- Open Access
Advances in understanding the regulation of apoptosis and mitosis by peroxisome-proliferator activated receptors in pre-clinical models: relevance for human health and disease
© Boitier et al; licensee BioMed Central Ltd. 2003
- Received: 3 December 2002
- Accepted: 31 January 2003
- Published: 31 January 2003
Peroxisome proliferator activated receptors (PPARs) are a family of related receptors implicated in a diverse array of biological processes. There are 3 main isotypes of PPARs known as PPARα, PPARβ and PPARγ and each is organized into domains associated with a function such as ligand binding, activation and DNA binding. PPARs are activated by ligands, which can be both endogenous such as fatty acids or their derivatives, or synthetic, such as peroxisome proliferators, hypolipidaemic drugs, anti-inflammatory or insulin-sensitizing drugs. Once activated, PPARs bind to DNA and regulate gene transcription. The different isotypes differ in their expression patterns, lending clues on their function. PPARα is expressed mainly in liver whereas PPARγ is expressed in fat and in some macrophages. Activation of PPARα in rodent liver is associated with peroxisome proliferation and with suppression of apoptosis and induction of cell proliferation. The mechanism by which activation of PPARα regulates apoptosis and proliferation is unclear but is likely to involve target gene transcription. Similarly, PPARγ is involved in the induction of cell growth arrest occurring during the differentiation process of fibroblasts to adipocytes. However, it has been implicated in the regulation of cell cycle and cell proliferation in colon cancer models. Less in known concerning PPARβ but it was identified as a downstream target gene for APC/β-catenin/T cell factor-4 tumor suppressor pathway, which is involved in the regulation of growth promoting genes such as c-myc and cyclin D1. Marked species and tissue differences in the expression of PPARs complicate the extrapolation of pre-clinical data to humans. For example, PPARα ligands such as the hypolipidaemic fibrates have been used extensively in the clinic over the past 20 years to treat cardiovascular disease and side effects of clinical fibrate use are rare, despite the observation that these compounds are rodent carcinogens. Similarly, adverse clinical responses have been seen with PPARγ ligands that were not predicted by pre-clinical models. Here, we consider the response to PPAR ligands seen in pre-clinical models of efficacy and safety in the context of human health and disease.
- Kupffer Cell
- Peroxisome Proliferator
The evaluation of the safety of drugs is a vital but complex process. Normally, candidate drugs are tested in a range of in vivo and in vitro pre-clinical models that serve to evaluate genotoxicity, general toxicity, reproductive toxicology and cardiovascular safety. In vivo studies use both rodent and non-rodent animal dosing models depending on the endpoint and the compound characteristics. Although such models provide useful information, for some classes of compounds, the rodent models are poor predictors of human response, in some cases due to marked species differences in expression of the target receptors. For example, the family of peroxisome proliferator activated receptors (PPARs) display differences in expression and activation profiles between rodents and humans making the rodent models poor predictors of human response. However, this receptor family is an excellent drug target since the different isotypes PPARα, PPARβ and PPARγ play a central role in coordinating energy balance. Thus, PPARα ligands are hypolipidaemic and PPARγ ligands are insulin sensitizers with efficacy in type II diabetes. Here, we consider the response to PPAR ligands seen in pre-clinical models of efficacy and safety in the context of human health and disease.
PPARs are ligand-inducible transcription factors that belong to the nuclear hormone receptor superfamily, together with the receptors for thyroid hormone, retinoids, steroid hormones and vitamin D. According to the recently proposed nomenclature of nuclear hormone receptors [1, 2], PPARs form the group C in the subfamily 1 of the superfamily of nuclear hormone receptors, i.e., NR1C. PPARs occur in three different isotypes, namely PPARα (NR1C1), PPARβ (also called PPARδ, NUC-1 or FAAR), and PPARγ (NR1C3). These receptors have been found in various species such as cyclostoma , teleosts , amphibians , rodents  and humans [5–7]. There are three isoforms of PPARγ ; PPARγ1 and PPARγ3 are identical when fully translated and only differ in their splice variants, whereas PPARγ2 differs from the other isoforms in its N-terminus . The PPAR nomenclature for PPARβ and PPARγ is a misnomer, since neither of these PPAR isotypes has been associated with peroxisome proliferation.
The amino-terminal A/B region encodes a ligand-independent transcriptional activation domain (activation function-1) that is active in some cell types. The region is poorly conserved between the three PPAR isotypes. It has been shown that its phosphorylation state contributes to the modulation of PPARα and γ activity, by affecting the receptor/ligand affinity: insulin enhances transcriptional stimulation by human PPARα via phosphorylation of the conserved MAP-kinase sites Ser12 and Ser21 in the A/B domain [12, 13], whereas MAP-kinase mediated phosphorylation of Ser112 of mouse PPARγ2 lowers transcriptional activity [14, 15].
The ligand binding domain (LBD), or E/F domain of PPARs, is responsible for ligand-binding and converting PPARs to an active form that binds DNA and modulates gene expression. The interaction of PPARs with their ligands, because of the conformational changes that are induced especially involving the transactivation domain (activation function-2, AF-2) located in the C-terminal α-helix, allows recruitment of co-activators, such as the steroid receptor coactivator-1 [16, 17], the CREB-binding protein CBP/P300 , the tuberous sclerosis gene 2 product , the PPAR binding protein , PGC-1 , PGC-2 , Ara70 , and the release of corepressors, such as the nuclear receptor corepressors (or RXR-interacting protein 13) and the silencing mediator for retinoid and thyroid hormone receptors [18, 24, 25]. When co-transfected into cell lines, COUP-TFI  and COUP-TFII (also called ARP-1)  block PPAR action by binding specific DNA sequences in PPAR target genes called peroxisome proliferator responsive elements (PPREs). In addition, the E region is also important in nuclear localization and dimerization of the receptor. Indeed, dimerization is essential for the activity of PPARs, as it is for most of the other members of the nuclear hormone receptor superfamily. They heterodimerize with 9-cis retinoid X receptor (RXR), forming a complex that is able to bind, via a central DNA binding domain (C domain), to PPREs.
The C domain is highly conserved, with its two zinc finger-like structure and its α-helical DNA binding motifs, as often found in various transcription factors. The whole PPRE consensus sequence (TGACCT X TGACCT) fits a DR1 pattern (DR for direct repeat, 1 for one spacing base between the two consensus motifs TGACCT) . These elements bind PPAR-RXR heterodimers with PPAR occupying the 5' extended half site and RXR the 3' half site . PPAR-RXR heterodimers were shown to compete with hepatocyte nuclear factor-4 (HNF-4) homodimers for binding to DR1 elements, resulting in decreases in transcription of apolipoprotein C-III and transferrin genes [30, 31]. The first PPRE sequences were identified by promoter analysis of the peroxisome proliferator (PP)-responsive gene, acyl-CoA oxidase (ACO) [32, 33]. A number of studies point to the importance of the sequences flanking the PPREs for maintaining the optimal conformation of the PPAR-RXR heterodimers on the PPREs [34, 35]. These flanking sequences may provide an extra level of specificity to different nuclear receptors that recognize the DR1 element .
The D region encodes a flexible hinge region, thought to allow independent movement of the LBD relative to the DNA binding domain.
PPAR ligands: identification, interaction with PPARs and specificity
PPAR ligands can be both synthetic, such as peroxisome proliferators, hypolipidaemic drugs, anti-inflammatory or insulin-sensitizing drugs, or endogenous, most of them being fatty acids or their derivatives.
Among the group of synthetic ligands, fibrates are hypolipidaemic drugs used in the treatment of hyperlipidemia. Most of them preferentially activate PPARα. Others are industrial compounds . The insulin-sensitizing thiazolidinedione (TZD) class of compounds is selective for PPARγ , with an affinity (Kds) ranging from 40 nM (rosiglitazone) to several micromolars (troglitazone). These two compounds have been approved for the treatment of type II diabetes in humans. They efficiently reduce both insulin resistance and triglyceride plasma levels. Although their main effects are not mediated by PPARs, some non-steroidal anti-inflammatory drugs, such as indomethacin, flufenamic acid, ibuprofen or fenoprofen, activate both PPARα and PPARγ, which may contribute to their anti-inflammatory properties . Recently, the L165041 compound has been identified as being the first PPARβ-selective synthetic agonist .
Fatty acids have been discovered to bind to all three PPAR isotypes, demonstrating that they are not only energy storing molecules, but also "hormones" controlling nuclear receptor activities and consequently gene expression. Among the three isotypes, PPARα is not only the one that exhibits a high affinity for fatty acids, but is also the best characterized in terms of ligand specificity. It has been shown to have a clear preference for binding of long chain unsaturated fatty acids, such as the essential fatty acids linoleic, linolenic and arachidonic acids, at concentrations that correlate with circulating blood levels of these fatty acids. Fatty acid derivatives, such as the inflammatory mediators leukotriene B4 and 8(S)-hydroxy-eicosatetraenoic acid, were also identified as relatively high-affinity ligands for PPARα . In the case of PPARγ, a metabolite of the eicosanoid prostaglandin G2, 15-desoxy-Δ12,14-PGJ2 (15d-PGJ2) is the most potent natural ligand described so far, with reported Kds varying from 325 nM to 2.5 μM. Polyunsaturated fatty acids, such as 18:2, 18:3 and 20:4, seem to be the most efficient PPARβ natural ligands.
Tissue expression distribution
Each of the three PPAR isotypes is expressed in a distinct, tissue-specific pattern. PPARα is highly expressed in liver, heart, proximal tubules of kidney cortex, skeletal muscle, intestinal mucosa and in brown adipose, tissues that are metabolically very active . PPARγ is most highly expressed in white and brown adipose tissue, large intestine and spleen [43, 44]. In contrast to PPARα and PPARγ, which are abundantly expressed in just a few tissues, PPARβ is expressed in virtually all tissues at comparable levels [45, 46]. Furthermore, there is no sex-specific expression of the three PPAR isotypes as analyzed in rats .
The fact that some tissues express more than one PPAR isotype raises the question of PPAR-specific PPRE recognition. Assessment of the relative DNA-capabilities of the three PPAR isotypes to 16 native PPREs led to the classification of PPREs into three functional groups: strong, intermediate and weak elements, which correlates with the level of PPRE conformity to the consensus element . Surprisingly, the number of identical nucleotides in the core DR1 region is rather homogeneous across the different elements, and it is mainly the number of identities in the 5'-flanking nucleotides, rather than the stricto sensu core DR1, which determines the binding strength of a given PPRE. In all cases, PPARγ binds more strongly than do PPARα and PPARβ and is thus less dependent on well-conserved 5'-flanking extension. In contrast, conservation of the 5'-flank is particularly essential for PPARα binding and therefore contributes to isotype specificity. The PPAR DNA-binding activity is also modulated by the isotype of the RXR heterodimeric partner. Binding of PPAR:RXR to strong elements is reinforced when RXRγ is the partner, whereas heterodimerization with RXRα is more favorable for binding to weak elements.
