Differential inhibition of macrophage foam-cell formation and atherosclerosis in mice by PPARα, β/δ, and γ
Andrew C. LiChristoph J. BinderAlejandra GutierrezKathleen K. BrownChristine R. PlotkinJennifer PattisonAnnabel F. ValledorRoger J. DavisTimothy M. WillsonJoseph L. WitztumWulf PalinskiChristopher K. Glass
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Abstract:
PPARα, β/δ, and γ regulate genes involved in the control of lipid metabolism and inflammation and are expressed in all major cell types of atherosclerotic lesions. In vitro studies have suggested that PPARs exert antiatherogenic effects by inhibiting the expression of proinflammatory genes and enhancing cholesterol efflux via activation of the liver X receptor–ABCA1 (LXR-ABCA1) pathway. To investigate the potential importance of these activities in vivo, we performed a systematic analysis of the effects of PPARα, β, and γ agonists on foam-cell formation and atherosclerosis in male LDL receptor–deficient (LDLR–/–) mice. Like the PPARγ agonist, a PPARα-specific agonist strongly inhibited atherosclerosis, whereas a PPARβ-specific agonist failed to inhibit lesion formation. In concert with their effects on atherosclerosis, PPARα and PPARγ agonists, but not the PPARβ agonist, inhibited the formation of macrophage foam cells in the peritoneal cavity. Unexpectedly, PPARα and PPARγ agonists inhibited foam-cell formation in vivo through distinct ABCA1-independent pathways. While inhibition of foam-cell formation by PPARα required LXRs, activation of PPARγ reduced cholesterol esterification, induced expression of ABCG1, and stimulated HDL-dependent cholesterol efflux in an LXR-independent manner. In concert, these findings reveal receptor-specific mechanisms by which PPARs influence macrophage cholesterol homeostasis. In the future, these mechanisms may be exploited pharmacologically to inhibit the development of atherosclerosis.Keywords:
Foam cell
Liver X receptor
ABCG1
Reverse cholesterol transport
Proinflammatory cytokine
Abstract Berberine, a botanical alkaloid purified from Cortidis rhizoma , has effects in cardiovascular diseases, yet the mechanism is not fully understood. Foam cells play a critical role in the progression of atherosclerosis. This study aimed to investigate the effect of berberine on the formation of foam cells by macrophages and the underlying mechanism. Treatment with berberine markedly suppressed oxidized low‐density lipoprotein (oxLDL)‐mediated lipid accumulation, which was due to an increase in cholesterol efflux. Berberine enhanced the mRNA and protein expression of ATP‐binding membrane cassette transport protein A1 (ABCA1) but did not alter the protein level of ABCG1 or other scavenger receptors. Additionally, functional inhibition of ABCA1 with a pharmacological inhibitor or neutralizing antibody abrogated the effects of berberine on cholesterol efflux and lipid accumulation. Moreover, berberine induced the nuclear translocation and activation of liver X receptor α (LXRα) but not its protein expression. Knockdown of LXRα mRNA expression by small interfering RNA abolished the berberine‐mediated protective effects on ABCA1 protein expression and oxLDL‐induced lipid accumulation in macrophages. These data suggest that berberine abrogates the formation of foam cells by macrophages by enhancing LXRα‐ABCA1‐dependent cholesterol efflux. J. Cell. Biochem. 111: 104–110, 2010. © 2010 Wiley‐Liss, Inc.
ABCG1
Foam cell
Scavenger Receptor
Reverse cholesterol transport
Efflux
Liver X receptor
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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.
Liver X receptor
ABCG1
Reverse cholesterol transport
Retinoid X receptor
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Liver X receptor (LXR) plays an important role in reverse cholesterol transport (RCT), and activation of LXR could reduce atherosclerosis. In the present study we used a cell-based screening method to identify new potential LXRβ agonists. A novel benzofuran-2-carboxylate derivative was identified with LXRβ agonist activity: E17110 showed a significant activation effect on LXRβ with an EC50 value of 0.72 μmol/L. E17110 also increased the expression of ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1) in RAW264.7 macrophages. Moreover, E17110 significantly reduced cellular lipid accumulation and promoted cholesterol efflux in RAW264.7 macrophages. Interestingly, we found that the key amino acids in the LXRβ ligand-binding domain had distinct interactions with E17110 as compared to TO901317. These results suggest that E17110 was identified as a novel compound with LXRβ agonist activity in vitro via screening, and could be developed as a potential anti-atherosclerotic lead compound.
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The nuclear receptor liver X receptor (LXR) has two isoforms: LXRα and LXRβ. LXR activation promotes cholesterol efflux in macrophages, but the relative importance of each LXR isoform in mediating cholesterol efflux remains elusive. We evaluated the ability of different doses of LXRs agonist T0901317 to affect cholesterol efflux in human macrophages and its relationship with mRNA and protein levels of several well-characterized proteins involved in cholesterol efflux, including ABCA1, ABCG1, SR-BI, LXRβ and LXRα, using quantitative real-time PCR, Western blotting, and siRNA techniques. Here we show that LXRα rather than LXRβ sustains baseline cholesterol efflux in human blood-derived macrophages. Treatment of human macrophages with a non-isoform-specific LXR agonist T0901317 substantially increased HDL- and apoA-I-mediated cholesterol efflux, which was associated with increased mRNA and protein expression levels of ABCA1, ABCG1, SR-BI, LXRα and LXRβ. The siRNA- mediated silencing of LXRα, but not LXRβ significantly reduced the protein levels of ABCA1,ABCG1, and SR-BI as wellas HDL- and ApoA1-mediated cholesterol in human macrophages. These findings imply that LXRα- rather than LXRβ- specific agonists may promote reverse cholesterol transport in humans.
