PPAR Medicines and Human Disease The ABCs of It All — Volkswagen L80

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PPAR Medicines and Human The ABCs of It All

1 Department of Pathology and Medicine, Queen’s University, ON, Canada K7L 3N6

2 Cancer Biology and Division, Cancer Research Queen’s University, Kingston, ON, K7L 3N6

Received 24 February 2012; 4 April 2012; Accepted 6 2012

Academic Editor:

Copyright © 2012 Anthony J. and Christopher J. B. Nicol. This is an access article distributed the Creative Commons Attribution which permits unrestricted distribution, and reproduction in any medium, the original work is properly


ATP-dependent binding (ABC) transporters are a family of proteins that pump a of hydrophobic compounds across and subcellular barriers and are implicated in diseases such as cancer and Inhibition of ABC transporter activity promise in early preclinical however, the outcomes in clinical with these agents not been as encouraging. Peroxisome receptors (PPARs) are ligand-activated factors that regulate involved in fat and glucose metabolism, and Activation of PPAR signaling is reported to regulate ABC gene This suggests the potential of medicines as a novel means of ABC transporter activity at the transcriptional This paper summarizes the made in understanding how PPAR affect ABC transporters, and the potential for impacting on human diseases, in with respect to cancer and

1. Introduction

Harnessing the energy from adenosine triphosphate hydrolysis, ATP-dependent binding (ABC) transporters shuttle a range of substrates, including metabolites, and xenobiotics, across membranes in order to maintain cell metabolism. They the largest family of transmembrane in humans, comprising 49 ABC genes, and are reviewed elsewhere [1 #x2013;3 ]. genes are subdivided among subfamilies (A-G) based on and structural homology and are highly among eukaryotic species, that most appeared in metazoan evolution [4 ]. The proteins by ABC genes consist of two distinct a transmembrane domain that specific compounds and transports across cellular and subcellular and a nucleotide-binding domain where ATP occurs to yield energy for transport [5 ]. Typically, ABC proteins are transporters expressed at the cell which move hydrophobic internally for metabolic pathways, or for elimination from the cell use by other tissues and organs. ABC transporters play important in a range of human physiologic, and pathologic functions. With to the latter, many preclinical that show promise in of regulating ABC transporters to overcome drug resistance in tumours, or lipid homeostasis in order to atherosclerotic risk, have not the same level of success in trials.

Peroxisome proliferator-activated (PPARs) are ligand-activated transcription that regulate expression of a of genes involved in sugar and fat inflammation, and cancer [6 #x2013;8 ]. PPAR homologs have characterized#x2014;PPAR


. and PPAR

displaying a unique pattern of expression that reflect distinctive functions [9 #x2013;11 ]. there is mounting in vitro and in evidence that activation of may alter ABC protein expression function. Accordingly, this will summarize recent in an emerging field where medicines, capable of modulating ABC genes at the transcriptional level, may useful when such provides novel therapeutic for treating cancer and atherosclerosis.

2. and Their Ligands

As members of the receptor superfamily, PPARs a ligand-binding domain that and binds specific PPAR and a DNA-binding domain that with specific peroxisome elements (PPREs) within the [12 ]. PPARs are localized to the nucleus and with retinoid

receptor to form complexes that to PPREs in the promoter regions of a range of target genes [13 ]. In its state, the PPAR#x2009;:#x2009;RXR complex with cell-specific corepressor that aid in the silencing of target transcription. Ligand binding a conformational change in PPAR leads to the release of corepressors, and the of coactivator molecules that target gene transcriptional Furthermore, ligand activation of may also repress signaling of gene targets through interaction with other factors or competition for available [14 ].

PPAR is highly expressed in the heart, kidney, skeletal and large intestine [15 ]. It is activated by the class of drugs, such as ciprofibrate, clofibrate, gemfibrozil, and used to treat elevated and low high-density lipoprotein (HDL) [16 ]. is more ubiquitously expressed highest levels noted the large intestine and placenta [15 ]. to other PPAR subtypes, it may be activated by various saturated and fatty acids [12 ]. Because is understood about PPAR. synthetic activators have developed; however, emerging supports the potential therapeutic of PPAR agonists, such as GW501516, and MBX-8025, which to be clinically tested [17 ].

