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PubMed2005

Chronic allograft nephropathy: expression and localization of PAI-1 and PPAR-gamma.

BACKGROUND: Chronic allograft nephropathy (CAN) is a major cause of loss of renal allografts. Mechanisms postulated to be involved include sequelae of rejection, warm ischaemia time, drug toxicity, ongoing hypertension and dyslipidaemia. Plasminogen activator inhibitor-1 (PAI-1) is implicated not only in thrombosis, but also in fibrosis, by inhibiting matrix degradation, and is expressed in renal parenchymal cells as well as in macrophages. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the steroid receptor superfamily, and plays a major beneficial role in lipid regulation, insulin sensitivity and macrophage function, factors that may play a role in CAN. We therefore studied the expression of these molecules in CAN. METHODS: All renal biopsy/nephrectomy files from Vanderbilt and Nashville VAMC from a 6 year period were reviewed to identify all renal transplant biopsies or nephrectomies more than 6 months after transplant with CAN. CAN was defined as fibrosis in the graft, vascular, interstitial or glomerular. All cases were scored for severity of fibrosis in vasculature (0-3 scale), glomeruli (% affected with either segmental and/or global sclerosis) and interstitial fibrosis (% of sample affected). PAI-1 and PPAR-gamma immunostaining was assessed on a 0-3 scale in glomeruli, vessels and tubules. RESULTS: Eighty-two patients with a total of 106 samples met entry criteria. The population consisted of 59 Caucasians and 23 African-Americans; 49 males, 33 females with average age 37.9+/-1.7 years. Average time after transplant at time of biopsy was 60.5+/-4.9 months (range 7-229). Glomerulosclerosis extent in CAN was on average 26.5+/-2.4% compared with 3.6+/-1.2% in normal control kidneys from native kidney cancer nephrectomies and 0% in transplanted kidney biopsies from patients obtained > or =6 months after transplantation without CAN. Native control kidneys showed mild interstitial fibrosis (8.0+/-1.2%), whereas transplant controls showed very minimal fibrosis (2.0+/-2.0%). Interstitial fibrosis in CAN kidneys was on average 47.9+/-2.4%. Glomerular PAI-1 and PPAR-gamma staining scores were markedly increased in CAN (1.8+/-0.1, 2.3+/-0.1, respectively) compared with normal control kidneys from native kidney cancer nephrectomies (PAI-1 0.2+/-0.2 and PPAR-gamma 0.4+/-0.2, P<0.001) and transplanted kidney biopsies from patients obtained > or =6 months after transplantation without CAN (PAI-1 0 and PPAR-gamma 0, P<0.001). Tubular PAI-1 and PPAR-gamma staining scores were 1.9+/-0.1 and 1.9+/-0.1, respectively, and also increased over both native and transplant kidney controls (0.8+/-0.2 for both categories for PAI-1, 1.2+/-0.2 for both categories for PPAR-gamma, respectively). Vascular sclerosis in CAN was 1.0+/-0.1 with increased PAI-1 and PPAR-gamma scores (1.7+/-0.1, 1.2+/-0.1, respectively) compared with controls. Infiltrating macrophages were increased in CAN, and were positive for both PAI-1 and PPAR-gamma. Biopsies with less sclerosis overall showed a trend for less PAI-1 and PPAR-gamma staining. CONCLUSION: PAI-1 and PPAR-gamma are both increased in CAN compared with non-scarred native or transplant control kidneys. We speculate that altered matrix metabolism and macrophage function might be involved in the development of CAN.

Adolescent↗
PubMed1996

The peroxisome proliferator activated receptors (PPARS) and their effects on lipid metabolism and adipocyte differentiation.