PPAR target genes
PPARα is a central regulator of hepatic lipid metabolism as well as participant in genes involved in bile acid synthesis . The first identified PPARα target genes code for several enzymes involved in the β-oxidation pathway, namely acyl-CoA oxidase , bifunctional enzyme  and thiolase . The activation of long-chain fatty acid into acyl-CoA thioester by the long-chain fatty acyl-CoA synthetase is likely to be regulated by PPARα .
There are also PP-responsive genes that have a link to cell cycle control although no PPREs have been found in these genes to date. Induction of the oncogenes c-Ha-ras, jun and c-myc by PP has been reported and the ability to induce these genes correlates well with tumor-promoting potential [65–68]. For example, Wy-14,643, clofibrate, ciprofibrate and DEHP were inducers of c-fos, c-jun, junB egr-1, and NUP475 whereas the noncarcinogenic PP dehydroepiandrosterone was ineffective . In addition, an immediate early gene (IEG) critically involved in lipid metabolism, tumor promotion and inflammation, cyclooxygenase-2, is also regulated by PP . IEG are key genes involved in regulating the cell cycle and are characterized by rapid response to mitogens as well as serum and cycloheximide inducibility . Recently, a novel IEG involved in neuronal differentiation, rZFP-37, was characterized as a PP-regulated gene in rodent liver . These regulatory genes are critical in the progression of the cell cycle, particularly the G1 to S transition. For example, PP-induced expression of growth regulatory genes precedes entry of the cell in S phase . In addition, alterations in CDK1, CDK2, CDK4, cyclin D1 and cyclin E have been reported following exposure to PP [67, 68, 71].
Because expression of PPARγ is highest in adipose tissue, the search for PPARγ target genes has concentrated on adipocytes. The two markers of terminal adipocyte differentiation – aP2, a fatty acid-binding protein, and phosphoenolpyruvate carboxykinase, an enzyme of the glyceroneogenesis pathway – are indeed regulated by PPARγ . Similarly, PPARγ also regulates the expression of the genes coding for lipoprotein lipase, fatty acid transport protein, and the fatty acid translocase . Recently, the idea of a link between PPARγ and the insulin signaling has been reinforced by the finding that the c-Cbl-associated protein, a signaling protein interacting with the insulin receptor, could be encoded by a potential PPARγ target gene .
Probably because of its ubiquitous expression, it has been hard to anticipate a function for PPARβ. However, some of its target genes have been identified. For example, PPARβ can promote cellular lipid accumulation in macrophages by increasing the expression of genes that are involved in lipid uptake and by repressing key genes implicated in lipid metabolism and efflux .
Role of PPARα activation on mitosis
The process of peroxisome proliferation-induced hepatocarcinogenesis is dependent on PPARα . Mice lacking this receptor are totally resistant to Wy-14,643-induced liver tumors . Remarkably, the mice that lack PPARα do not display the typical pleiotropic response when challenged with the PP, such as peroxisome proliferation, abnormal lipid homeostasis  and transcriptional activation of target genes . Importantly, PPARα-null mice do not exhibit enhanced cell proliferation as evident by hepatomegaly, incorporation of bromodeoxyuridine into DNA, and expression of proteins involved in progression of the cell cycle, like the proliferating cell nuclear antigen PCNA . These data clearly demonstrate that PPARα is a key contributor for the process of peroxisome proliferation, hypertrophy, cell proliferation and hepatocarcinogenesis. However, even though PPARα regulates PP-mediated cell proliferation, it is unclear whether this function is direct or indirect.
PP have mitogenic effects when given directly to primary hepatocytes in culture . However, others have suggested that Kupffer cells are responsible for the mitogenic effects of PP on hepatocytes, presumably via an interleukin  or tumor necrosis factor α (TNFα)-dependent mechanism . Kupffer cells represent about 2% of the liver mass and share many properties with macrophages such as secretion of the cytokines TNFα, interleukin-1 (IL-1), IL-2 and IL-6 . In support of the hypothesis that Kupffer cells are required for the proliferation of hepatocytes, Rose et al.  showed that inhibition of Kupffer cell activity by dietary glycine and methylpalmitate inhibited Wy-14,643-induced hepatocyte proliferation. Furthermore, the hepatocyte growth response to PP can be prevented by antibodies to TNFα [83, 86] or TNFα receptor 1 (TNRF1) . More recent studies have revealed that hepatocytes cultured in the absence of Kupffer cells do not exhibit cell proliferation when treated with Wy-14,643 or nafenopin [88, 89], and this response can be restored by returning the Kupffer cells to purified hepatocytes.
In support of the role of TNFα as a key mediator in the stimulation of hepatocellular proliferation, recent findings suggest that down-regulation of the iron-binding protein lactoferrin (LF) upon PP treatment may play a role in initiating the growth response . Indeed, LF may putatively be able to regulate liver expression of TNFα, and possibly other pro-inflammatory cytokines. Following PP exposure, the down-regulation of LF expression would result in increased levels of TNFα, which, in turn, would mediate some or all the growth changes associated with PP. These increased levels would occur by bioactivation or release of preexisting TNFα protein from hepatic Kupffer cells rather than by increase in TNFα expression as no changes in TNFα mRNA levels were detected following PP treatment .
IL-1α was shown to be able to induce DNA synthesis in mouse hepatocytes, even in the presence of the anti-TNFR1 antibody, suggesting that IL-1α acts independently rather than by elaborating TNFα . However, the mandatory roles of TNFα and interleukins in the regulation of mitosis in the liver have recently been questioned. Indeed, mice lacking TNFα [92, 93] respond to Wy-14,643 no differently than wild-type animals in terms of stimulation of hepatocyte proliferation. Moreover, cell proliferation can be still triggered by PP in the liver of IL-6 null transgenic mice [94, 95]. Perhaps multiple cytokines are required to elicit the mitogenic response to PP. Alternatively, a cytokine that has not yet been characterized might be responsible for hepatocyte proliferation. Mitogen-activated protein (MAP) kinase pathways contribute to the transmission of extracellular signals, resulting in the direct or indirect phosphorylation of transcription factors and subsequent alterations in gene expression . The MEK (MAP kinase kinase) and extracellular signal regulated kinases (ERK) pathway primarily responds to cellular proliferation signals, while the p38 MAP kinases and c-Jun N-terminal kinases are modulated by cytokines, growth factors and a variety of cellular stress signals . Inhibition of either enzyme in hepatocytes using specific inhibitors prevented PP-induced increase in S-phase , suggesting a role of MAP kinase activity in PP-regulated cell proliferation. The activation of both p38 and ERK has been shown to lead to the release of TNFα and IL-6 by macrophages and other cell types [99, 100]. Therefore, one of the functions of MAP kinase signaling pathway may be to regulate the levels of cytokines or interleukines, thereby controlling cell mitosis in the liver. As mentioned before, PPARα activation also leads to increase in S-phase. It has therefore been suggested that PPARα activation would rely upon p38 MAP kinase-induced phosphorylation . In support of this assumption, Barger et al.  showed that transcription of PPARα target genes was induced upon PP exposure in a P38 MAP kinase dependent manner. Moreover, a ligand-independent transcriptional activation domain in PPARα has been shown to contain MAP kinase sites . Activation of the MEK-ERK pathway seems to be a prerequisite for the growth response of rodent liver cells to PP [65, 98, 104], suggesting that PP may be using both stress and growth pathways. Induction of oxidative stress by PP [85, 105] may also play a role in the activation of MAP kinase pathways. In particular, p38 MAP kinase has been associated with oxidative stress  and has been reported to be constitutively active in mouse liver .
Role of PPARα activation on apoptosis
Many PPs such as nafenopin were shown to suppress both spontaneous apoptosis [108–111] and that induced by diverse stimuli including transforming growth factor-β1 (TGFβ1) . The PP-induced suppression of apoptosis can be reproduced in cultured rodent hepatocytes with high concentrations of TNFα , suggesting that TNFα may play a role in permitting or mediating such an inhibition. In line with this assumption, removal of TNFα-producing Kupffer cells from hepatocyte cultures abolishes the decrease in apoptosis typically observed with hepatocytes exposed to PPs . Suppression of apoptosis is restored when the Kupffer cells are added back to the hepatocyte cultures. Furthermore, in vitro experiments using a dominant negative repressor of PPARα activity suggested that PPARα mediates the PP-induced suppression of apoptosis . This was later confirmed in experiments using PP-stimulated hepatocytes from PPARα null transgenic mice [110, 114]. TNFα has been found to be still capable of suppressing apoptosis in cultured PPARα null mice in the absence of PPs and PPARα, suggesting that TNFα is clearly a downstream effector on apoptosis suppression compared to PPs or PPARα. In the presence of the protein synthesis inhibitor cycloheximide, the response of hepatocytes to TNFα is reversed, with a clear induction of cell death . This finding perhaps explains the pleiotropic response of rodent liver to TNFα. Depending on the signaling context, this cytokine may induce or may suppress hepatocyte apoptosis.
PP-induced suppression of hepatocyte apoptosis was shown to rely upon the activation of the MEK/ERK signalling pathway  as well as the p38 MAP kinase pathway . The response to PP is also dependent upon the transcription factor NFκB since a dominant negative form of the upstream kinase Iκ that activates NFκB prevents the suppression of apoptosis in response to PP .
Recent findings showed that the liver from aged rats is exceedingly sensitive to the anti-apoptotic effect of PPARα agonists . This high sensitivity could be related to the remarkably higher levels of the anti-apoptotic protein Bcl-2 in aged livers than in livers of young, adult, and middle-aged animals. Interestingly, the PPARα agonist Wy-14,643 significantly diminished elements of the pro-apoptotic machinery (e.g., Bax, caspases, and fas) in the aged liver.
In summary, suppression of apoptosis induced by PP may prevent the removal of damaged or excess cells that would normally be eliminated, these cells then remaining as targets for further mitogenic stimulation and DNA mutations .
Role of PPARγ activation on mitosis
PPARγ is involved in the induction of cell growth arrest occurring during the differentiation process of fibroblasts to adipocytes. Differentiation of 3T3-L1 cells into adipocytes necessitates withdrawal from the cell cycle in addition to the coexpression of PPARγ and C/EBP, and involves phosphorylation of the retinoblastoma susceptibility gene product Rb . However, activation of PPARγ in Rb-/- mouse embryo fibroblasts is sufficient to induce adipocyte terminal differentiation and thus the link between PPARγ and Rb phosphorylation remains to be established .