As a chief of adipogenesis, PPAR is abundantly in adipose tissue [18 ], and like is also detected in vascular and cells, as well as tissues as the colon, breast, and prostate 20 ]. Synthetic agents known as (TZDs) like troglitazone, rosiglitazone, and pioglitazone are classic of PPAR activators [21 ]. In North rosiglitazone and pioglitazone are still to treat type 2 diabetic However, there are reports increased myocardial infarction with rosiglitazone use and bladder risk with long-term use of [22. 23 ]. As a followup on the former, a review of rosiglitazone by a panel of experts deemed the available inconclusive and requiring further In the latter case, direct evidence of this possible is also required. Despite the for more evidence, these remain FDA approved, albeit warning updates to package clarifying the potential for risk 25 ], and a Risk Evaluation and Mitigation (REMS) is in place to restrict and distribution of rosiglitazone-containing medicines to healthcare providers and their who confirm their awareness of the new [26 ]. Nevertheless, the utility of these remains valuable not only for ability to provide mechanistic into the role of PPAR target regulation, but also for potential benefit in certain uses.

Dual and pan PPAR were also developed to therapeutic potential via simultaneously two or more PPAR isoforms. include PPAR modulators tesaglitazar, muraglitazar, and aleglitazar, and the pan

agonist chiglitazar [27 ].

The reported between the above listed medicines and their in vitro and in effects on ABC transporters are summarized in 1 and 2. respectively, and described in detail in the context of several human

Table 1: In vitro effects of ligands on ABC transporters.

Table 2: In effects of PPAR ligands on ABC

The goal of chemotherapy is to target dividing cells or deregulated pathways to suppress tumour and ultimately, cure cancer however, one primary roadblock to the of chemotherapy is acquisition of multidrug (MDR). A well-known cause of MDR is ABC drug efflux from cells instilling resistance to agents [28 ]. The well-known ABC transporters, (Pgp)/MDR1/ABCB1, multidrug resistance (MRP)1/ABCC1, and breast cancer-resistance (BCRP)/MXR/ABCG2, are overexpressed in a variety of human cancers and transport a of chemotherapeutic drugs [4 ]. Pgp, an blood brain barrier and regulator of intestinal drug was the first ABC transporter to be characterized in [29 ]. Its overexpression in tumours of the kidney, colon, and breast correlates chemoresistance [30 #x2013;32 ]. Substrates of Pgp anthracyclines, vinca alkaloids, camptothecins, mitoxantrone, and methotrexate [33 ]. The ABC gene discovered was the more expressed MRP1 [34 ], which anthracyclines, vinca alkaloids, and in addition to organic anions and conjugates [28 ]. Its overexpression confers resistance in prostate, lung, and neuroblastoma cancer [35. 36 ]. BCRP is normally expressed in and small intestine, as well as stem cell populations 38 ]. Several drug-resistant cell also contain elevated of this ABC transporter, which to the efflux of several antitumour such as doxorubicin, daunorubicin, and topotecan [39 #x2013;41 ].

In addition to MDR, other of ABC transporters in cancer are beginning to further implicating these as important targets of chemotherapy. For Pgp expression, devoid of ATP-dependent transport, suppresses cell in the presence of apoptotic signals in and cancer cells [42 #x2013;44 ]. Pgp knockdown reduced the migration and potential of MCF7 human cancer cells [45 ]. As a result of studies, direct inhibition of ABC activity has become an appealing for researchers in the development of improved chemotherapeutics; however, several trials using ABC inhibitors proven unsuccessful [46 ].

