) (Figure 2) [13]. ABC transporters transport substrates such as nutrients, metabolites, and xenobiotics using energy obtained from ATP hydrolysis. Multiple ABC transporters, including ABCA1, ABCA3, ABCA4, ABCA7, ABCA12, ABCB4, ABCB11, ABCD1, ABCG1, ABCG4, ABCG5, and ABCG8, are involved in lipid transport. ABCB4 transports phosphatidylcholine, whereas ABCB11 transports bile acids. Among them, ABCA1, ABCG1, ABCG4, ABCG5, and ABCG8 transport cholesterol. ABCA1 has two NBDs and two TMDs in a single molecule, whereas ABCG1, ABCG5, and ABCG8 are half-type ABC transporters that have one NBD and one TMD and function as a homodimer or a heterodimer (Figure 2). ABCG1 forms a homodimer [19,20,21,22], whereas ABCG5 and ABCG8 are highly homologous transporters and form a heterodimer [15,16]. ABCA1 and ABCG1 are ubiquitously expressed, but highly expressed in macrophages. ABCG5/ABCG8 heterodimer is expressed in the intestine and liver. ABCA1 mediates the efflux of cholesterol and phosphatidylcholine into apoA-I [23,24], whereas ABCG1 mediates the efflux of cholesterol and sphingomyelin to cholesterol-poor HDL (Figure 2A) [19,25,26,27]. Mutations in ABCA1 cause Tangier disease, a genetic disorder characterized by low HDL cholesterol levels and the accumulation of cholesterol in various tissues [28,29,30]. Studies have shown that ABCG1 also plays a critical role in macrophage cholesterol efflux and the prevention of atherosclerosis [31,32,33]. Mice lacking Abcg1 showed accumulation of cholesterol and triglyceride in macrophages of liver and lung [32]. Furthermore, mice lacking both Abca1 and Abcg1 showed greater accumulation of neutral lipids in tissues than mice lacking Abca1 or Abcg1 alone [34]. ABCA1 and ABCG1 are shown to transport cholesterol sequentially [26]. This suggests that ABCA1 and ABCG1 play important roles in the removal of excess cholesterol from peripheral cells, especially from macrophages, and that ABCA1 and ABCG1 function cooperatively. ABCG5 and ABCG8 mediate the efflux of cholesterol and plant sterols from the liver and intestines into the bile (Figure 2B) [15,16]. Mutations in either ABCG5 or ABCG8 cause sitosterolemia, a rare genetic disorder characterized by the accumulation of plant sterols and cholesterol in various tissues [35,36,37], indicating that ABCG5/ABCG8 suppresses the absorption of sterols in the intestine and enhances the excretion of sterols in the liver.

4. Nuclear Receptors Involved in the Regulation of Cholesterol Transporters

Nuclear receptors translate hormonal, metabolic, and nutritional signals into alterations in gene expressions [38]. Most nuclear receptors consist of several domains; N-terminal activation function 1, DNA-binding, hinge, and ligand-binding domains (Figure 3). Multiple nuclear receptors are involved in lipid homeostasis by regulating the expression of genes related to lipid biosynthesis, absorption, and excretion [38,39]. Expression of ABCA1, ABCG1, ABCG5, and ABCG8 is regulated by nuclear receptors such as liver X receptor (LXR; NR1H2/NR1H3), retinoid X receptor (RXR; NR2B1/NR2B2/NR2B3), retinoic acid receptor (RAR: NR1B1/NR1B2/NR1B3), peroxisome proliferator-activated receptor (PPAR; NR1C1/NR1C2/NR1C3), and farnesoid X receptor (FXR; NR1H4) [13,40].