PPARγ ligands may protect the vasculature against injury. Inhibition of cell growth is among others one mechanism involved in this process. The antiproliferative effects of PPARγ ligands on vascular smooth muscle cells are mediated by targeting critical cell cycle regulators, including Rb and p27Kip1, that regulate the progression of cells from G1 phase into S phase to conduct DNA synthesis . PPARγ ligands have been recently shown to suppress development of atherosclerosis in LDL receptor-deficient mice .
Ligand activation of PPARγ results in the inhibition of proliferation of various cancer cells. Primary human liposarcoma cells, which express high levels of PPARγ, can be stimulated to undergo cell cycle arrest and terminal differentiation by treatment with PPARγ and RXR-specific ligands . Activation of PPARγ also induces a reduction in growth rate and clonogenic capacity of human breast cancer cells in culture. In one breast cancer cell line, which expresses high levels of PPARγ, the resistance to TZD was associated with a high MAP kinase activity, which might explain a low PPARγ activity due to phosphorylation of the A/B region of the receptor .
Human colon tumor cell lines express PPARγ and respond to diverse PPARγ agonists with a reduced rate of growth and an increased degree of differentiation. Morphological maturation, defined by an increased cytoplasmic-to-nuclear ratio, was observed concomitantly with changes in gene expression consistent with a transition to a more differentiated state . PPARγ-selective targets included genes linked to growth regulatory pathways (regenerating gene IA), colon epithelial cell maturation (GOB-4 and keratin 20), and immune modulation (neutrophil-gelatinase-associated lipocalin) . Drg-1 (differentiation-related gene-1), a putative suppressor gene in human colorectal cancer, and PTEN, a tumor suppressor gene which modulates several cellular functions, including cell migration, survival, and proliferation, were found to be controlled at least in part by PPARγ agonists in colon cancer cell lines [127, 128].
Human colorectal carcinoma cells implanted in nude mice were shown to grow more slowly in mice treated with troglitazone [125, 129]. On the other hand, two independent studies performed in mice bearing a mutation in the adenomatous polyposis coli tumor suppressor gene (APCmin) showed an increase in tumors or polyps in the colon after these mice were fed a diet containing a PPARγ agonist for 8 or 5 weeks [130, 131]. The discrepancy with the above mentioned results obtained with colon cancer cell lines does not seem to be attributable to the genetic defect that causes the tumors in mice, since some of these lines also bear this specific mutation [125, 132]. Interestingly, recent studies with mice heterozygous for PPARγ have shown that heterozygous loss of PPARγ causes an increase in β-catenin levels and a greater incidence of colon cancer when animals are treated with azoxymethane . However, mice with preexisting damage to APC, a regulator of β-catenin, develop tumors in a manner insensitive to the status of PPARγ. These data show that PPARγ can suppress β-catenin levels and colon carcinogenesis but only before damage to the APC/β-catenin pathway. This finding suggests a potentially important use for PPARγ ligands as chemopreventative agents in colon cancer.
Troglitazone showed a potent dose-dependent effect on the growth inhibition of six hepatocellular carcinoma (HCC) cell lines . The growth inhibition was linked to the G1 phase cell cycle arrest through the up-expression of the cyclin-dependent kinase inhibitors, p21 and p27 proteins, and the hypophosphorylation of retinoblastoma protein. Unfortunately, no PPARγ knock-out transgenic mice are available since deletion of the PPARγ gene in mice results in embryonic lethality at approximately day 10 of gestation due to placental insufficiency .
Role of PPARγ activation on apoptosis
PPARγ ligands have been implicated in inducing apoptosis in a number of cell types. For example, rosiglitazone (at low concentrations, in the range of its Kd value of 20 nM) was able to increase the number of TUNEL-positive cells and to increase activation of caspase-3 in human monocyte-derived macrophages . Similarly, TZDs triggered apoptosis in cultured astrocytes  or in B lymphocytes via PPARγ. 15d-PGJ2 can also trigger the apoptosis of endothelial cells via a PPAR-dependent pathway . Part of the effectiveness of the PPARγ agonists troglitazone and 15d-PGJ2 in the rat adjuvant arthritis model of human rheumatoid arthritis is via inducing apoptosis in synoviocytes . PPARγ ligands also induce apoptosis in human hepatocellular and esophageal carcinoma cells [134, 141].
The mechanism underlying the induction of apoptosis is not clear, but evidence suggests that TZDs could interfere with the anti-apoptotic NFκB signaling pathway. The induction of apoptosis by PPARγ is increased by costimulation with TNFα-related apoptosis-inducing ligand (TRAIL), a member of the TNF family . It has not been determined whether a similar NFκB inhibition might be responsible for the observed TRAIL-induced pro-apoptotic effects of TZDs, which enhances apoptosis in tumor cells. To date, no reports are available on ligand-induced apoptosis in liver with high PPARγ expression levels.
The inhibition of cell growth observed in human breast cancer cells treated in vitro with ligands for PPARγ and retinoic acid receptor is accompanied with a profound decrease of Bcl-2 gene expression and a marked increase in apoptosis . Troglitazone induced apoptosis in six HCC by caspase-dependent (mitochondrial transmembrane potential decrease, cleavage of poly [adenosine diphosphate ribose] polymerase, 7A6 antigen exposure, Bcl-2 decrease, and activation of caspase 3) and caspase-independent (phosphatidylserine externalization) mechanisms .
Role of PPARβ activation on mitosis
PPARβ was identified as a downstream target gene for APC/β-catenin/T cell factor-4 (TCF-4) tumor suppressor pathway, which is involved in the regulation of growth promoting genes such as c-myc and cyclin D1. Indeed, PPARβ expression was elevated in human colorectal cancer cells and was down-regulated upon restoration of APC expression in these cells . This down-regulation appeared to be direct as the promoter of PPARβ contains β-catenin/TCF-4-responsive elements, and PPARβ promoter reporters were repressed by APC as well as stimulated by mutants of β-catenin (resistant to the inhibitory effect of APC). Genetic disruption of PPARβ also decreased the tumorigenicity of human colon cancer cells transplanted in mice, thus suggesting that PPARβ contributes to the growth-inhibitory properties of the APC tumor suppressor . In other experiments with vascular tissues, PPARβ was found up-regulated during vascular lesion formation and promoted post-confluent cell proliferation in vascular smooth muscle cells (VSMC) by increasing the cyclin A and CDK2 as well as decreasing p57kip2 .
Role of PPARβ activation on apoptosis
PPARβ plays an antiapoptotic role in keratinocytes via transcriptional control of the Akt1 signaling pathway . Both 3-phosphoinositide-dependent kinase-1 and integrin-linked kinase are target genes of PPARβ. The up-regulation of these genes together with the down-regulation of PTEN led to an increase of Akt1 activity in keratinocytes and suppressed apoptosis induced by growth factors deprivation in cell culture.
Role of PPARα
Although rodents are sensitive to the hepatocarcinogenic effects of PP, there is little evidence that humans are at increased risk of liver cancer, even after chronic exposure. The hypolipidemic drugs gemfibrozil and clofibrate have been used in the clinic for 15 and 30 years, respectively, and epidemiological studies do not reveal a statistically significant increase in cancer up to 8 years after initiation of therapy . Livers from humans and monkeys given fibrate drugs showed no evidence of peroxisome proliferation [149–152]. Human and marmoset hepatocyte cultures, in contrast to rats, are unresponsive to treatment to MEHP .
There are several possibilities that could account for lack of peroxisome proliferation in human liver compared to rats and mice. Even though functionally active, the human PPARα is expressed at only about 10% of that in mouse liver , and extracts from human liver contain little PPARα that can bind to PPRE . Recently, mutant forms have been described in some human liver samples: hPPARα8/14 is a truncated receptor that results from aberrant splicing of the PPARα mRNA ; hPPARα6/29 is a full length receptor that binds to PPRE, yet cannot be activated by PPs . However, screening of a sample of the human population for the presence of hPPARα6/29 revealed that this form is rare. An alteration of the PPRE sequence in the human acyl-CoA oxidase gene might also explain the relative human unresponsiveness to PPARα ligands . Finally, species-specific responses to some synthetic PPARα ligands, as analyzed in Xenopus, mouse and human PPARα have also been observed [157, 158]. These dramatic differences in PPARα expression and activity or in PPRE structure may account for the absence of indicators of PP response in human liver, including peroxisome proliferation and cell proliferation/apoptosis suppression . Different levels of expression of PPARα may have differential effects on gene expression. The PPARα activity induced by these drugs in humans could be sufficient to mediate hypolipidaemia but too low to trigger transcriptional induction of genes involved in peroxisome proliferation and adverse effects . As well as being resistant to peroxisome proliferation, human hepatocytes are also resistant to PP-mediated induction of mitosis and suppression of apoptosis [148, 160]. Because the rodent hepatocarcinogenesis following PP exposure is mediated by PPARα, the current evidence suggests that humans exposed to these compounds are not likely to develop liver tumors.
Anecdotically, PPARα agonists have been reported to suppress the growth of a human hepatoma cell line . A massive apoptosis was observed in the AH-130 hepatoma, a poorly differentiated tumor, maintained by weekly transplantations in rats, upon exposure to clofibrate. Similar results were obtained with HepG2 cells. The mechanisms by which clofibrate induces apoptosis are still unclear. Since the peroxisome proliferator-activated receptor was expressed at a very low level and was not stimulated by clofibrate in the AH-130 hepatoma cells, its involvement seems unlikely. Phospholipids and cholesterol were significantly decreased, suggesting an inhibition of the mevalonate pathway and, therefore, of isoprenylation of proteins involved in cell proliferation.
Role of PPARγ
Recent evidence suggests that PPARγ ligands could have an anti-tumor effect in humans as these compounds decrease cell growth and induce apoptosis in several malignant human cell types, including HCC , breast adenocarcinoma [124, 143] and colon adenocarcinoma . In addition, loss-of-function mutations in PPARγ were identified in a subset of human colorectal tumors, supporting a role for PPARγ as a tumor suppressor of colorectal carcinogenesis . In agreement with a potential role of PPARγ ligands for the treatment of cancer, troglitazone treatment was found active in the treatment of advanced liposarcoma . On the other hand, although some recent findings have suggested a potentially important use for PPARγ ligands as chemo-preventative agents in colon cancer , the PPARγ ligand troglitazone was not found active in the treatment of metastatic colorectal cancer during a phase II clinical trial . The potential beneficial effect of PPARγ ligands in the treatment of human HCC has not yet been tested.