Research has that PPAR activation expression of both mouse Mdr2/Abcb4, and Mdr3/Mdr1a/Abcb1a) and human homologs of Pgp, which similar chemotherapy substrates as [33 ]. Fasting-induced fatty acid increased hepatic expression of mRNA and protein, as well as in wild-type but not PPAR -knockout [77 ]. Similar results were in ciprofibrate-treated mice [73 ]. Interestingly, the trial demonstrated that Mdr1 and Mdr3 mRNA accompanied Mdr2 induction in however, in cultured mouse only Mdr2 levels elevated by PPAR agonists that in vivo induction of and Mdr3 may be influenced by PPAR in surrounding tissue. Furthermore, ciprofibrate and clofibrate increased expression of Mdr2 mRNA in CF1 This was associated with Mdr2 redistribution into canaliculi and enhanced biliary secretion [78 ]. Similarly, in a chimeric model with humanized bezafibrate increased hepatic mRNA and protein, and promoted localization of the transporter [71 ]. Bezafibrate-treated human hepatocellular liver cells also showed expression of MDR2/MDR3 mRNA. there was no subsequent change in levels, there was a redistribution of the into pseudocanaliculi between accompanied by enhanced apical of phospholipids, which could be by PPAR -specific knockdown [72 ].

MRP1 homologs may also be by PPARs, including MRP2/ABCC2, and MRP4/ABCC4, which are known to substrates belonging to a variety of drug classes [33 ]. Although normal physiological function elusive, it has been suggested these transporters may play a in MDR [79. 80 ]. Additionally, MRP4 may play a role in migration, as or pharmacological inhibition of this appears to prevent human cell motility [81 ]. Moffit et al. the effect of clofibrate on hepatic in mice. Following 10 days of clofibrate upregulated hepatic of Bcrp, Mrp3, and Mrp4 and protein in CD1 mice. Similar for Mrp3 and Mrp4 were in liver tissue isolated clofibrate-treated wild-type SV129 while no changes were in liver from similarly PPAR -knockout mice [82 ]. expression of Mrp3 was also in C57BL mice treated clofibrate, ciprofibrate, and diethylhexyl (DEHP) [83 ]. Maher et al. also the hepatic induction of Mrp3 and transcription in perfluorodecanoic-acid- (PFDA-) mice [84 ]. This was associated elevated serum levels of bilirubin and bile acids of Mrp3- and Mrp4-specific hepatic activity. These effects attenuated in PPAR -knockout treated with PFDA. putative PPRE sequences identified upstream of the Mrp3 and promoters, providing further that PPAR may directly transcription of these transporters in the

Activation of PPARs may also expression of BCRP. PPAR upregulate Bcrp transcription in intestine [85 ]. Furthermore, PPAR activation induces BCRP and efflux activity in human endothelial cells [75 ]. Here, induction is accompanied by binding of to a PPRE within the BCRP In human monocyte-derived dendritic BCRP was directly induced by PPAR through three PPRE sequences located the gene#x2019;s promoter [76 ]. This of BCRP activity elevated efflux and maintained intracellular low of mitoxantrone, which could be by addition of a BCRP inhibitor. In MCF7 breast cancer and human leukemia cell troglitazone downregulated expression of and restored sensitivity to doxorubicin [69 ]. Although troglitazone may elicit that are PPAR -dependent, it is known to operate via pathways are independent of this nuclear [86 ]. Inhibition of PPAR in untreated cells reduced BCRP indicating that the observed of troglitazone were PPAR and providing evidence that TZD may suppress BCRP transcription in cells by indirectly antagonizing itself.