4.1. LXR and RXR

LXR and RXR are members of the nuclear receptor superfamily that regulate various physiological processes including metabolism, inflammation, and immunity. LXR is activated by oxysterols, which are sterol metabolites, such as 22-(R)-hydroxycholesterol, 24-(S)-hydroxy-cholesterol, 25-hydroxycholesterol, 27-hydroxycholesterol, and 24-(S),25-epoxycholesterol [38,41,42,43], and it regulates the expression of genes involved in cholesterol transport and metabolism, as well as genes involved in inflammatory responses. The LXR is also involved in the regulation of the metabolism of other lipids such as fatty acids and triglycerides [44]. There are two types of LXR, LXRα (NR1H3) and LXRβ (NR1H2). LXRβ is ubiquitously expressed, whereas LXRα is expressed in the liver, adipose tissue, adrenal glands, intestine, lungs, kidneys, and myeloid cells. Human LXRα expression is autoregulated, whereas human LXRβ is stably expressed even in the absence of excess cholesterol.
RXR functions as a heterodimer with other nuclear receptors such as RAR, vitamin D receptors (VDRs), and PPAR [38,45,46]. There are three types of RXR, RXRα (NR2B1), RXRβ (NR2B2), and RXRγ (NR2B3). RXR itself can also bind to DNA as a homodimer, recognizing the RXR response element (RXRE), which is composed of two direct repeats of the core sequence, such as the DR1 motif, in which the two half-sites are separated by a single nucleotide. LXR regulates the expression of genes involved in cholesterol metabolism, whereas RXR regulates the expression of genes involved in cell differentiation and proliferation.
LXR and RXR form heterodimers that regulate gene expression by binding to the LXR response elements (LXREs) in the regulatory regions of target genes. The LXREs contain direct repeats of the core sequence (A/G)GGTCA separated by four nucleotides (DR4 motif). The binding of LXR to the LXREs leads to the recruitment of coactivator proteins, which in turn activates the transcription of target genes. The LXR/RXR heterodimer regulates the expression of genes involved in lipid metabolism, such as ABCA1, ABCG1, and sterol regulatory element-binding protein (SREBP)-1.
Activation of LXR and RXR has been shown to have beneficial effects on cholesterol metabolism and inflammation, and LXR agonists have been developed as potential therapeutic agents for the treatment of various diseases, including atherosclerosis, whereas they show adverse effects of increased fatty acid levels because of the activation of SREBP-1 [47,48].

4.2. RAR

RAR plays a crucial role in mediating the biological effects of retinoic acid, a derivative of vitamin A [45,49]. There are three types of RAR, RARα (NR1B1), RARβ (NR1B2), and RARγ (NR1B3). Retinoic acid serves as the ligand for RARs. Upon binding, retinoic acid induces conformational changes in the receptor, leading to the dissociation of corepressors and recruitment of coactivators. The activated RAR/RXR heterodimer then binds to retinoic acid response elements (RAREs) located in the regulatory regions of the target genes. RAR is involved in various physiological processes, including embryonic development, cell differentiation, and homeostasis [45,49].

4.3. PPAR

PPAR plays a key role in regulating metabolism, inflammation, and cell differentiation [39,46]. There are three types of PPARs, PPARα (NR1C1), PPARδ (NR1C2), and PPARγ (NR1C3). PPAR is activated by fatty acids and other lipid molecules and regulates the expression of genes involved in lipid metabolism and inflammation. PPARα is mainly expressed in the liver and is involved in the regulation of fatty acid oxidation and ketone body synthesis. PPARδ is expressed in various tissues and is involved in the regulation of fatty acid oxidation and glucose metabolism. PPARγ is mainly expressed in the adipose tissue and is involved in the regulation of adipogenesis and glucose metabolism.
Studies have shown that activation of PPAR can have beneficial effects on metabolism and inflammation, and PPAR agonists have been developed as drugs for the treatment of various metabolic disorders, including type 2 diabetes and dyslipidemia [50].