The three types of peroxisome proliferator activated receptor (PPAR), alpha, beta (or delta), and gamma, each with a specific tissue distribution, compose a subfamily of the nuclear hormone receptor gene family. Although peroxisome proliferators, including fibrates and fatty acids, activate the transcriptional activity of these receptors, only prostaglandin J2 derivatives have been identified as natural ligands of the PPAR gamma subtype, which also binds thiazolidinedione antidiabetic agents with high affinity. Activated PPARs heterodimerize with RXR and alter the transcription of target genes after binding to specific response elements or PPREs, consisting of a direct repeat of the nuclear receptor hexameric DNA core recognition motif spaced by one nucleotide. The different PPARs can be considered key messengers responsible for the translation of nutritional, pharmacological and metabolic stimuli into changes in the expression of genes, more specifically those genes involved in lipid metabolism. PPAR alpha is involved in stimulating beta-oxidation of fatty acids. In rodents, a PPAR alpha-mediated change in the expression of genes involved in fatty acid metabolism lies at the basis of the phenomenon of peroxisome proliferation, a pleiotropic cellular response, mainly limited to liver and kidney and which can lead to hepatocarcinogenesis. In addition to their role in peroxisome proliferation in rodents, PPAR is also involved in the control of HDL cholesterol levels by fibrates and fatty acids in rodents and humans. This effect is, at least partially, based on a PPAR-mediated transcriptional regulation of the major HDL apolipoproteins, apo A-I and apo A-II. The hypotriglyceridemic action of fibrates and fatty acids also involves PPARs and can be summarized as follows: (1) an increased lipolysis and clearance of remnant particles, due to changes in LPL and apo C-III levels, (2) a stimulation of cellular fatty acid uptake and their conversion to acyl-CoA derivatives by the induction of FAT, FATP and ACS activity, (3) an induction of fatty acid beta-oxidation pathways, (4) a reduction in fatty acid and triglyceride synthesis, and finally (5) a decrease in VLDL production. Hence, both enhanced catabolism of triglyceride-rich particles as well as reduced secretion of VLDL particles are mechanisms that contribute to the hypolipidemic effect of fibrates and FFAs. Whereas for PPAR beta no function so far has been identified, PPAR gamma triggers adipocyte differentiation by inducing the expression of several genes critical for adipogenesis.

Adipocytes↗
PubMed1995

PPAR: a mediator of peroxisome proliferator action.

Peroxisome proliferators are a diverse group of rodent hepatocarcinogens that include hypolipidemic drugs, plasticizers and herbicides. These compounds when administered to rats and mice produce a dramatic increase in the size and number of hepatic peroxisomes and increase the capacity of the hepatocyte to metabolise fatty acids by inducing peroxisomal beta-oxidation enzymes such as acyl CoA oxidase. Members of the steroid hormone receptor superfamily of ligand-activated transcription factors have been identified that can be activated by peroxisome proliferators and are therefore called 'peroxisome proliferator activated receptors' (PPAR). There appear to be four PPAR isoforms within vertebrates termed alpha, beta, gamma and delta and the alpha isoform appears to be the one that is most strongly activated by synthetic peroxisome proliferators such as Wy-14,643. It has been demonstrated that PPAR alpha forms a heterodimer with the retinoid X receptor (RXR) and binds to specific DNA sequences located upstream of peroxisome proliferator responsive genes. It is therefore suggested that PPARs mediate the pleiotropic effects of peroxisome proliferators including the regulation of gene expression and rodent hepatocarcinogenesis. Rodents fed a high-fat diet develop peroxisome proliferation and many of the enzymes induced by peroxisome proliferators are involved in fatty acid metabolism. Furthermore, PPARs are activated by a wide range of fatty acids and hypolipidemic drugs, such as clofibrate, that lower triglyceride levels in man. Although it remains to be determined whether fatty acids and peroxisome proliferators bind directly to any PPAR these data suggest that the natural role of PPARs in man is to regulate lipid homeostasis. Interestingly, hypolipidaemic drugs fail to elicit peroxisome proliferation in human hepatocytes although hypolipidaemic effects are observed in patients. A further understanding of the role of PPAR in man will require: (1) the identification of additional human PPARs combined with functional analyses using these and other nuclear receptors that can antagonise PPAR action; (2) a comparison of the expression of these different receptors in human tissues; (3) a clearer understanding of how peroxisome proliferators and fatty acids activate PPAR; and (4) sequence analysis of the regulatory regions in the human counterparts of rodent peroxisome proliferator responsive genes. Together, these data will provide an important mechanism-based framework to assess the hazard of peroxisome proliferators to humans.