Role of PPARβ
A link exists between PPARβ and human cancer via the APC tumor repressor gene. In the majority of human colorectal cancers, APC is inactivated by deletions, thus giving rise to increased levels of β-catenin/TCF-4 mediated transcriptional activity. PPARβ is, beside c-myc and cyclin D1, one of the target genes regulated by this transcription complex and thus may contribute to cell proliferation in cancer. Epidemiological studies have shown a decrease risk of colorectal carcinoma deaths associated with the use of the non-steroidal anti-inflammatory drug (NSAID) aspirin. Moreover, in individuals with familial adenomatous polyposis, an inherited predisposition to multiple colorectal polyps, the NSAID sulindac can reduce both the size and the number of colorectal tumors. Interestingly, sulindac was shown to bind and antagonize PPARβ leading to increased apoptosis in colon cancer cells . Thus PPARβ may be a critical intermediate in the tumorigenesis pathway of the APC gene and may be a molecular target of the effect of NSAID in colorectal cancer.
Hepatic toxicity induced by the PPARγ agonist troglitazone
Troglitazone is an antidiabetic agent, which has been reported to cause severe hepatic injury in certain individuals. The mechanism underlying this rare but severe adverse drug reaction associated with troglitazone is not clear. Results obtained with HepG2 cells suggest that troglitazone induces apoptotic hepatocyte death, which may be one of the factors of liver injury in humans . As hepatocytes in some diabetes type II patients contain higher level of PPARγ level, this could be related to an increased risk of troglitazone-induced hepatotoxicity in these patients .
PPARγ agonists have been proposed as therapeutic targets against inflammation and atherosclerosis in humans. Indeed, PPARγ agonists, which decrease cytokine secretion as TNFα, IL-1, IL-6 in macrophages, and which increase apoptosis in macrophages and synoviocytes , could potentially be used to treat rheumatoid arthritis . PPARγ agonists, which protect against the proliferation of vascular smooth muscle cells after vascular injury in animal models may have a similar effect in humans .
The regulation of apoptosis and mitosis by PPAR ligands in rodent models is complex but much has been done in the last 10 years towards understanding the pathways involved. For the rodent liver, the mode of action of PPARα ligands is understood sufficiently to permit us to conclude that this is not relevant to humans. However, the genes that are activated by PPARα ligands to regulate apoptosis and mitosis remain to be determined.
For other modes of action, the pathways are less clear, limiting the usefulness of rodent models of clinical toxicity. However, the advent of new technologies such as proteomics, genomics and pharmacogenetics is allowing more innovative approaches to these difficult issues.
- Smirnov AN: Nuclear receptors: nomenclature, ligands, mechanisms of their effects on gene expression. Biochemistry (Engl Trans Biokhimiya). 2002, 67: 957-977.View ArticleGoogle Scholar
- Auwerx J, Baulieu E, Beato M, Becker-Andre M, Burbach PH, Camerino G, Chambon P, Cooney A, Dejean A, Dreyer C, Evans RM, Gannon F, Giguere V, Gronemeyer H, Gustafsson JA, Laudet V, Lazar MA, Mangelsdorf DJ, Millbrandt J, Milgrom E, Moore DD, O'Malley B, Parker M, Parker K, Perimann T, Pfahl M, Rosenfeld MG, Samuels H, Schutz G, Sladek FM, Stunnenberg HG, Spedding M, Thummel C, Tsai MJ, Umesono K, Vennstrom B, Wahli W, Weinberg C, Willson TM, Yamamoto K: A unified nomenclature system for the nuclear receptor superfamily. Cell. 1999, 97: 161-163.View ArticleGoogle Scholar
- Escriva H, Safi R, Hanni C, Langlois MC, Saumitou-Laprade P, Stehelin D, Capron A, Pierce R, Laudet V: Ligand binding was acquired during evolution of nuclear receptors. Proc Natl Acad Sci U S A. 1997, 94: 6803-6808.PubMed CentralPubMedView ArticleGoogle Scholar
- Kliewer SA, Forman BM, Blumberg B, Ong ES, Borgmeyer U, Mangelsdorf DJ, Umesono K, Evans RM: Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci U S A. 1994, 91: 7355-7359.PubMed CentralPubMedView ArticleGoogle Scholar
- Sher T, Yi HF, McBride OW, Gonzalez FJ: cDNA cloning, chromosomal mapping, and functional characterization of the human peroxisome proliferator activated receptor. Biochemistry. 1993, 32: 5598-5604.PubMedView ArticleGoogle Scholar
- Schmidt A, Endo N, Rutledge SJ, Vogel R, Shinar D, Rodan GA: Identification of a new member of the steroid hormone receptor superfamily that is activated by a peroxisome proliferator and fatty acids. Mol Endocrinol. 1992, 6: 1634-1641.PubMedGoogle Scholar
- Greene ME, Blumberg B, McBride OW, Yi HF, Kronquist K, Kwan K, Hsieh L, Greene G, Nimer SD: Isolation of the human peroxisome proliferator activated receptor gamma cDNA: expression in hematopoietic cells and chromosomal mapping. Gene Expr. 1995, 4: 281-299.PubMedGoogle Scholar
- Schoonjans K, Martin G, Staels B, Auwerx J: Peroxisome proliferator-activated receptors, orphans with ligands and functions. Curr Opin Lipidol. 1997, 8: 159-166.PubMedView ArticleGoogle Scholar
- Gelman L, Fruchart JC, Auwerx J: An update on the mechanisms of action of the peroxisome proliferator-activated receptors (PPARs) and their roles in inflammation and cancer. Cell Mol Life Sci. 1999, 55: 932-943.PubMedView ArticleGoogle Scholar
- Green S, Chambon P: Nuclear receptors enhance our understanding of transcription regulation. Trends Genet. 1988, 4: 309-314.PubMedView ArticleGoogle Scholar
- Evans RM: The steroid and thyroid hormone receptor superfamily. Science. 1988, 240: 889-895.PubMedView ArticleGoogle Scholar
- Juge-Aubry CE, Hammar E, Siegrist-Kaiser C, Pernin A, Takeshita A, Chin WW, Burger AG, Meier CA: Regulation of the transcriptional activity of the peroxisome proliferator-activated receptor alpha by phosphorylation of a ligand-independent trans-activating domain. J Biol Chem. 1999, 274: 10505-10510.PubMedView ArticleGoogle Scholar
- Shalev A, Siegrist-Kaiser CA, Yen PM, Wahli W, Burger AG, Chin WW, Meier CA: The peroxisome proliferator-activated receptor alpha is a phosphoprotein: regulation by insulin. Endocrinol. 1996, 137: 4499-4502.Google Scholar
- Zhang B, Berger J, Zhou G, Elbrecht A, Biswas S, White-Carrington S, Szalkowski D, Moller DE: Insulin- and mitogen-activated protein kinase-mediated phosphorylation and activation of peroxisome proliferator-activated receptor gamma. J Biol Chem. 1996, 271: 31771-31774.PubMedView ArticleGoogle Scholar
- Adams M, Reginato MJ, Shao D, Lazar MA, Chatterjee VK: Transcriptional activation by peroxisome proliferator-activated receptor gamma is inhibited by phosphorylation at a consensus mitogen-activated protein kinase site. The J Biol Chem. 1997, 272: 5128-5132.PubMedView ArticleGoogle Scholar
- Krey G, Braissant O, L'Horset F, Kalkhoven E, Perroud M, Parker MG, Wahli W: Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay. Mol Endocrinol. 1997, 11: 779-791.PubMedView ArticleGoogle Scholar
- Onate SA, Tsai SY, Tsai MJ, O'Malley BW: Sequence and characterization of a coactivator for the steroid hormone receptor superfamily. Science. 1995, 270: 1354-1357.PubMedView ArticleGoogle Scholar
- Dowell P, Ishmael JE, Avram D, Peterson VJ, Nevrivy DJ, Leid M: p300 functions as a coactivator for the peroxisome proliferator-activated receptor [alpha]. J Biol Chem. 1997, 272: 33435-33443.PubMedView ArticleGoogle Scholar
- Henry KW, Yuan X, Koszewski NJ, Onda H, Kwiatkowski DJ, Noonan DJ: Tuberous sclerosis gene 2 product modulates transcription mediated by steroid hormone receptor family members. J Biol Chem. 1998, 273: 20535-20539.PubMedView ArticleGoogle Scholar
- Zhu Y, Qi C, Jain S, Rao MS, Reddy JK: Isolation and characterization of PBP, a protein that interacts with peroxisome proliferator-activated receptor. J Biol Chem. 1997, 272: 25500-25506.PubMedView ArticleGoogle Scholar
- Puigserver P, Wu Z, Park CW, Graves R, Wright M, Spiegelman BM: A cold-inducible coactivator of nuclear receptors linked to adaptive thermogenesis. Cell. 1998, 92: 829-839.PubMedView ArticleGoogle Scholar
- Castillo G, Brun RP, Rosenfield JK, Hauser S, Park CW, Troy AE, Wright ME, Spiegelman BM: An adipogenic cofactor bound by the differentiation domain of PPAR gamma. EMBO J. 1999, 18: 3676-3687.PubMed CentralPubMedView ArticleGoogle Scholar
- Heinlein CA, Ting HJ, Yeh S, Chang C: Identification of ARA70 as a ligand-enhanced coactivator for the peroxisome proliferator-activated receptor gamma. J Biol Chem. 1999, 274: 16147-16152.PubMedView ArticleGoogle Scholar
- DiRenzo J, Soderstrom M, Kurokawa R, Ogliastro MH, Ricote M, Ingrey S, Horlein A, Rosenfeld MG, Glass CK: Peroxisome proliferator-activated receptors and retinoic acid receptors differentially control the interactions of retinoid X receptor heterodimers with ligands, coactivators, and corepressors. Mol Cell Biol. 1997, 17: 2166-2176.PubMed CentralPubMedView ArticleGoogle Scholar