4.4. FXR

FXR plays a crucial role in regulating bile acid metabolism and homeostasis [38,43,51]. FXR is predominantly expressed in the liver and intestine, where it controls bile acid synthesis, transport, and enterohepatic circulation. FXR is activated by bile acids, which serve as endogenous ligands for FXR. Upon activation, the FXR or FXR/RXR heterodimer binds to the FXR response elements (FXREs) in the promoter regions of target genes. The activation of FXR has numerous physiological effects. One of its primary functions is to regulate bile acid synthesis by suppressing the expression of cholesterol 7α-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid biosynthesis, and upregulating the expression of small heterodimer partner (SHP), a repressor of CYP7A1. By reducing bile acid synthesis, FXR maintains bile acid homeostasis and prevents the accumulation of toxic levels of bile acids in the liver.
FXR also regulates the transport of bile acids by modulating the expression of various transporters, such as organic solute transporter α/β (OSTα/β), bile salt export pump (BSEP, ABCB4), and ileal bile acid transporter (IBAT). By controlling the expression of these transporters, FXR ensures efficient bile acid uptake in the intestine, promotes bile acid secretion into the bile, and limits its reabsorption from the intestine, thereby contributing to the enterohepatic circulation of bile acids. Furthermore, FXR has been implicated in various diseases, including cholestasis, non-alcoholic fatty liver disease (NAFLD), and inflammatory bowel disease (IBD) [51].

5. Transcriptional and Post-Transcriptional Regulation of ABCA1 and ABCG1

ABC transporters that mediate the efflux of cholesterol are regulated by multiple mechanisms. ABCA1, ABCG1, and ABCG5/ABCG8 are regulated at transcriptional, post-transcriptional, and post-translational levels.
The expression of ABCA1 and ABCG1 is tightly regulated transcriptionally and post-transcriptionally because ABCA1 and ABCG1 play important roles in lipid homeostasis in the body. Transcriptional regulation of ABCA1 and ABCG1 involves multiple transcription factors and co-regulators, including LXR, PPAR, and RXR (Figure 4A). When intracellular cholesterol levels rise, oxysterols, oxidized metabolites of cholesterol such as 25-hydroxy cholesterol, also increase. ABCA1 and ABCG1 expressions are physiologically induced by oxysterols via the LXR pathway [52,53,54]. When LXR is activated by oxysterols, the LXR/RXR heterodimers induce ABCA1 and ABCG1 by binding to the LXRE of promoters of the genes [55]. Agonists for PPARα and PPARγ also induce the expression of ABCA1 and ABCG1 via LXR [56,57,58]. In addition to nuclear receptors, other transcription factors are also involved in the regulation of ABCA1 expression, including SREBP, activator protein 2 (AP2), CCAAT/enhancer-binding protein (C/EBP), and zinc finger protein202 (ZNF202) [59,60,61,62,63]. These factors may bind to specific promoter regions and regulate ABCA1 and ABCG1 expression in response to various stimuli such as cholesterol and inflammatory signals.
The post-transcriptional regulation of ABCA1 and ABCG1 involves several mechanisms, including mRNA stability, alternative splicing, and microRNA (miRNA) regulation. The 3’-untranslated regions (UTRs) of ABCA1 and ABCG1 mRNA contain cis-acting elements that regulate mRNA stability and translation efficiency. For example, the RNA-binding protein human antigen R (HuR) binds to and stabilizes the 3’-UTR of ABCA1 mRNA. Conversely, the stability of ABCA1 and ABCG1 mRNA is negatively regulated by miRNAs (miR-33a and miR-33b), which exist in the introns of SREBP-2 [64]. Additionally, other miRNAs such as miR-17, miR-19b, miR-93, miR-101, and miR-144 also downregulate ABCA1 mRNA [65,66].