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Nuclear Liver X Receptors activation by synthetic agonists was proven to be atheroprotective in mice; an effect likely based on stimulation of cellular cholesterol efflux from arterial macrophages. However, mechanisms involved in free cholesterol efflux from mouse macrophages appear distinct from those operating in human macrophages. The objective of this study was to decipher precise cellular mechanisms controlling free cholesterol efflux from human macrophages upon LXR stimulation. In THP-1 and human monocyte-derived macrophages (HMDM), treatment with the LXR agonist GW3965 efficiently induced ARL7 expression (6-fold, p<0.05), an effect associated with an increased amount of plasma membrane free cholesterol available for efflux (+25%, p<0.05) and a higher lipid rafts formation (+10%, p<0.05). Both effects were abolished in ARL7 Knockdown (KD) macrophages, leading to a lack of stimulation of cholesterol efflux by GW3965. Specific targeting of each LXR isoforms, LXRα and LXRβ, by RNAi revealed that LXRα silencing in THP-1 and HMDM reduced significantly expression of cholesterol transporters ABCA1, ABCG1 and receptor SR-BI/Cla-1 mRNA levels, as well as free cholesterol efflux to apoA1 (-30%, p<0.05) and to HDL (-20%, p<0.05) upon stimulation with LXR, whereas LXRβ silencing has no impact. Interestingly, stimulation of cholesterol efflux to HDL by GW3965 was significantly reduced (-50%, p<0.05) in ABCA1 KD THP-1 macrophages; those cells being incapable to promote cholesterol efflux to apoA1. However, silencing of ABCG1 or SR-B1/Cla-1 had no impact on cholesterol efflux to HDL from either control or ABCA1 KD THP-1 macrophages treated or not with LXR agonist. By contrast stimulation of cholesterol efflux to HDL by GW3965 was completely abolished in LXRα/ABCA1 double KD macrophages, highlighting the major contribution of ABCA1 in cholesterol efflux from human macrophage. We conclude that LXR-mediated stimulation of cholesterol efflux from human macrophages is a two-steps mechanism. First, LXR activation promotes ARL7-dependent free cholesterol transport to plasma membrane, mostly in lipid raft domains. Then, membrane free cholesterol is exported to apoA1 and HDL acceptors through ABCA1; this latter step being controlled selectively by LXRα.
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The association of hypercholesterolemia and obesity with airway hyperresponsiveness has drawn increasing attention to the potential role of cholesterol and lipid homeostasis in lung physiology and in chronic pulmonary diseases such as asthma. We have recently shown that activation of the nuclear hormone receptor liver X receptor (LXR) stimulates cholesterol efflux in human airway smooth muscle (hASM) cells and induces expression of the ATP-binding cassette (ABC) transporters ABCA1 and ABCG1, members of a family of proteins that mediate reverse cholesterol and phospholipid transport. We show here that ABCA1 is responsible for all LXR-mediated cholesterol and phospholipid efflux to both apolipoprotein AI and high-density lipoprotein acceptors. In contrast, ABCG1 does not appear to be required for this process. Moreover, we show that hASM cells respond to increased levels of cholesterol by inducing expression of ABCA1 and ABCG1 transporters, a process that is dependent on LXR expression. These findings establish a critical role for ABCA1 in reverse cholesterol and phospholipid transport in airway smooth muscle cells and suggest that dysregulation of cholesterol homeostasis in these cells may be important in the pathogenesis of diseases such as asthma.
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Liver X receptors (LXRs) are oxysterol-activated nuclear receptors regulating reverse cholesterol transport, in part by modulating cholesterol efflux from macrophages to apoAI and HDL via the ABCA1 and ABCG1/ABCG4 pathways. Moreover, LXR activation increases intracellular cholesterol trafficking via the induction of NPC1 and NPC2 expression. However, implication of LXRs in the selective uptake of cholesteryl esters from lipoproteins in human macrophages has never been reported.Our results show that (1) selective CE uptake from HDL(3) is highly efficient in human monocyte-derived macrophages; (2) surprisingly, HDL(3)-CE uptake is strongly increased by LXR activation despite antiatherogenic effects of LXRs; (3) HDL(3)-CE uptake increase is not linked to SR-BI expression modulation but it is dependent of proteoglycan interactions; (4) HDL(3)-CE uptake increase is associated with increased expression and secretion of apoE and LPL, two proteins interacting with proteoglycans; (5) HDL(3)-CE uptake increase depends on the integrity of raft domains and is associated with an increased caveolin-1 expression.Our study identifies a new role for LXRs in the control of cholesterol homeostasis in human macrophages. LXR activation results in enhanced dynamic intracellular cholesterol fluxes through an increased CE uptake from HDL and leads to an increased cholesterol availability to efflux to apoAI and HDL.
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Liver X receptor
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Reverse cholesterol transport
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Enhancing reverse cholesterol transport from macrophages in the arterial wall tothe liver for biliary excretion has been identified as a potential the rapeutic strategy to reduce and eventually regress atherogenesis. In addition to HDL -raising therapies, modulating macrophage cholesterol efflux pathways might be aninteresting new approach in the treatment of atherosclerosis. Recently, twoATP-binding cassette transporters, ABCA1 and ABCG1, have been indentified toplay a critical role in the efflux of cholesterol from macrophages, suggesting afunction in maintaining normal cellular cholesterol homeostasis and the preventionof atherogenesis. This review focuses on the recent findings on the role ofmacrophage ABCA1 and ABCG1 in atherosclerotic lesion development andhighlights the complex regulatory mechanisms and possible consequences oftherapeutic upregulation of these transporters.
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Reverse cholesterol transport
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