Animals↗
PubMed2003

Regulation of PPAR gamma transcriptional activity in 3T3-L1 adipocytes.

PPAR gamma is a member of the nuclear hormone receptor superfamily and functions as a transcriptional regulator of genes linked to adipogenesis and lipid metabolism. The regulation of PPAR gamma activity by insulin signaling molecules in adipocytes has yet to be clarified. Therefore, it is important to measure endogenous PPAR gamma transcriptional activities in response to various stimuli in adipocytes. Herein, with a transcription reporter assay using recombinant adenovirus vectors expressing PPRE (PPAR responsive elements)-reporter genes, we established a novel system for measuring endogenous PPAR gamma transcriptional activity in 3T3-L1 adipocytes. By means of this system, a marked increase (8.5-fold) in PPAR gamma transcriptional activity was detected after treatment with 10(-6)M pioglitazone, a thiazolidinedione (TZD), indicating that this system can measure PPAR gamma activity accurately. Furthermore, MAPK activation, achieved by overexpressing constitutively activated MEK1, inhibited PPAR gamma transcriptional activity. In contrast, treatment with PKA stimulators markedly increased PPAR gamma activity. Interestingly, PI 3-kinase overexpression resulted in a marked decrease in PPAR gamma activity. These observations have important implications for understanding the regulation of PPAR gamma transcriptional activity.

3T3 Cells↗
PubMed2002

Synergistic effect of 4-hydroxynonenal and PPAR ligands in controlling human leukemic cell growth and differentiation.

Peroxisome proliferator-activated receptors play an important role in the differentiation of different cell lines. In this study we demonstrate that PPAR-alpha ligands (clofibrate and ciprofibrate) and PPAR-gamma ligands (troglitazone and 15d-prostaglandin J2) inhibit growth and induce monocytic differentiation in HL-60 cells, whereas only PPAR-gamma ligands inhibit growth of U937 cells. Differentiation was demonstrated by the analysis of surface antigen expression CD11b and CD14, and by the characteristic morphological changes. PPAR-gamma ligands are more effective than PPAR-alpha ligands in the inhibition of cell growth and in the induction of differentiation. The physiological product of lipid peroxidation, 4-hydroxynonenal (HNE), which alone induces granulocytic-like differentiation of HL-60 cells, potentiates the monocytic differentiation induced by ciprofibrate, troglitazone, and 15d-prostaglandin J2. The same HNE treatment significantly inhibits U937 cell growth and potentiates the inhibition of cell growth in PPAR-gamma ligand-treated cells. However, HNE does not induce a significant number of CD14-positive U937 cells. HNE causes a great increase of PPAR-gamma expression in both HL-60 and U937 cells, whereas it does not modify the PPAR-alpha expression. This observation may account for the high synergistic effect displayed by HNE and PPAR-gamma ligands in the inhibition of cell growth and differentiation induction. These results represent the first evidence of the involvement of a product of lipid peroxidation in the modulation of PPAR ligand activity and suggest a relationship between HNE and PPAR ligand pathways in leukemic cell growth and differentiation.

Aldehydes↗
PubMed2003

Early stimulation and late inhibition of peroxisome proliferator-activated receptor gamma (PPAR gamma) gene expression by transforming growth factor beta in human aortic smooth muscle cells: role of early growth-response factor-1 (Egr-1), activator protein 1 (AP1) and Smads.

Transforming growth factor beta (TGF beta) and peroxisome proliferator-activated receptor gamma (PPAR gamma) play major roles in the development of vascular diseases. It has been documented that PPAR gamma activation inhibits the TGF beta signal pathway in vascular smooth muscle cells (VSMC). Here we examined whether TGF beta can regulate PPAR gamma expression. Northern blot analyses revealed that both TGF beta 1 and 2 exert a biphasic effect (early stimulation and late repression) on PPAR gamma gene expression in VSMC. TGF beta rapidly and transiently induced early growth-response factor-1 (Egr-1) expression through the mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1 (MEK1)/ERK-mediated pathway. Inhibition of MEK1/ERK by PD98059 not only abrogated the induction of Egr-1 but also abolished the rapid and transient induction of PPAR gamma by TGF beta. Furthermore, overexpression of NAB2, a repressor of Egr-1 activation, also blocked the induction of PPAR gamma by TGF beta in VSMC, suggesting that Egr-1 mediates the rapid and transient induction of PPAR gamma by TGF beta. With regard to the TGF beta repression of PPAR gamma expression, activator protein 1 (AP1) and Smad3/4 dramatically inhibited the PPAR gamma promoter activity in transient-transfection studies. In contrast, adenovirus-mediated overexpression of a dominant-negative form of c-Jun partially rescued the TGF beta-induced PPAR gamma repression in VSMC. Taken together, our data demonstrate that Egr-1, AP1 and Smad are part components of the TGF beta signal transduction pathway that regulates PPAR gamma expression.