6. Post-Translational Regulation of ABCA1 by LXR

In addition to transcriptional regulation of ABCA1 by LXR, ABCA1 is also post-translationally regulated by LXR [67,68]. The LXRβ/RXR complex directly binds to the C-terminal region of ABCA1 on the plasma membrane of macrophages and influences cholesterol secretion [67,68].
Excessive elimination of cholesterol can be detrimental to cells since cholesterol is an essential component of cell membranes. Hence, ABCA1 protein is degraded by the calpain and proteasome pathways with a half-life of 1–2 h [12,69]. LXR suppresses the degradation of ABCA1, and the addition of exogenous LXR ligands, which mimic cholesterol accumulation, results in the dissociation of LXRβ from ABCA1, thereby reversing the effects of LXR on ABCA1 degradation [67].
Under conditions in which intracellular cholesterol does not accumulate, the ABCA1-LXRβ complex localizes to the plasma membrane, which makes ABCA1 inactive (Figure 5). However, when cholesterol accumulates and the intracellular concentration of oxysterols rises, LXRβ binds oxysterol and dissociates from ABCA1 [68]. This dissociation enables the restoration of ABCA1 activity and apoA-I-dependent cholesterol efflux, resulting in an immediate decrease in intracellular cholesterol levels. Therefore, LXR can elicit both a post-translational response by directly binding to ABCA1 and a transcriptional response to maintain cholesterol homeostasis (Figure 5).

7. Transcriptional and Post-Transcriptional Regulation of ABCG5/ABCG8

The transcriptional regulation of ABCG5/ABCG8 is complex and involves a variety of mechanisms, including regulatory factors and genetic polymorphisms (Figure 4B). ABCG5 and ABCG8 possess a shared bidirectional promoter [35,70,71]. LXR and FXR have been shown to regulate the expression of ABCG5 and ABCG8 [72,73,74,75]. LXR binds to the LXREs within the promoters of ABCG5 and ABCG8 genes and enhances their transcription in combination with RXR [72,73]. The hepatic and intestinal expression of ABCG5/ABCG8 is modulated by bile acids via FXR [74,75]. FXR agonists have also been shown to regulate the mRNA expression of ABCG5 and ABCG8 in cultured hepatocytes [76]. In addition to nuclear receptors, other transcriptional regulators, including nuclear factor-kappa B (NF-kB), forkhead box protein O1 (FoxO1), PPARγ, liver receptor homolog-1 (LRH-1; NR5A2), hepatocyte nuclear factor 4α (HNF4α; NR2A1), and GATA4 have been shown to modulate ABCG5/ABCG8 expression [77,78,79,80,81]. Regulatory elements for HNF4α, LRH-1, NFκB, and FoxO1 were found within the intergenic regions of the initiation codons of ABCG5 and ABCG8 [78,79]. These factors can modulate the activity of LXR or directly interact with the promoter regions of ABCG5/ABCG8 to enhance or suppress their transcription.
Similar to ABCA1 and ABCG1, ABCG5 and ABCG8 are also post-transcriptionally regulated. Several miRNAs have been shown to regulate the expression of ABCG5/ABCG8. For instance, miR-33a downregulates the expression of both ABCG5 and ABCG8 [82]. Similarly, miR-223 has been shown to downregulate the expression of ABCG5/ABCG8 [83].