- Zamir I, Zhang J, Lazar MA: Stoichiometric and steric principles governing repression by nuclear hormone receptors. Genes & Dev. 1997, 11: 835-846.View ArticleGoogle Scholar
- Baes M, Castelein H, Desmet L, Declercq PE: Antagonism of COUP-TF and PPAR[alpha]/RXR[alpha] on the activation of the malic enzyme gene promoter: Modulation by 9-cis RA. Biochem Biophys Res Commun. 1995, 215: 338-345.PubMedView ArticleGoogle Scholar
- Marcus SL, Capone JP, Rachubinski RA: Identification of COUP-TFII as a peroxisome proliferator response element binding factor using genetic selection in yeast: COUP-TFII activates transcription in yeast but antagonizes PPAR signaling in mammalian cells. Mol Cell Endocrinol. 1996, 120: 31-39.PubMedView ArticleGoogle Scholar
- Osada S, Tsukamoto T, Takiguchi M, Mori M, Osumi T: Identification of an extended half-site motif required for the function of peroxisome proliferator-activated receptor alpha. Genes Cells. 1997, 2: 315-327.PubMedView ArticleGoogle Scholar
- IJpenberg A, Jeannin E, Wahli W, Desvergne B: Polarity and specific sequence requirements of peroxisome proliferator-activated receptor (PPAR)/retinoid X receptor heterodimer binding to DNA. A functional analysis of the malic enzyme gene PPAR response element. J Biol Chem. 1997, 272: 20108-20117.PubMedView ArticleGoogle Scholar
- Hertz R, Bishara-Shieban J, Bar-Tana J: Mode of action of peroxisome proliferators as hypolipidemic drugs. Suppression of apolipoprotein C-III. J Biol Chem. 1995, 270: 13470-13475.PubMedView ArticleGoogle Scholar
- Hertz R, Seckbach M, Zakin MM, Bar-Tana J: Transcriptional suppression of the transferrin gene by hypolipidemic peroxisome proliferators. J Biol Chem. 1996, 271: 218-224.PubMedView ArticleGoogle Scholar
- Tugwood JD, Aldridge TC, Lambe KG, Macdonald N, Woodyatt NJ: Peroxisome proliferator-activated receptors: structures and function. Ann N Y Acad Sci. 1996, 804: 252-265.PubMedView ArticleGoogle Scholar
- Osumi T, Osada S, Tsukamoto T: Analysis of peroxisome proliferator-responsive enhancer of the rat acyl-CoA oxidase gene. Ann N Y Acad Sci. 1996, 804: 202-213.PubMedView ArticleGoogle Scholar
- Palmer CN, Hsu MH, Griffin HJ, Johnson EF: Novel sequence determinants in peroxisome proliferator signaling. J Biol Chem. 1995, 270: 16114-16121.PubMedView ArticleGoogle Scholar
- Varanasi U, Chu R, Huang Q, Castellon R, Yeldandi AV, Reddy JK: Identification of a peroxisome proliferator-responsive element upstream of the human peroxisomal fatty acyl coenzyme A oxidase gene. J Biol Chem. 1996, 271: 2147-2155.PubMedView ArticleGoogle Scholar
- Johnson EF, Palmer CN, Griffin KJ, Hsu MH: Role of the peroxisome proliferator-activated receptor in cytochrome P450 4A gene regulation. FASEB J. 1996, 10: 1241-1248.PubMedGoogle Scholar
- Issemann I, Green S: Activation of a member of the steroid hormone receptor superfamily by peroxisome proliferators. Nature. 1990, 347: 645-650.PubMedView ArticleGoogle Scholar
- Lehmann JM, Moore LB, Smith-Oliver TA, Wilkison WO, Willson TM, Kliewer SA: An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma (PPAR gamma). J Biol Chem. 1995, 270: 12953-12956.PubMedView ArticleGoogle Scholar
- Lehmann JM, Lenhard JM, Oliver BB, Ringold GM, Kliewer SA: Peroxisome proliferator-activated receptors [alpha] and [gamma] are activated by indomethacin and other non-steroidal anti-inflammatory drugs. J Biol Chem. 1997, 272: 3406-3410.PubMedView ArticleGoogle Scholar
- Berger J, Leibowitz MD, Doebber TW, Elbrecht A, Zhang B, Zhou G, Biswas C, Cullinan CA, Hayes NS, Li Y, Tanen M, Ventre J, Wu MS, Berger GD, Mosley R, Marquis R, Santini C, Sahoo SP, Tolman RL, Smith RG, Moller DE: Novel peroxisome proliferator-activated receptor (PPAR) gamma and PPARdelta ligands produce distinct biological effects. J Biol Chem. 1999, 274: 6718-6725.PubMedView ArticleGoogle Scholar
- Devchand PR, Keller H, Peters JM, Vazquez M, Gonzalez FJ, Wahli W: The PPARalpha-leukotriene B4 pathway to inflammation control. Nature. 1996, 384: 39-43.PubMedView ArticleGoogle Scholar
- Beck F, Plummer S, Senior PV, Byrne S, Green S, Brammar WJ: The ontogeny of peroxisome-proliferator-activated receptor gene expression in the mouse and rat. Proc R Soc London B Biol Sci. 1992, 247: 83-87.View ArticleGoogle Scholar
- Tontonoz P, Hu E, Graves RA, Budavari AI, Spiegelman BM: mPPAR gamma 2: tissue-specific regulator of an adipocyte enhancer. Genes & Dev. 1994, 8: 1224-1234.View ArticleGoogle Scholar
- Mansen A, Guardiola-Diaz H, Rafter J, Branting C, Gustafsson JA: Expression of the peroxisome proliferator-activated receptor (PPAR) in the mouse colonic mucosa. Biochem Biophys Res Commun. 1996, 222: 844-851.PubMedView ArticleGoogle Scholar
- Amri EZ, Bonino F, Ailhaud G, Abumrad NA, Grimaldi PA: Cloning of a protein that mediates transcriptional effects of fatty acids in preadipocytes. Homology to peroxisome proliferator-activated receptors. J Biol Chem. 1995, 270: 2367-2371.PubMedView ArticleGoogle Scholar
- Xing G, Zhang L, Zhang L, Heynen T, Yoshikawa T, Smith M, Weiss S, Detera-Wadleigh S: Rat PPAR[delta] contains a CGG triplet repeat and is prominently expressed in the thalamic nuclei. Biochem Biophys Res Commun. 1995, 217: 1015-1025.PubMedView ArticleGoogle Scholar
- Escher P, Braissant O, Basu-Modak S, Michalik L, Wahli W, Desvergne B: Rat PPARs: quantitative analysis in adult rat tissues and regulation in fasting and refeeding. Endocrinology. 2001, 142: 4195-4202.PubMedView ArticleGoogle Scholar
- Qi C, Zhu Y, Reddy JK: Peroxisome proliferator-activated receptors, coactivators, and downstream targets. Cell Biochem Biophys. 2000, 32: 187-204.PubMedView ArticleGoogle Scholar
- Dreyer C, Krey G, Keller H, Givel F, Helftenbein G, Wahli W: Control of the peroxisomal beta-oxidation pathway by a novel family of nuclear hormone receptors. Cell. 1992, 68: 879-887.PubMedView ArticleGoogle Scholar
- Zhang B, Marcus SL, Sajjadi FG, Alvares K, Reddy JK, Subramani S, Rachubinski RA, Capone JP: Identification of a peroxisome proliferator-responsive element upstream of the gene encoding rat peroxisomal enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase. Proc Natl Acad Sci U S A. 1992, 89: 7541-7545.PubMed CentralPubMedView ArticleGoogle Scholar
- Lee SS, Pineau T, Drago J, Lee EJ, Owens JW, Kroetz DL, Fernandez-Salguero PM, Westphal H, Gonzalez FJ: Targeted disruption of the alpha isoform of the peroxisome proliferator-activated receptor gene in mice results in abolishment of the pleiotropic effects of peroxisome proliferators. Mol Cell Biol. 1995, 15: 3012-3022.PubMed CentralPubMedView ArticleGoogle Scholar
- Schoonjans K, Watanabe M, Suzuki H, Mahfoudi A, Krey G, Wahli W, Grimaldi P, Staels B, Yamamoto T, Auwerx J: Induction of the acyl-coenzyme A synthetase gene by fibrates and fatty acids is mediated by a peroxisome proliferator response element in the C promoter. J Biol Chem. 1995, 270: 19269-19276.PubMedView ArticleGoogle Scholar
- Motojima K, Passilly P, Peters JM, Gonzalez FJ, Latruffe N: Expression of putative fatty acid transporter genes are regulated by peroxisome proliferator-activated receptor alpha and gamma activators in a tissue- and inducer-specific manner. J Biol Chem. 1998, 273: 16710-16714.PubMedView ArticleGoogle Scholar
- Desvergne B, Wahli W: Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocrine Rev. 1999, 20: 649-688.Google Scholar
- Mascaro C, Acosta E, Ortiz JA, Marrero PF, Hegardt FG, Haro D: Control of human muscle-type carnitine palmitoyltransferase I gene transcription by peroxisome proliferator-activated receptor. J Biol Chem. 1998, 273: 8560-8563.PubMedView ArticleGoogle Scholar
- Brandt JM, Djouadi F, Kelly DP: Fatty acids activate the expression of a gene involved in cardiac mitochondrial lipid import via peroxisome proliferator-activated receptor alpha. Circulation. 1998, 98: I628-View ArticleGoogle Scholar
- Rodriguez JC, Gil-Gomez G, Hegardt FG, Haro D: Peroxisome proliferator-activated receptor mediates induction of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene by fatty acids. J Biol Chem. 1994, 269: 18767-18772.PubMedGoogle Scholar
- Aldridge TC, Tugwood JD, Green S: Identification and characterization of DNA elements implicated in the regulation of CYP4A1 transcription. Biochem J. 1995, 306 (Pt 2): 473-479.PubMed CentralPubMedView ArticleGoogle Scholar
- Muerhoff AS, Griffin KJ, Johnson EF: The peroxisome proliferator-activated receptor mediates the induction of CYP4A6, a cytochrome P450 fatty acid omega-hydroxylase, by clofibric acid. J Biol Chem. 1992, 267: 19051-19053.PubMedGoogle Scholar
- Michaud SE, Renier G: Direct regulatory effect of fatty acids on macrophage lipoprotein lipase: potential role of PPARs. Diabetes. 2001, 50: 660-666.PubMedView ArticleGoogle Scholar