Aorta↗
PubMed2002

PPAR alpha is necessary for the lipopenic action of hyperleptinemia on white adipose and liver tissue.

Adenovirus-induced hyperleptinemia causes rapid disappearance of body fat in normal rats, presumably by up-regulating fatty acid oxidation within white adipocytes. To determine the role of peroxisomal proliferation-activated receptor (PPAR)alpha expression, which was increased during the rapid loss of fat, we infused adenovirus-leptin into PPAR alpha(-/-) and PPAR alpha(+/+) mice. Despite similar degrees of hyperleptinemia and reduction in food intake, epididymal fat pad weight declined 55% in wild-type but only 6% in PPAR alpha(-/-) mice; liver triacylglycerol fell 39% in the wild-type group but was unchanged in PPAR(-/-) mice. Carnitine palmitoyl transferase-1 mRNA rose 52% in the wild-type mice but did not increase in PPAR alpha(-/-) mice. PPAR gamma coactivator-1 alpha rose 3-fold in the fat and 46% in the liver of wild-type mice but was unchanged in PPAR alpha(-/-) mice. Although AMP-activated protein kinase could not be implicated in the lipopenic actions of hyperleptinemia, acetyl CoA carboxylase protein was reduced in the liver of wild-type but not in PPAR alpha(-/-) mice. Thus, in PPAR alpha(-/-) mice, up-regulation of carnitine palmitoyl transferase-1 mRNA in fat, down-regulation of acetyl CoA carboxylase in liver, and up-regulation of PPAR gamma coactivator-1 alpha mRNA in both tissues are abolished, as is the reduction in their triacylglycerol content.

AMP-Activated Protein Kinases↗
PubMed2003

Down-regulation of STAT5b transcriptional activity by ligand-activated peroxisome proliferator-activated receptor (PPAR) alpha and PPARgamma.

The nuclear receptor peroxisome proliferator-activated receptor (PPAR) is activated by a diverse group of acidic ligands, including many peroxisome proliferator chemicals present in the environment. Janus tyrosine kinase-signal transducer and activator of transcription (JAK-STAT) signaling is activated by multiple cytokines and hormones and leads to the translocation of dimerized STAT proteins to the nucleus where they activate transcription of target genes. Previous studies have shown that growth hormone (GH)-activated STAT5b can inhibit PPAR-regulated transcription. Here, we show that this inhibitory cross-talk is mutual, and that GH-induced, STAT5b-dependent beta-casein promoter-luciferase reporter gene transcription can be inhibited up to approximately 80% by ligand-activated PPARalpha or PPARgamma. Dose-response experiments showed a direct relationship between the extent of PPAR activation and the degree of inhibition of STAT5-regulated transcription. PPAR did not block STAT5b tyrosine phosphorylation or inhibit DNA-binding activity. Both PPARs inhibited the transcriptional activity of a constitutively active STAT5b mutant, indicating that inhibition occurs downstream of the GH-stimulated STAT5 activation step. Transcriptionally inactive, dominant-negative PPAR mutants did not block STAT5b inhibition by wild-type PPAR, indicating that PPAR target gene transcription is not required. PPARalpha retained its STAT5b inhibitory activity in the presence of the histone deacetylase inhibitor trichostatin, indicating that enhanced histone deacetylase recruitment does not contribute to STAT5b inhibition. PPARalpha lacking the ligand-independent AF-1 trans-activation domain failed to inhibit STAT5b, highlighting the importance of the AF-1 region in STAT5-PPAR inhibitory cross-talk. These findings demonstrate the bidirectionality of cross-talk between the PPAR and STAT pathways and provide a mechanism whereby exposure to environmental chemical activators of PPAR can suppress expression of GH target genes.