8. Transcriptional Activation of ABCA1, ABCG1, and ABCG5/ABCG8 by Pharmacological Compounds

Transcriptional activation of ABCA1, ABCG1, and ABCG5/ABCG8 can be achieved by various pharmacological compounds (Table 1). Synthetic LXR agonists, such as GW3965 and T0901317, have been shown to upregulate the expression of ABCA1 and ABCG1 in various cell types [84,85,86,87,88]. Moreover, these LXR ligands can prevent the development of atherosclerosis in vivo [84]. T0901317 highly induced the expression of ABCA1 and ABCG1, which increased cholesterol efflux and prevented the development of atherosclerosis [47,86,89,90]. However, LXR agonists exert adverse effects by enhancing lipogenesis, because they activate the SREBP-1c pathway [47]. Several PPAR agonists such as pioglitazone, rosiglitazone, WY14643, and GW501515 have been shown to induce the expression of ABCA1 and ABCG1 in various cell types [57,58,91,92,93]. Fibrates also induce the expression of ABCA1, ABCG1, and ABCG5/ABCG8 [91,94]. Statins, which are oral drugs used for the treatment of atherosclerosis by inhibiting HMG-CoA reductase, have not only demonstrated a reduction in cholesterol synthesis but also an upregulation of ABCA1 and ABCG1 expression [95,96]. Considering that both statins and fibrates are PPAR-activating compounds, it is plausible that they upregulate ABCA1 and ABCG1 via the PPAR-LXR pathway [93], although pitavastatin did not activate LXR but increased ABCA1 by PPARα-dependent protein stabilization [96] and the effects of statins depend on cellular conditions [97]. Agonists for RXR and RAR, including all-trans retinoic acid and 9-cis retinoic acid, increased ABCA1 and ABCG1 in a RAR/LXR/RXR pathway [52,98,99].
In the case of ABCG5/ABCG8 transcriptional activation, several pharmacological compounds have been demonstrated to be effective. Because ABCG5/ABCG8 is induced by LXR, LXR agonists, such as T0901317 and GW3936, increased ABCG5/ABCG8 expression [72,73]. Additionally, PPAR agonists, such as pioglitazone and rosiglitazone, have been reported to elevate ABCG5/ABCG8 expressions [80,81]. Treatment with metformin has also been shown to enhance ABCG5/ABCG8 expression in hepatocytes, possibly through the suppression of period2 and/or cryptochrome1, which are transcriptional repressors for ABCG5 and ABCG8 [100].
Table 1. Transcriptional activation of ABCA1, ABCG1, and ABCG5/ABCG8 by pharmacological compounds.
Table 1. Transcriptional activation of ABCA1, ABCG1, and ABCG5/ABCG8 by pharmacological compounds.
Pharmacological CompoundMechanism of ActionTarget TransportersReferences
LXR agonists (e.g., GW3965, T0901317)Activation of LXRABCA1, ABCG1, ABCG5, ABCG8[72,73,84,85,86,87,88]
RXR agonists (e.g., 9-cis retinoic acid)Activation of RXRABCA1, ABCG1[99]
RAR agonists (e.g., all-trans retinoic acid and 9-cis retinoic acid)Activation of RARABCA1, ABCG1[52,98,99]
PPAR agonists (e.g., fibrates, pioglitazone)Activation of PPARABCA1, ABCG1, ABCG5, ABCG8[57,58,80,81,91,92,93]
Statins (e.g., pitavastatin, atorvastatin)Inhibition of HMG-CoA reductaseABCA1, ABCG1[95,96]