- Chianale J, Vollrath V, Wielandt AM, Amigo L, Rigotti A, Nervi F, Gonzalez S, Andrade L, Pizarro M, Accatino L: Fibrates induce mdr2 gene expression and biliary phospholipid secretion in the mouse. Biochem J. 1996, 314 (Pt 3): 781-786.PubMed CentralPubMedView ArticleGoogle Scholar
- Hunt MC, Yang YZ, Eggertsen G, Carneheim CM, Gafvels M, Einarsson C, Alexson SE: The peroxisome proliferator-activated receptor alpha (PPARalpha) regulates bile acid biosynthesis. J Biol Chem. 2000, 275: 28947-28953.PubMedView ArticleGoogle Scholar
- Patel DD, Knight BL, Soutar AK, Gibbons GF, Wade DP: The effect of peroxisome-proliferator-activated receptor-alpha on the activity of the cholesterol 7 alpha-hydroxylase gene. Biochem J. 2000, 351: 747-753.PubMed CentralPubMedView ArticleGoogle Scholar
- Marrapodi M, Chiang JY: Peroxisome proliferator-activated receptor alpha (PPARalpha) and agonist inhibit cholesterol 7alpha-hydroxylase gene (CYP7A1) transcription. J Lipid Res. 2000, 41: 514-520.PubMedGoogle Scholar
- Rokos CL, Ledwith BJ: Peroxisome proliferators activate extracellular signal-regulated kinases in immortalized mouse liver cells. J Biol Chem. 1997, 272: 13452-13457.PubMedView ArticleGoogle Scholar
- Ledwith BJ, Pauley CJ, Wagner LK, Rokos CL, Alberts DW, Manam S: Induction of cyclooxygenase-2 expression by peroxisome proliferators and non-tetradecanoylphorbol 12,13-myristate-type tumor promoters in immortalized mouse liver cells. J Biol Chem. 1997, 272: 3707-3714.PubMedView ArticleGoogle Scholar
- Ledwith BJ, Johnson TE, Wagner LK, Pauley CJ, Manam S, Galloway SM, Nichols VW: Growth regulation by peroxisome proliferators: opposing activities in early and late G1. Cancer Res. 1996, 56: 3257-3264.PubMedGoogle Scholar
- Ledwith BJ, Manam S, Troilo P, Joslyn DJ, Galloway SM, Nichols WW: Activation of immediate-early gene expression by peroxisome proliferators in vitro. Mol Carcinog. 1993, 8: 20-27.PubMedView ArticleGoogle Scholar
- Gashler A, Sukhatme VP: Early growth response protein 1 (Egr-1): prototype of a zinc-finger family of transcription factors. Prog Nucleic Acid Res Mol Biol. 1995, 50: 191-224.PubMedView ArticleGoogle Scholar
- Vanden Heuvel JP, Holden P, Tugwood J, Ingle C, Yen W, Galjart N, Greenlee WF: Identification of a novel peroxisome proliferator responsive cDNA isolated from rat hepatocytes as the zinc-finger protein ZFP-37. Toxicol Appl Pharmacol. 1998, 152: 107-118.PubMedView ArticleGoogle Scholar
- Peters JM, Aoyama T, Cattley RC, Nobumitsu U, Hashimoto T, Gonzalez FJ: Role of peroxisome proliferator-activated receptor alpha in altered cell cycle regulation in mouse liver. Carcinogenesis. 1998, 19: 1989-1994.PubMedView ArticleGoogle Scholar
- Tontonoz P, Hu E, Devine J, Beale EG, Spiegelman BM: PPAR gamma 2 regulates adipose expression of the phosphoenolpyruvate carboxykinase gene. Mol Cell Biol. 1995, 15: 351-357.PubMed CentralPubMedView ArticleGoogle Scholar
- Ribon V, Johnson JH, Camp HS, Saltiel AR: Thiazolidinediones and insulin resistance: peroxisome proliferatoractivated receptor gamma activation stimulates expression of the CAP gene. Proc Natl Acad Sci U S A. 1998, 95: 14751-14756.PubMed CentralPubMedView ArticleGoogle Scholar
- Vosper H, Patel L, Graham TL, Khoudoli GA, Hill A, Macphee CH, Pinto I, Smith SA, Suckling KE: The peroxisome proliferator-activated receptor delta promotes lipid accumulation in human macrophages. J Biol Chem. 2001, 276: 44258-44265.PubMedView ArticleGoogle Scholar
- Cattley RC, DeLuca J, Elcombe C, Fenner-Crisp P, Lake BG, Marsman DS, Pastoor TA, Popp JA, Robinson DE, Schwetz B: Do Peroxisome Proliferating Compounds Pose a Hepatocarcinogenic Hazard to Humans?. Regul Toxicol and Pharmacol. 1998, 27: 47-60.View ArticleGoogle Scholar
- Moody DE, Reddy JK, Lake BG, Popp JA, Reese DH: Peroxisome proliferation and nongenotoxic carcinogenesis: commentary on a symposium. Fundam and Appl Toxicol. 1991, 16: 233-248.View ArticleGoogle Scholar
- Glauert HP, Reddy JK, Kennan WS, Sattler GL, Rao VS, Pitot HC: Effect of hypolipidemic peroxisome proliferators on unscheduled DNA synthesis in cultured hepatocytes and on mutagenesis in Salmonella. Cancer Lett. 1984, 24: 147-156.PubMedView ArticleGoogle Scholar
- Roberts RA, Nebert DW, Hickman JA, Richburg JH, Goldsworthy TL: Perturbation of the mitosis/apoptosis balance: a fundamental mechanism in toxicology. Fundam Appl Toxicol. 1997, 38: 107-115.PubMedView ArticleGoogle Scholar
- Peters JM, Cattley RC, Gonzalez FJ: Role of PPAR alpha in the mechanism of action of the nongenotoxic carcinogen and peroxisome proliferator Wy-14,643. Carcinogenesis. 1997, 18: 2029-2033.PubMedView ArticleGoogle Scholar
- Aoyama T, Peters JM, Iritani N, Nakajima T, Furihata K, Hashimoto T, Gonzalez FJ: Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor alpha (PPARalpha). J Biol Chem. 1998, 273: 5678-5684.PubMedView ArticleGoogle Scholar
- Karam WG, Ghanayem BI: Induction of replicative DNA synthesis and PPAR alpha-dependent gene transcription by Wy-14 643 in primary rat hepatocyte and non-parenchymal cell co-cultures. Carcinogenesis. 1997, 18: 2077-2083.PubMedView ArticleGoogle Scholar
- Rose ML, Germolec DR, Schoonhoven R, Thurman RG: Kupffer cells are causally responsible for the mitogenic effect of peroxisome proliferators. Carcinogenesis. 1997, 18: 1453-1456.PubMedView ArticleGoogle Scholar
- Rolfe M, James NH, Roberts RA: Tumour necrosis factor alpha (TNF alpha) suppresses apoptosis and induces DNA synthesis in rodent hepatocytes: a mediator of the hepatocarcinogenicity of peroxisome proliferators?. Carcinogenesis. 1997, 18: 2277-2280.PubMedView ArticleGoogle Scholar
- Decker K: Biologically active products of stimulated liver macrophages (Kupffer cells). Eur J Biochem. 1990, 192: 245-261.PubMedView ArticleGoogle Scholar
- Rose ML, Rusyn I, Bojes HK, Belyea J, Cattley RC, Thurman RG: Role of Kupffer cells and oxidants in signaling peroxisome proliferator-induced hepatocyte proliferation. Mutat Res. 2000, 448: 179-192.PubMedView ArticleGoogle Scholar
- Bojes HK, Germolec DR, Simeonova P, Bruccoleri A, Schoonhoven R, Luster MI, Thurman RG: Antibodies to tumor necrosis factor alpha prevent increases in cell replication in liver due to the potent peroxisome proliferator, WY-14,643. Carcinogenesis. 1997, 18: 669-674.PubMedView ArticleGoogle Scholar
- West DA, James NH, Cosulich SC, Holden PR, Brindle R, Rolfe M, Roberts RA: Role for tumor necrosis factor alpha receptor 1 and interleukin-1 receptor in the suppression of mouse hepatocyte apoptosis by the peroxisome proliferator nafenopin. Hepatology. 1999, 30: 1417-1424.PubMedView ArticleGoogle Scholar
- Hasmall SC, West DA, Olsen K, Roberts RA: Role of hepatic non-parenchymal cells in the response of rat hepatocytes to the peroxisome proliferator nafenopin in vitro. Carcinogenesis. 2000, 21: 2159-2165.PubMedView ArticleGoogle Scholar
- Parzefall W, Berger W, Kainzbauer E, Teufelhofer O, Schulte-Hermann R, Thurman RG: Peroxisome proliferators do not increase DNA synthesis in purified rat hepatocytes. Carcinogenesis. 2001, 22: 519-523.PubMedView ArticleGoogle Scholar
- Hasmall S, Orphanides G, James N, Pennie W, Hedley K, Soames A, Kimber I, Roberts RA: Downregulation of Lactoferrin by PPARalpha Ligands: Role in Perturbation of Hepatocyte Proliferation and Apoptosis. Toxicol Sci. 2002, 68: 304-313.PubMedView ArticleGoogle Scholar
- Holden PR, Hasmall SC, James NH, West DR, Brindle RD, Gonzalez FJ, Peters JM, Roberts RA: Tumour necrosis factor alpha (TNFalpha): role in suppression of apoptosis by the peroxisome proliferator nafenopin. Cell Mol Biol. 2000, 46: 29-39.PubMedGoogle Scholar
- Lawrence JW, Wollenberg GK, DeLuca JG: Tumor necrosis factor alpha is not required for WY14,643-induced cell proliferation. Carcinogenesis. 2001, 22: 381-386.PubMedView ArticleGoogle Scholar
- Anderson SP, Dunn CS, Cattley RC, Corton JC: Hepatocellular proliferation in response to a peroxisome proliferator does not require TNFalpha signaling. Carcinogenesis. 2001, 22: 1843-1851.PubMedView ArticleGoogle Scholar
- Ledda-Columbano GM, Curto M, Piga R, Zedda AI, Menegazzi M, Sartori C, Shinozuka H, Bluethmann H, Poli V, Ciliberto H: In vivo hepatocyte proliferation is inducible through a TNF and IL-6-independent pathway. Oncogene. 1998, 17: 1039-1044.PubMedView ArticleGoogle Scholar
- Ledda-Columbano GM, Piga R, Shinozuka H, Bluethmann H, Ciliberto H, Menegazzi M, Columbano A: Mouse liver cell proliferation induced by primary mitogens does not require TNA-alpha or IL-6. Proc Am Assoc Cancer Res. 1998, 39: 252-Google Scholar
- Schaeffer HJ, Weber MJ: Mitogen-activated protein kinases: specific messages from ubiquitous messengers. Mol Cell Biol. 1999, 19: 2435-2444.PubMed CentralPubMedView ArticleGoogle Scholar