In contrast to the studies previously a number of reports indicate PPAR activation may inhibit ABC expression and activity. Chen et al. that troglitazone increased activity and reversed Pgp-mediated in vincristine-resistant SGC7901 human cancer cells [70 ]. Furthermore, and Yamuna performed genetic analysis on a doxorubicin-resistant 143B osteosarcoma cell line and increased expression of Pgp and Kruppel-like 2 [91 ]. Given that the latter is a suppressor of PPAR expression [92 ], findings may implicate the PPAR as a negative regulator of Pgp transcription. et al. also demonstrated that necrosis factor (TNF) partially reverse MDR by inducing and suppressing Pgp in an adriamycin-resistant cell derived from HepG2 [93 ]. In another study, PPAR downregulated Mrp1 expression in intestine [85 ]. Hepatic expression of protein was reduced in male rats treated with the agonists, clofibrate, DEHP, and [89 ]. Furthermore, efflux of bile by Mrp2 may be suppressed by troglitazone in rat hepatocytes [74 ]. Both rosiglitazone and inhibited BCRP function in MDCKII canine kidney cells, but induced its transcription in the human hepatoma cell [68 ]. These PPAR activators decreased Pgp-mediated drug in doxorubicin-resistant P388 mouse cells. Moreover, fenofibrate Mdr1 transport activity in porcine kidney epithelial [67 ]. Finally, in doxorubicin-resistant MCF7 and cells, troglitazone downregulated of Pgp and reversed chemoresistance to doxorubicin [69 ]. among these studies it was not if these activities were on PPAR activation and signaling.

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the laboratory perspective, the involvement of ABC in MDR and other cancer hallmarks these genes as vital of chemotherapy, whereas their role in the clinical manifestation of remains elusive. This is why clinical trials with Pgp failed to reduce drug and subsequent chemoresistance [94 ]. Regulation of ABC transcription by PPARs may be another but primarily, a detailed understanding of the and clinical relevance of the entire ABC family in tumour samples and lines is obligatory. Future may identify new roles for ABC transporters in which could be targeted by pharmacological inhibition or regulation of Most of the evidence implies PPARs are positive regulators of ABC genes, indicating that expression can be suppressed by antagonizing On the other hand, controversial have also been therefore, improved understanding of the by which PPARs regulate ABC is required. In particular, delineating the of PPAR-dependent and -independent signaling on ABC transcription will determine the link between PPARs and ABC in cancer and may predict the success of ligand therapy in reversing Additional studies exploring the of PPAR activation as an adjuvant to in a wide range of drug-resistant cell lines may also insightful.

4. Atherosclerosis

The atherosclerotic condition is by the thickening of arterial vessels as a of an accumulation of oxidized low-density (LDL), and subsequently, cholesterol-laden as a consequence of a maladaptive immune The associated chronic inflammation and drives plaque formation and hardening, which can invariably to coronary artery disease leading cause of death [95 ]. Interestingly, recent evidence that PPAR induction of ABC expression may improve lipid through enhanced cholesterol and excretion, and thus represents a avenue to prevent cardiovascular progression.

As noted above, and PPAR isoforms are also in immune cells, such as macrophages, where they genes involved in inflammation, and TNF- /IFN- -mediated [96 #x2013;98 ]. Expression of these two isoforms is also observed in foam cells that atherosclerotic lesions [20. 99 ]. Recent studies suggest PPARs exerts antiatherosclerotic via improved cholesterol homeostasis the regulation of specific ABC transporters. is one such transporter that apolipoprotein-A1- (apoA1-) mediated efflux in macrophages [102 ]. ABCG1, also promotes the of cholesterol from macrophages to although the underlying mechanism unclear [103 ]. This is a critical step in reverse transport, a process that for cholesterol displacement and excretion by the and represents a protective modality atherosclerotic risk.

Activation of stimulates apoA1-mediated cholesterol from human and mouse and foam cells through a cascade that culminates in induction [52. 57. 62 ]. This is mediated via PPAR -dependent of liver X receptor (LXR ), an nuclear receptor, that ABCA1 transcription via interaction specific response elements in the promoter [104 ]. Although putative PPRE sequences initially identified in the LXR promoter ], only one was confirmed as a preferential binding site in macrophages [57 ]. In specific ligands for PPAR. and PPAR all increase LXR and ABCA1 and protein and enhance apoA1-mediated efflux and HDL synthesis in THP1 suggesting that non-PPRE-dependent mechanisms may be responsible for some of activities [47. 51 ]. In a similar THP1 macrophages treated various PPAR ligands that PPAR activation greater ABCA1 mRNA and apoA1-mediated cholesterol efflux to PPAR and PPAR agonists [61 ]. rosiglitazone and pioglitazone treatment of macrophages also stimulated efflux and induced ABCA1 and protein expression, implicating a role for PPAR [56. 58. 59 ]. treatment of mouse RAW264.7 foam cells with linoleic acid (CLA) ( c 9 t 11-CLA and t 10 c 12-CLA) or the hydroxylated of linoleic acid (13-HODE), ligands of both PPAR and decreased cholesterol accumulation, cholesterol clearance, and induced of Abca1, and other genes in cholesterol homeostasis [54. 55 ]. in other tissues, such as gallbladder epithelial cells, and mesangial and skeletal muscle PPAR activators upregulate LXR ABCA1 transcription and prevent accumulation [48. 53. 64 ].