9. Transcriptional Activation of ABCA1, ABCG1, and ABCG5/ABCG8 by Natural Products

Multiple foods, dietary components, and natural compounds have been reported to activate transcription of ABCA1, ABCG1, ABCG5, and ABCG8 (Table 2). Cineole, a terpene oxide and a major constituent of eucalyptus and rosemary oils, increased ABCA1 mRNA levels [101]. 6-Gingerol, the pungent ingredient in ginger, increased ABCA1 mRNA, possibly by LXRα [102]. 8(R)-Hydroxyeicosapentaenoic acid (8R-HEPE) from North Pacific krill (Euphausia pacifica) induced ABCA1 and ABCG1 by activation of LXR [103]. Vitamin D upregulated ABCA1 and ABCG1 mRNA by increasing 27-hydroxycholesterol levels and activating LXR [104]. Riccardin C, a non-sterol natural product isolated from liverworts that functions as an LXRα agonist and an LXRβ antagonist, induced ABCA1 and ABCG1 expression [105]. Quercetin, a flavonoid, enhanced ABCA1 expression and cholesterol efflux through p38- and LXRα-dependent pathways in macrophages [106].
The activation of PPAR by natural products has been reported to upregulate ABCA1 and ABCG1 through the PPAR-LXRα pathway. Leonurine, an alkaloid compound of Herba leonuri, can prevent the development of atherosclerosis in the PPARγ-LXRα signaling pathway [107]. Allicin increased ABCA1 mRNA levels in THP-1 cells by acting through the PPARγ-LXRα pathway [108]. Anthocyanins induced ABCA1 in the PPARγ-LXRα pathway, which was blocked by the PPAR antagonist GW9662 [109]. Hydroxytyrosol, a phenolic compound, also enhances ABCA1 expression in a PPARγ-LXRα pathway, resulting in reduced foam cell formation [110]. Lycopene induced ABCA1 mRNA by the PPARγ-LXRα pathway in prostate cancer cells, although the induction was slow [111]. Evodiamine, one of the main alkaloids obtained from the medicinal evodia fruit of the plant Evodia rutaecarpa Benth, induced ABCG1 mRNA via the PPARγ-LXRα pathway [112]. Baicalin, a major flavonoid in Scutellaria baicalensis, induced ABCA1 and ABCG1 expression in the PPARγ-LXRα pathway [113]. Similarly, curcumin, a polyphenolic compound found in turmeric, has been shown to induce the expression of ABCA1 and ABCG1 in macrophages and adipocytes, possibly mediated by the activation of PPARγ and LXR [114,115]. In macrophages, the binding of 13-hydroxy linoleic acid to PPAR has been shown to induce the expression of ABCA1 and ABCG1 [116]. Mangiferin, a xanthonoid from Salacia oblonga, increased ABCA1 and ABCG1 via the PPARα-LXR pathway in macrophage Raw264.7 cells and decreased atherosclerotic plaque size in apoE knockout mice [117]. Resveratrol, a polyphenolic compound found in grapes and red wine, has been reported to induce the expression of ABCA1 and ABCG1 in macrophages [118,119]. These effects are thought to be mediated by activation of PPARγ and LXRα. While the natural products described above increased the expression of ABCA1 and ABCG1, unsaturated fatty acids such as eicosapentaenoic acid and linoleic acid inhibited the LXR/RXR pathway via DR4 and suppressed the transcription of ABCA1 and ABCG1 [120].
Dietary soy protein induced hepatic ABCG5/ABCG8 mRNA expression and promoted cholesterol efflux [121]. The cell wall of lactobacillus promoted the expression of ABCG5/ABCG8 protein and mRNA [72]. Marine-derived furanone, 5-hydroxy-3-methoxy-5-methyl-4-butylfuran-2(5H)-one, isolated from the fungus Setosphaeria increased ABCA1, ABCG1, and ABCG5/ABCG8 in a manner dependent on LXRα and PPARα [122]. Diosgenin, the aglycone form of bioactive saponin found in wild yam (Dioscorea villosa Linn) increased ABCG5/ABCG8 mRNA possibly through indirect activation of LXRα [123]. In addition to ABCA1 and ABCG1, intestinal ABCG5/ABCG8 was also induced by resveratrol dependent on the LXRα pathway, but liver ABCG5/ABCG8 was not upregulated [124]. Plant sterols and stanols, which are commonly found in foods such as nuts, seeds, and vegetable oils, have been reported to activate the transcription of ABCA1, ABCG1, and ABCG5/ABCG8 in hepatocytes and enterocytes by the activation of LXR [125,126]. Taurine (2-aminoethanesulfonic acid), which is abundant in seafood and traditionally used to treat heart and liver disorders, increased ABCA1 and ABCG1 mRNAs levels in THP-1 cells and ABCA1, ABCG5, and ABCG8 mRNAs in HepG2 and Caco2 cells by binding to LXRα [127]. The effects of these natural products on ABCA1, ABCG1, ABCG5, and ABCG8 expression may vary depending on the specific cell type and experimental conditions used in the studies, and the mechanisms underlying these effects are likely multifactorial. Since many natural products targeting LXR, RXR, PPAR, or FXR have been reported [38,128,129], we expect that increasing numbers of natural products will activate transcription of ABCA1, ABCG1, ABCG5, and ABCG8 in the future.
Table 2. Transcriptional activation of ABCA1, ABCG1, and ABCG5/ABCG8 by natural compounds.
Table 2. Transcriptional activation of ABCA1, ABCG1, and ABCG5/ABCG8 by natural compounds.
Natural CompoundMechanism of ActionTarget TransportersReferences
AllicinActivation of PPAR and LXRABCA1[108]
AnthocyaninsActivation of PPAR and LXRABCA1[109]
BaicalinActivation of PPAR and LXRABCA1, ABCG1[113]
CurcuminActivation of LXRABCA1, ABCG1[114,115]
DiosgeninActivation of LXRABCG5, ABCG8[123]
EvodiamineActivation of PPAR and LXRABCG1[112]
6-GingerolActivation of LXRABCA1[102]
8(R)-hydroxyeicosapentaenoic acidActivation of LXRABCA1, ABCG1[103]
13-hydroxy linoleic acidActivation of PPARABCA1, ABCG1[116]
5-hydroxy-3-methoxy-5-methyl-4-butylfuran-2(5H)-oneActivation of LXRABCA1, ABCG1, ABCG5, ABCG8[122].
LycopeneActivation of PPAR and LXRABCA1[111]
MangiferinActivation of PPAR and LXRABCA1, ABCG1[117]
QuercetinActivation of LXRABCA1[106]
ResveratrolActivation of PPAR and LXRABCA1, ABCG1, ABCG5, ABCG8[118,119,124]
Riccardin CActivation of LXRABCA1, ABCG1[105]
Soy protein?ABCG5, ABCG8[121]
TaurineActivation of LXRABCA1, ABCG1, ABCG5, ABCG8[127]
Vitamin DActivation of LXRABCA1, ABCG1[104]