Animals↗
PubMed2001

Disturbances in the normal regulation of SREBP-sensitive genes in PPAR alpha-deficient mice.

Peroxisome proliferator-activated receptor alpha (PPAR alpha)-null mice were used to investigate the nature of the relationship between the normal circadian rhythm of hepatic PPAR alpha expression and the expression of the lipogenic and cholesterogenic sterol regulatory element-binding protein (SREBP)-regulated genes, acetyl-CoA carboxylase, fatty acid synthase (FAS), and 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoAR). The expression of FAS and HMG-CoAR varied rhythmically over the diurnal cycle in the normal mice, with patterns that were the opposite of that of PPAR alpha. The diurnal variation of lipogenic and cholesterogenic gene expression was attenuated or abolished in the PPAR alpha-null mice. This resulted in decreased expression compared with normal mice, but only during the dark phase of the cycle, when food intake was high. The diurnal variation in hepatic fatty acid and cholesterol synthesis was also abolished in the PPAR alpha-null animals and the variations in the concentration of plasma triacylglycerol, nonesterified fatty acids, and cholesterol were all attenuated. The failure of HMG-CoAR expression to increase during the feeding period in the PPAR alpha-null mice was associated with a decrease in hepatic nonesterified cholesterol content and an increase in cholesteryl ester compared with normal mice. There was no defect in the downregulation of hepatic HMG-CoAR mRNA in response to dietary cholesterol in the PPAR alpha-null mice. Under these conditions, hepatic PPAR gamma expression increased in both the control and PPAR alpha-deficient mice. The results suggest that PPAR alpha-deficiency disturbs the normal circadian regulation of certain SREBP-sensitive genes in the liver, but does not affect their response to dietary cholesterol. -- Patel, D. D., B. L. Knight, D. Wiggins, S. M. Humphreys, and G. F. Gibbons. Disturbances in the normal regulation of SREBP-sensitive genes in PPAR alpha-deficient mice. J. Lipid Res. 2001. 42: 328--337.

Acetyl-CoA Carboxylase↗
PubMedDate not supplied

[Peroxisome proliferator-activated receptors (PPARs) in obesity and insulin resistance development].

The peroxisome proliferator-activated receptors (PPARs) are a family of nuclear transcription factors that belong to the steroid receptor superfamily. PPARs family includes PPARalpha, PPARbeta/delta, PPARgamma1 and PPARgamma2. PPARs form an heterodimer with the 9-cis retinoic acid receptor (RXR) and bind to response elements present in target genes activated by these transcription factors. PPARs control the expression of genes involved in fatty acid synthesis, oxidation and storage. PPARs are present in most tissues, where PPARalpha is most abundant in liver and skeletal muscle, whereas PPARgamma is found mainly in adipose tissue. Natural ligands for PPARs are polyunsaturated fatty acids (PUFAs) and some eicosanoids, however they are also activated by compounds such as fibrates and thiazolidinediones (TZDs). In this review is shown the different PPARs isoforms, identification, and regulation of their expression and activity. Also shows which are the natural ligands, and the chemical compounds that activate PPARs. Finally, it shows the target genes activated by the different isoforms of PPARs, the metabolic integration between the different PPAR isoforms to maintain a balance between fatty acid synthesis and oxidation and the association with the development of obesity and insulin resistance. Also shows information about the nutritional requirements of PUFAs that are the main natural ligands of PPARs.

Animals↗
PubMed2005

Beneficial effects of PPAR-gamma ligands in ischemia-reperfusion injury, inflammation and shock.