- Raingeaud J, Gupta S, Rogers JS, Dickens M, Han J, Ulevitch RJ, Davis DJ: Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J Biol Chem. 1995, 270: 7420-7426.PubMedView ArticleGoogle Scholar
- Cosulich S, James N, Roberts R: Role of MAP kinase signalling pathways in the mode of action of peroxisome proliferators. Carcinogenesis. 2000, 21: 579-584.PubMedView ArticleGoogle Scholar
- Beyaert R, Cuenda A, Vanden Berghe W, Plaisance S, Lee JC, Haegeman G, Cohen P, Fiers W: The p38/RK mitogen-activated protein kinase pathway regulates interleukin-6 synthesis response to tumor necrosis factor. EMBO J. 1996, 15: 1914-1923.PubMed CentralPubMedGoogle Scholar
- Vanden Berghe W, Plaisance S, Boone E, De Bosscher K, Schmitz ML, Fiers W, Haegeman G: p38 and extracellular signal-regulated kinase mitogen-activated protein kinase pathways are required for nuclear factor-kappaB p65 transactivation mediated by tumor necrosis factor. J Biol Chem. 1998, 273: 3285-3290.PubMedView ArticleGoogle Scholar
- Roberts RA: Evidence for cross talk between PPARalpha and p38 MAP kinase. Toxicol Sci. 2002, 68: 270-274.PubMedView ArticleGoogle Scholar
- Barger PM, Browning AC, Garner AN, Kelly DP: p38 mitogen-activated protein kinase activates peroxisome proliferator-activated receptor alpha: a potential role in the cardiac metabolic stress response. J Biol Chem. 2001, 276: 44495-44501.PubMedView ArticleGoogle Scholar
- Juge-Aubry C, Pernin A, Favez T, Burger AG, Wahli W, Meier CA, Desvergne B: DNA binding properties of peroxisome proliferator-activated receptor subtypes on various natural peroxisome proliferator response elements: Importance of the 5'-flanking region. J Biol Chem. 1997, 272: 25252-25259.PubMedView ArticleGoogle Scholar
- Mounho BJ, Thrall BD: The extracellular signal-regulated kinase pathway contributes to mitogenic and antiapoptotic effects of peroxisome proliferators in vitro. Toxicol Appl Pharmacol. 1999, 159: 125-133.PubMedView ArticleGoogle Scholar
- Chu S, Huang Q, Alvares K, Yeldandi AV, Rao MS, Reddy JK: Transformation of mammalian cells by overexpressing H2O2-generating peroxisomal fatty acyl-CoA oxidase. Proc Natl Acad Sci U S A. 1995, 92: 7080-7084.PubMed CentralPubMedView ArticleGoogle Scholar
- Uchida K, Shiraishi M, Naito Y, Torii Y, Nakamura Y, Osawa T: Activation of stress signaling pathways by the end product of lipid peroxidation. 4-hydroxy-2-nonenal is a potential inducer of intracellular peroxide production. J Biol Chem. 1999, 274: 2234-2242.PubMedView ArticleGoogle Scholar
- Mendelson KG, Contois LR, Tevosian SG, Davis RJ, Paulson KE: Independent regulation of JNK/p38 mitogen-activated protein kinases by metabolic oxidative stress in the liver. Proc Natl Acad Sci U S A. 1996, 93: 12908-12913.PubMed CentralPubMedView ArticleGoogle Scholar
- Roberts RA, Soames AR, Gill JH, James NH, Wheeldon EB: Non-genotoxic hepatocarcinogens stimulate DNA synthesis and their withdrawal induces apoptosis, but in different hepatocyte populations. Carcinogenesis. 1995, 16: 1693-1698.PubMedView ArticleGoogle Scholar
- Bayly AC, Roberts RA, Dive C: Suppression of liver cell apoptosis in vitro by the non-genotoxic hepatocarcinogen and peroxisome proliferator nafenopin. J Cell Biol. 1994, 125: 197-203.PubMedView ArticleGoogle Scholar
- Christensen JG, Gonzales AJ, Cattley RC, Goldsworthy TL: Regulation of apoptosis in mouse hepatocytes and alteration of apoptosis by nongenotoxic carcinogens. Cell Growth & Differ. 1998, 9: 815-825.Google Scholar
- Oberhammer F, Fritsch G, Pavelka M, Froschl G, Tiefenbacher R, Purchio T, Schulte-Hermann R: Induction of apoptosis in cultured hepatocytes and in the regressing liver by transforming growth factor-beta 1 occurs without activation of an endonuclease. Toxicol Lett. 1992, 64–65 Spec No: 701-704.PubMedView ArticleGoogle Scholar
- James NH, Roberts RA: Species differences in response to peroxisome proliferators correlate in vitro with induction of DNA synthesis rather than suppression of apoptosis. Carcinogenesis. 1996, 17: 1623-1632.PubMedView ArticleGoogle Scholar
- Roberts RA, James NH, Woodyatt NJ, Macdonald N, Tugwood JD: Evidence for the suppression of apoptosis by the peroxisome proliferator activated receptor alpha (PPAR alpha). Carcinogenesis. 1998, 19: 43-48.PubMedView ArticleGoogle Scholar
- Hasmall SC, James NH, Macdonald N, Gonzalez FJ, Peters JM, Roberts RA: Suppression of mouse hepatocyte apoptosis by peroxisome proliferators: role of PPARalpha and TNFalpha. Mutat Res. 2000, 448: 193-200.PubMedView ArticleGoogle Scholar
- Cosulich SC, Roberts RA: Peroxisome proliferators require p38 RK activity to suppress apoptosis and induce S-phase in rat primary hepatocytes. Proc Am Assoc Cancer Res. 1999, 40: 741-Google Scholar
- Cosulich SC, James NH, Needham MR, Newham PP, Bundell KR, Roberts RA: A dominant negative form of IKK2 prevents suppression of apoptosis by the peroxisome proliferator nafenopin. Carcinogenesis. 2000, 21: 1757-1760.PubMedView ArticleGoogle Scholar
- Youssef J, Badr M: Enhanced hepatocarcinogenicity due to agonists of peroxisome proliferator-activated receptors in senescent rats: Role of peroxisome proliferation, cell proliferation, and apoptosis. ScientificWorldJournal. 2002, 2: 1-10.View ArticleGoogle Scholar
- Lowe SW, Lin AW: Apoptosis in cancer. Carcinogenesis. 2000, 21: 485-495.PubMedView ArticleGoogle Scholar
- Shao D, Lazar MA: Peroxisome proliferator activated receptor gamma, CCAAT/enhancer-binding protein alpha, and cell cycle status regulate the commitment to adipocyte differentiation. J Biol Chem. 1997, 272: 21473-21478.PubMedView ArticleGoogle Scholar
- Hansen JB, Petersen RK, Larsen BM, Bartkova J, Alsner J, Kristiansen K: Activation of peroxisome proliferator-activated receptor gamma bypasses the function of the retinoblastoma protein in adipocyte differentiation. J Biol Chem. 1999, 274: 2386-2393.PubMedView ArticleGoogle Scholar
- Wakino S, Law RE, Hsueh WA: Vascular protective effects by activation of nuclear receptor PPARgamma. J Diabetes Complications. 2002, 16: 46-49.PubMedView ArticleGoogle Scholar
- Li AC, Brown KK, Silvestre MJ, Willson TM, Palinski W, Glass CK: Peroxisome proliferator-activated receptor gamma ligands inhibit development of atherosclerosis in LDL receptor-deficient mice. J Clin Invest. 2000, 106: 523-531.PubMed CentralPubMedView ArticleGoogle Scholar
- Tontonoz P, Singer S, Forman BM, Sarraf P, Fletcher JA, Fletcher CD, Brun RP, Mueller E, Altiok S, Oppenheim H: Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferator-activated receptor gamma and the retinoid X receptor. Proc Natl Acad Sci U S A. 1997, 94: 237-241.PubMed CentralPubMedView ArticleGoogle Scholar
- Mueller E, Sarraf P, Tontonoz P, Evans RM, Martin KJ, Zhang M, Fletcher CD, Singer S, Spiegelman BM: Terminal differentiation of human breast cancer through PPAR gamma. Mol Cell. 1998, 1: 465-470.PubMedView ArticleGoogle Scholar
- Sarraf P, Mueller E, Jones D, King FJ, DeAngelo DJ, Partridge JB, Holden SA, Chen LB, Singer S, Fletcher CD: Differentiation and reversal of malignant changes in colon cancer through PPARgamma. Nat Med. 1998, 4: 1046-1052.PubMedView ArticleGoogle Scholar
- Gupta RA, Brockman JA, Sarraf P, Willson TM, DuBois RN: Target genes of peroxisome proliferator-activated receptor gamma in colorectal cancer cells. J Biol Chem. 2001, 276: 29681-29687.PubMedView ArticleGoogle Scholar
- Guan RJ, Ford HL, Fu Y, Li Y, Shaw LM, Pardee AB: Drg-1 as a differentiation-related, putative metastatic suppressor gene in human colon cancer. Cancer Res. 2000, 60: 749-755.PubMedGoogle Scholar
- Patel L, Pass I, Coxon P, Downes CP, Smith SA, Macphee CH: Tumor suppressor and anti-inflammatory actions of PPARgamma agonists are mediated via upregulation of PTEN. Curr Biol. 2001, 11: 764-768.PubMedView ArticleGoogle Scholar
- Brockman JA, Gupta RA, DuBois RN: Activation of PPARgamma leads to inhibition of anchorage-independent growth of human colorectal cancer cells. Gastroenterology. 1998, 115: 1049-1055.PubMedView ArticleGoogle Scholar
- Saez E, Tontonoz P, Nelson MC, Alvarez JG, Ming UT, Baird SM, Thomazy VA, Evans RM: Activators of the nuclear receptor PPARgamma enhance colon polyp formation. Nat Med. 1998, 4: 1058-1061.PubMedView ArticleGoogle Scholar
- Lefebvre AM, Chen I, Desreumaux P, Najib J, Fruchart JC, Geboes K, Briggs M, Heyman R, Auwerx J: Activation of the peroxisome proliferator-activated receptor gamma promotes the development of colon tumors in C57BL/6J-APCMin/+ mice. Nat Med. 1998, 4: 1053-1057.PubMedView ArticleGoogle Scholar
- Seed B: PPARgamma and colorectal carcinoma: conflicts in a nuclear family. Nat Med. 1998, 4: 1004-1005.PubMedView ArticleGoogle Scholar
- Girnun GD, Smith WM, Drori S, Sarraf P, Mueller E, Eng C, Nambiar P, Rosenberg DW, Bronson RT, Edelmann W: APC-dependent suppression of colon carcinogenesis by PPARgamma. Proc Natl Acad Sci U S A. 2002, 99: 13771-13776.PubMed CentralPubMedView ArticleGoogle Scholar