10. Conclusions and Perspectives

ABCA1, ABCG1, and ABCG5/ABCG8, the key players in cholesterol removal from the body, are good candidates for the prevention of atherosclerosis. The development of compounds that induce the expression of ABCA1, ABCG1, ABCG5, and ABCG8 by transcriptional regulation is desired. A synthetic ligand for LXR is one of the candidates that can promote transcription and activate ABCA1 and ABCG1 by increasing their expression levels; however, LXR agonists show an adverse effect due to the induction of SREBP-1c, which regulates fatty acid synthesis, resulting in elevated serum triglyceride levels [47,101,127]. Consequently, possible candidates are LXR agonists capable of inducing ABCA1, ABCG1, and ABCG5/ABCG8 without upregulating SREBP-1c [130]. Another possible target is PPAR, which induces the expression of ABCA1, ABCG1, ABCG5, and ABCG8 without increasing fatty acid synthesis. Combining PPAR agonists with LXR agonists may serve as a promising strategy to overcome the aforementioned adverse effects because ABCA1 and ABCG1 are induced by LXR agonists and PPAR stimulation suppresses triglyceride levels by increasing β-oxidation and liver lipoprotein lipase [47]. Furthermore, transcription factors could be therapeutic targets. Compounds that suppress AP-2 or activate LRH-4 and HNF4α are expected to elevate ABCA1, ABCG1, and ABCG5/ABCG8 expression. Further research is needed to fully understand the molecular mechanisms underlying this regulation and its potential therapeutic implications. In the future, it is considered that new strategies to prevent and cure atherosclerosis and cardiovascular diseases using pharmacological and natural compounds will be developed.


This research was funded by JSPS KAKENHI grant number JP20K11592 from the Japan Society for the Promotion of Science.

Data Availability Statement

The data presented in this study are available on request from the author.

Conflicts of Interest

The author declares no conflict of interest.