Another activator, telmisartan, induced and Abcg1 expression in murine and in the aorta of ApoE-deficient mice, it suppressed macrophage proliferation and progression [63 ]. It was also reported the conditional deletion of PPAR in led to decreased expression of LXR. and ApoE in mice [106 ]. was accompanied by a significant reduction in efflux from macrophages to Furthermore, granulocyte macrophage factor (GM-CSF) knockout showed reduced expression of and Abcg1 in alveolar macrophages of the Given that GM-CSF is a positive regulator of PPAR. of PPAR in alveolar macrophages Abcg1 expression and cholesterol activity and decreased intracellular content [107 ]. Consequently, activation by pioglitazone induced efflux activity and increased mRNA and protein in THP1 and macrophages [56 ]. Fenofibrate also Abcg1 transcription, which was with increased HDL particle in Zucker diabetic fatty [90 ].

In the liver, ABCA1 is implicated in of HDL synthesis, which represents means of protecting against HDLs are specialized carrier in the blood that transport from peripheral tissues and macrophages to the liver for excretion ]. This process is thought to be the mechanism underlying HDL#x2019;s properties [109 ]. Indeed, HDL levels correspond inversely cardiovascular risk [110 ]. impaired ABCA1 activity is with low plasma HDL, is linked to Tangier disease, HDL deficiency, and accelerated atherosclerosis ]. Furthermore, Abcg1-overexpressing transgenic have greater plasma HDL improved cholesterol efflux macrophages, and reduced atherosclerotic [112 ].

Several studies demonstrated the ability of PPARs to ABCA1 expression in the liver. In one PPAR activation with a of fibrates upregulated LXR expression with enhanced ABCA1 and HDL biosynthesis in HepG2 cells [49 ]. Of the used, fenofibrate and LY518674 exclusively through PPAR. bezafibrate and gemfibrozil preferred and PPAR. respectively, in addition to activity. Accordingly, antagonism of in HepG2 cells blocked of ABCA1 mRNA and protein; PPAR activation also ABCA1 protein levels in cell line despite ABCA1 transcription [60 ]. In this activation of PPAR caused the of LXR from ABCA1 at the cell leading to increased ABCA1 degradation. Subsequently, translocation of LXR to the increased ABCA1 transcription via of this nuclear receptor to the region of the ABCA1 gene. this affected HDL biosynthesis or efflux from HepG2 remains to be seen.

Fasting-associated acid release induces expression of Abca1, Abcg5, and in wild-type but not PPAR -null [77 ]. Although these ABC transporters are in hepatobiliary cholesterol transport, cholesterol excretion from the was decreased by #x7e;50#x25; after This raises the possibility of PPARs and PPAR agonists a role in ABC transporter-mediated liver efflux under normal More recently, a clinical examined the effect of fenofibrate on HDL subclass particle concentrations on with triglycerides #x2265;150#x2009;mg/dL [87 ]. 3 weeks of therapy, stratification of by ABCA1 polymorphism genotypes two variants (R1587K and R219K) were associated with increases in small HDL particles. suggests a synergism between polymorphism and PPAR agonists.