- Yoshizawa K, Cioca DP, Kawa S, Tanaka E, Kiyosawa K: Peroxisome proliferator-activated receptor gamma ligand troglitazone induces cell cycle arrest and apoptosis of hepatocellular carcinoma cell lines. Cancer. 2002, 95: 2243-2251.PubMedView ArticleGoogle Scholar
- Barak Y, Nelson MC, Ong ES, Jones YZ, Ruiz-Lozano P, Chien KR, Koder A, Evans RM: PPAR gamma is required for placental, cardiac, and adipose tissue development. Mol Cell. 1999, 4: 585-595.PubMedView ArticleGoogle Scholar
- Chinetti G, Griglio S, Antonucci M, Torra IP, Delerive P, Majd Z, Fruchart JC, Chapman J, Najib J, Staels B: Activation of proliferator-activated receptors alpha and gamma induces apoptosis of human monocyte-derived macrophages. J Biol Chem. 1998, 273: 25573-25580.PubMedView ArticleGoogle Scholar
- Chattopadhyay N, Singh DP, Heese O, Godbole MM, Sinohara T, Black PM, Brown EM: Expression of peroxisome proliferator-activated receptors (PPARS) in human astrocytic cells: PPARgamma agonists as inducers of apoptosis. J Neurosci Res. 2000, 61: 67-74.PubMedView ArticleGoogle Scholar
- Padilla J, Kaur K, Cao HJ, Smith TJ, Phipps RP: Peroxisome proliferator activator receptor-gamma agonists and 15-deoxy-Delta(12,14)(12,14)-PGJ(2) induce apoptosis in normal and malignant B-lineage cells. J Immunol. 2000, 165: 6941-6948.PubMedView ArticleGoogle Scholar
- Bishop-Bailey D, Hla T: Endothelial cell apoptosis induced by the peroxisome proliferator-activated receptor (PPAR) ligand 15-deoxy-Delta12, 14-prostaglandin J2. J Biol Chem. 1999, 274: 17042-17048.PubMedView ArticleGoogle Scholar
- Kawahito Y, Kondo M, Tsubouchi Y, Hashiramoto A, Bishop-Bailey D, Inoue K, Kohno M, Yamada R, Hla T, Sano H: 15-deoxy-delta(12,14)-PGJ(2) induces synoviocyte apoptosis and suppresses adjuvant-induced arthritis in rats. J Clin Invest. 2000, 106: 189-197.PubMed CentralPubMedView ArticleGoogle Scholar
- Takashima T, Fujiwara Y, Higuchi K, Arakawa T, Yano Y, Hasuma T, Otani S: PPAR-gamma ligands inhibit growth of human esophageal adenocarcinoma cells through induction of apoptosis, cell cycle arrest and reduction of ornithine decarboxylase activity. Int J Oncol. 2001, 19: 465-471.PubMedGoogle Scholar
- Goke R, Goke A, Goke B, Chen Y: Regulation of TRAIL-induced apoptosis by transcription factors. Cell Immunol. 2000, 201: 77-82.PubMedView ArticleGoogle Scholar
- Elstner E, Muller C, Koshizuka K, Williamson EA, Park D, Asou H, Shintaku P, Said JW, Heber D, Koeffler HP: Ligands for peroxisome proliferator-activated receptorgamma and retinoic acid receptor inhibit growth and induce apoptosis of human breast cancer cells in vitro and in BNX mice. Proc Natl Acad Sci U S A. 1998, 95: 8806-8811.PubMed CentralPubMedView ArticleGoogle Scholar
- He TC, Chan TA, Vogelstein B, Kinzler KW: PPARdelta is an APC-regulated target of nonsteroidal anti-inflammatory drugs. Cell. 1999, 99: 335-345.PubMed CentralPubMedView ArticleGoogle Scholar
- Park BH, Vogelstein B, Kinzler KW: Genetic disruption of PPARdelta decreases the tumorigenicity of human colon cancer cells. Proc Natl Acad Sci U S A. 2001, 98: 2598-2603.PubMed CentralPubMedView ArticleGoogle Scholar
- Zhang J, Fu M, Zhu X, Xiao Y, Mou Y, Zheng H, Akinbami MA, Wang Q, Chen YE: Peroxisome proliferator-activated receptor delta is up-regulated during vascular lesion formation and promotes post-confluent cell proliferation in vascular smooth muscle cells. J Biol Chem. 2002, 277: 11505-11512.PubMedView ArticleGoogle Scholar
- Di Poi N, Tan NS, Michalik L, Wahli W, Desvergne B: Antiapoptotic role of PPARbeta in keratinocytes via transcriptional control of the Akt1 signaling pathway. Mol Cell. 2002, 10: 721-733.PubMedView ArticleGoogle Scholar
- Ashby J, Brady A, Elcombe CR, Elliott BM, Ishmael J, Odum J, Tugwood JD, Kettle S, Purchase IF: Mechanistically-based human hazard assessment of peroxisome proliferator-induced hepatocarcinogenesis. Hum & Exp Toxicol. 1994, 13: S1-117.View ArticleGoogle Scholar
- Blumcke S, Schwartzkopff W, Lobeck H, Edmondson NA, Prentice DE, Blane GF: Influence of fenofibrate on cellular and subcellular liver structure in hyperlipidemic patients. Atherosclerosis. 1983, 46: 105-116.PubMedView ArticleGoogle Scholar
- De La Iglesia FA, Lewis JE, Buchanan RA: Light and electron microscopy of liver in hyperlipoproteinemic patients under long-term gemfibrozil treatment. Atherosclerosis. 1982, 43: 19-37.PubMedView ArticleGoogle Scholar
- Gariot P, Barrat E, Drouin P, Genton P, Pointel JP, Foliguet B, Kolopp M, Debry G: Morphometric study of human hepatic cell modifications induced by fenofibrate. Metabolism. 1987, 36: 203-210.PubMedView ArticleGoogle Scholar
- Lock EA, Mitchell AM, Elcombe CR: Biochemical mechanisms of induction of hepatic peroxisome proliferation. Annu Rev Pharmacol Toxicol. 1989, 29: 145-163.PubMedView ArticleGoogle Scholar
- Elcombe CR, Mitchell AM: Peroxisome proliferation due to di(2-ethylhexyl) phthalate (DEHP): species differences and possible mechanisms. Environ Health Perspect. 1986, 70: 211-219.PubMed CentralPubMedView ArticleGoogle Scholar
- Tugwood JD, Holden PR, James NH, Prince RA, Roberts RA: A peroxisome proliferator-activated receptor-alpha (PPARalpha) cDNA cloned from guinea-pig liver encodes a protein with similar properties to the mouse PPARalpha: implications for species differences in responses to peroxisome proliferators. Arch Toxicol. 1998, 72: 169-177.PubMedView ArticleGoogle Scholar
- Palmer CNA, Hsu MH, Griffin KJ, Raucy JL, Johnson EF: Peroxisome proliferator activated receptor-[alpha] expression in human liver. Mol Pharmacol. 1998, 53: 14-22.PubMedGoogle Scholar
- Woodyatt NJ, Lambe KG, Myers KA, Tugwood JD, Roberts RA: The peroxisome proliferator (PP) response element upstream of the human acyl CoA oxidase gene is inactive among a sample human population: significance for species differences in response to PPs. Carcinogenesis. 1999, 20: 369-372.PubMedView ArticleGoogle Scholar
- Keller H, Devchand PR, Perroud M, Wahli W: PPAR alpha structure-function relationships derived from species-specific differences in responsiveness to hypolipidemic agents. Biol Chem. 1997, 378: 651-655.PubMedView ArticleGoogle Scholar
- Mukherjee R, Jow L, Noonan D, McDonnell DP: Human and rat peroxisome proliferator activated receptors (PPARs) demonstrate similar tissue distribution but different responsiveness to PPAR activators. J Steroid Biochem Mol Biol. 1994, 51: 157-166.PubMedView ArticleGoogle Scholar
- Chevalier S, Roberts RA: Perturbation of rodent hepatocyte growth control by nongenotoxic hepatocarcinogens: mechanisms and lack of relevance for human health (review). Oncol Rep. 1998, 5: 1319-1327.PubMedGoogle Scholar
- Hasmall SC, James NH, Macdonald N, Soames AR, Roberts RA: Species differences in response to diethylhexylphthalate: suppression of apoptosis, induction of DNA synthesis and peroxisome proliferator activated receptor alpha-mediated gene expression. Arch Toxicol. 2000, 74: 85-91.PubMedView ArticleGoogle Scholar
- Canuto RA, Muzio G, Bonelli G, Maggiora M, Autelli R, Barbiero G, Costelli P, Brossa A, Baccino FM: Peroxisome proliferators induce apoptosis in hepatoma cells. Cancer Detect Prev. 1998, 22: 357-366.PubMedView ArticleGoogle Scholar
- Sarraf P, Mueller E, Smith WM, Wright HM, Kum JB, Aaltonen LA, de la Chapelle A, Spiegelman BM, Eng C: Loss-of-function mutations in PPAR gamma associated with human colon cancer. Mol Cell. 1999, 3: 799-804.PubMedView ArticleGoogle Scholar
- Demetri GD, Fletcher CD, Mueller E, Sarraf P, Naujoks R, Campbell N, Spiegelman BM, Singer S: Induction of solid tumor differentiation by the peroxisome proliferator-activated receptor-gamma ligand troglitazone in patients with liposarcoma. Proc Natl Acad Sci U S A. 1999, 96: 3951-3956.PubMed CentralPubMedView ArticleGoogle Scholar
- Kulke MH, Demetri GD, Sharpless NE, Ryan DP, Shivdasani R, Clark JS, Spiegelman BM, Kim H, Mayer RJ, Fuchs CS: A phase II study of troglitazone, an activator of the PPARgamma receptor, in patients with chemotherapy-resistant metastatic colorectal cancer. Cancer J. 2002, 8: 395-399.PubMedView ArticleGoogle Scholar
- Yamamoto Y, Nakajima M, Yamazaki H, Yokoi T: Cytotoxicity and apoptosis produced by troglitazone in human hepatoma cells. Life Sci. 2001, 70: 471-482.PubMedView ArticleGoogle Scholar
- Boelsterli UA, Bedoucha M: Toxicological consequences of altered peroxisome proliferator-activated receptor gamma (PPARgamma) expression in the liver: insights from models of obesity and type 2 diabetes. Biochem Pharmacol. 2002, 63: 1-10.PubMedView ArticleGoogle Scholar
- Oates JC, Reilly CM, Crosby MB, Gilkeson GS: Peroxisome proliferator-activated receptor gamma agonists: potential use for treating chronic inflammatory diseases. Arthritis Rheum. 2002, 46: 598-605.PubMedView ArticleGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.