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Figure 1. Cholesterol transport facilitated by ABC transporters. Cholesterol is absorbed in the intestine and delivered to the liver via chylomicrons. Cholesterol, absorbed in the intestine and synthesized in the liver, is transferred to peripheral cells via LDL. The accumulation of cholesterol in peripheral cells, especially in macrophages, contributes to the development of atherosclerosis. The excess cholesterol is eliminated by ABCA1 and ABCG1, resulting in the formation of HDL. HDL is then delivered to the liver, where it is taken up by SR-BI. Finally, cholesterol is excreted to bile duct by ABCG5/ABCG8.
Figure 1. Cholesterol transport facilitated by ABC transporters. Cholesterol is absorbed in the intestine and delivered to the liver via chylomicrons. Cholesterol, absorbed in the intestine and synthesized in the liver, is transferred to peripheral cells via LDL. The accumulation of cholesterol in peripheral cells, especially in macrophages, contributes to the development of atherosclerosis. The excess cholesterol is eliminated by ABCA1 and ABCG1, resulting in the formation of HDL. HDL is then delivered to the liver, where it is taken up by SR-BI. Finally, cholesterol is excreted to bile duct by ABCG5/ABCG8.
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Figure 2. Structures and functions of ABC transporters involved in cholesterol transport. (A) ABCA1 mediates the efflux of cholesterol (Chol) and phosphatidylcholine (PC) to apoA-I, which initiates the formation of nascent HDL (preβ-HDL). ABCG1 forms a homodimer and mediates the efflux of cholesterol and sphingomyelin (SM) to cholesterol-poor HDL. (B) ABCG5 and ABCG8 form a heterodimer and mediate the efflux of Chol to bile.
Figure 2. Structures and functions of ABC transporters involved in cholesterol transport. (A) ABCA1 mediates the efflux of cholesterol (Chol) and phosphatidylcholine (PC) to apoA-I, which initiates the formation of nascent HDL (preβ-HDL). ABCG1 forms a homodimer and mediates the efflux of cholesterol and sphingomyelin (SM) to cholesterol-poor HDL. (B) ABCG5 and ABCG8 form a heterodimer and mediate the efflux of Chol to bile.
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Figure 3. Schematic structure of nuclear receptors. Nuclear receptors consist of an N-terminal ligand-independent activation function (AF1) domain, a DNA-binding domain, a hinge domain, and a ligand-binding domain with a ligand-dependent activation function (AF2).
Figure 3. Schematic structure of nuclear receptors. Nuclear receptors consist of an N-terminal ligand-independent activation function (AF1) domain, a DNA-binding domain, a hinge domain, and a ligand-binding domain with a ligand-dependent activation function (AF2).
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Figure 4. Transcriptional regulation of ABC transporters. (A) ABCA1 and ABCG1 are induced by PPAR and LXR/RXR. AP2 suppresses the expression of ABCA1 and ABCG1. (B) ABCG5 and ABCG8 are induced by PPAR, LXR/RXR, and FXR. LRH-1 and HNF4α enhance the expression of ABCG5 and ABCG8, while NFκB suppresses it.
Figure 4. Transcriptional regulation of ABC transporters. (A) ABCA1 and ABCG1 are induced by PPAR and LXR/RXR. AP2 suppresses the expression of ABCA1 and ABCG1. (B) ABCG5 and ABCG8 are induced by PPAR, LXR/RXR, and FXR. LRH-1 and HNF4α enhance the expression of ABCG5 and ABCG8, while NFκB suppresses it.
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Figure 5. Post-translational regulation of ABCA1 by LXR. LXRβ interacts with the C-terminal region of ABCA1 and inhibits ATP binding at the NBDs and apoA-I binding at the extracellular domain under cholesterol-depleted conditions. Under cholesterol-accumulated conditions, LXRβ binds oxysterol and dissociates from ABCA1, enabling ABCA1 to transport cholesterol using energy derived from ATP hydrolysis.
Figure 5. Post-translational regulation of ABCA1 by LXR. LXRβ interacts with the C-terminal region of ABCA1 and inhibits ATP binding at the NBDs and apoA-I binding at the extracellular domain under cholesterol-depleted conditions. Under cholesterol-accumulated conditions, LXRβ binds oxysterol and dissociates from ABCA1, enabling ABCA1 to transport cholesterol using energy derived from ATP hydrolysis.
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Matsuo, M. Regulation of Cholesterol Transporters by Nuclear Receptors. Receptors 2023, 2, 204-219.

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Matsuo M. Regulation of Cholesterol Transporters by Nuclear Receptors. Receptors. 2023; 2(4):204-219.

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Matsuo, Michinori. 2023. "Regulation of Cholesterol Transporters by Nuclear Receptors" Receptors 2, no. 4: 204-219.

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