One of the intuitive ways to reduce the of atherosclerosis is to regulate the uptake of cholesterol at the intestine. In mice, expression of Abca1 and Abcg8 is upon fasting [113 ]. normal mice maintained on a supplemented with a PPAR showed an increase in intestinal gene transcription and protein to PPAR -deficient mice, showed no effect to treatment [88 ]. increased expression was associated a reduction in cholesterol absorption, as as decreased plasma and liver concentrations.

Atherosclerotic heart is undoubtedly one of the most devastating worldwide. While pharmacological and interventions that lower LDL remain the current treatment for atherosclerosis, they may only the incidence of cardiovascular events by [109 ]. The literature indicates induction of ABCA1 and ABCG1 by PPAR activation may play a in preventing atherosclerosis by improving homeostasis and HDL synthesis. Moving additional studies are required to the clinical significance of these and to determine whether or not they are dependent. Clinical trials begun to examine the effect of PPAR activators in atherosclerosis, a mixture of results. For example, treatment barely increased HDL and marginally lowered the incidence of CAD in patients with type 2 [114. 115 ]. In a similar study, significantly reduced CAD, in by elevating HDL [116 ]. Studies also demonstrated that promote the destabilization of atherosclerotic in nondiabetic patients [117 ], still others report these PPAR activators may increase the risk of heart in type 2 diabetics [118 ]. these findings, a better of the pleiotropic effects of PPARs and role in atherosclerosis is required in to design and develop appropriate therapies devoid of detrimental

5. Ichthyosis

Derived from the ichthys for #x201c;fish,#x201d; ichthyosis to a group of dermatological disorders described by severely dry, and flaky skin that is to bear resemblance to fish [119 ]. The main pathophysiological of this disease is a failure of barrier permeability, leading to a of conditions ranging from the mild, such as the common vulgaris, to the most severe, as Harlequin type ichthyosis, is rare but fatal in newborns. mutations in ABCA12, a keratinocyte transporter, were shown to the latter phenotype [120. 121 ]. normal conditions, ABCA12 the uptake of lipids into secretory granules, called bodies, within keratinocytes. lipid-filled granules are then from the cell where release their cargo to the layer of the epidermis, a requirement for formation of skin barrier On the other hand, ABCA12 prevents lipid loading lamellar bodies, which to abnormal development of the skin and elevated rates of prenatal [122 ].

While studies in area are limited, they demonstrated that ABCA12 may be by PPARs, which may have implications in Harlequin ichthyosis. of PPARs promotes lamellar secretion and improved epidermal permeability in mice [123 ]. recently, Jiang et al. demonstrated ciglitazone, troglitazone, and the PPAR GW610742, induced expression of mRNA and protein in human [65 ]. Similarly, ceramide-induced transcription of was attenuated by siRNA knockdown of indicating that this was dependent on PPAR [66 ]. In a separate Jiang et al. also demonstrated clofibrate and the PPAR ligand, increased expression of the ABCA1 efflux pump in human [50 ]. Given that these require cholesterol for adequate of permeability barrier function ], ABCA1 regulation by PPARs may play an important role in the pathophysiology of Harlequin ichthyosis. findings implicate the potential of PPAR ligands for the treatment of disease, which should be validated in vivo .

6. Conclusion

studies describe compelling for PPAR medicines in the regulation of ABC expression and function. Beyond respective individual roles in human diseases, the overlap in distribution and regulatory potential PPARs and certain ABC transporters this emerging story an field for further research. also provide an alternative when the targeting of ABC transporter in human cancer, atherosclerosis, or may suggest therapeutic advantages for In addition, targeting ABC transporters at the level may circumvent issues identified during focused of transporter activity. Furthermore, the complex and multistage etiology of and atherosclerosis, dual/pan PPAR may prove especially useful in regulating multiple PPAR and ABC transporters. For example, examining agonists like aleglitazar, being assessed for cardiovascular in Phase 3 clinical trials, for effects on multiple ABC transporters may a fruitful area for future Improving our understanding of the interactions PPARs, their ligands, and ABC will further aid in developing targeted therapeutic strategies to the burden of human disease on and the healthcare system.

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