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a ligand-activated transcription factor belonging to the nuclear hormone receptor superfamily. PPAR-gamma regulates gene expression by forming a heterodimer with the retinoid X receptor (RXR) before binding to sequence-specific PPAR response elements (PPREs) in the promoter region of target genes, thereby regulating several metabolic pathways, including lipid biosynthesis and glucose metabolism. Thiazolidinediones (TZDs, i.e. rosiglitazone, pioglitazone), which are synthetic PPAR-gamma agonists, act as insulin sensitizers and are used in the treatment of type 2 diabetes. In the last few years, it has, however, become evident that the therapeutic effects of PPAR-gamma ligands reach far beyond their use as insulin sensitizers. Recently, PPAR-gamma has been implicated as a regulator of cellular inflammatory and ischemic responses. PPAR-gamma agonists may exert their anti-inflammatory effects by negatively regulating the expression of pro-inflammatory genes induced during macrophage differentiation and activation, by either PPAR-gamma-dependent or -independent mechanisms. Several lines of evidence suggest that TZDs protect the heart and other organs against the tissue injury caused by ischemia/reperfusion (I/R) injury and shock. This review discusses the anti-inflammatory signalling pathways activated by PPAR-gamma, as well as the potential therapeutic effects of PPAR-gamma agonists in animal models of ischemia/reperfusion, inflammation and shock.

Animals↗
PubMed2004

PPAR-gamma expression modulates insulin sensitivity in C2C12 skeletal muscle cells.

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) expression is very low in skeletal muscle cells, which is one of the most important target tissues for insulin and plays a predominant role in glucose homeostasis. It has recently been shown that muscle-specific PPAR-gamma deletion in mouse causes insulin resistance. However, it is likely that the observed effects might be due to secondary interaction in whole animal. The aim of the study was to explore the role of muscle PPAR-gamma in insulin sensitivity. We stably transfected C2C12 skeletal muscle cells with plasmids containing sense or antisense constructs of PPAR-gamma and examined the effect of modulation of PPAR-gamma expression in terms of glucose uptake. Effect was also examined in insulin-resistant C2C12 skeletal muscle cells. In transfected C2C12 cell line, the inhibition of PPAR-gamma expression (23.0 +/-0.005%) was observed to induce insulin resistance as determined by functional assessment of 2-deoxyglucose incorporation. Overexpression of PPAR-gamma (28.5 +/- 0.008%) produced an additional effect on insulin (100 nM) and Pioglitazone (50 microM), resulting in 42.7 +/- 3.5% increase in glucose uptake as against 29.2+/-2.8% in wild-type C2C12 skeletal muscle cells differentiated under normal (2% horse serum) condition. Under similar treatment, PPAR-gamma overexpressing cells resistant to insulin exhibited enhanced glucose uptake upto 60.7 +/- 4.08%, as compared to 23.8 +/- 5.1% observed in wild-type C2C12 skeletal muscle cells. These data demonstrate a direct involvement of PPAR-gamma in insulin sensitization of TZD action on skeletal muscle cells, and suggest that pharmacological overexpression of muscle PPAR-gamma gene in skeletal muscle might be a useful strategy for the treatment of insulin resistance.

Animals↗
PubMed2005

Peroxisome proliferator-activated receptor-gamma (PPAR(gamma)) inhibits tumorigenesis by reversing the undifferentiated phenotype of metastatic non-small-cell lung cancer cells (NSCLC).

Pharmacological activators of peroxisome proliferator-activated receptor-gamma (PPAR(gamma)) have been shown to inhibit growth of lung tumors largely through growth inhibition and induction of apopotosis. However, since many of these agents engage other effectors, the role of (PPAR(gamma) in lung tumorigenesis remains poorly defined. To specifically examine PPAR(gamma)-mediated events, non-small-cell lung cancer (NSCLC) cells overexpressing PPAR(gamma) were established. Overexpression of PPAR(gamma) in H2122 adenocarcinoma cells (H2122-PPAR(gamma)) blocked anchorage-independent growth compared to cells transfected with empty vector (H2122-LNCX), but had no significant effect on cell proliferation or apoptosis under standard tissue culture conditions. Orthotopic implantation of H2122-PPAR(gamma) cells into the lungs of nude rats inhibited tumor growth and metastasis in vivo and prolonged survival compared to implantation of H2122-LNCX cells. Consistent with these findings, H2122-PPAR(gamma) cells had an impaired invasiveness as assessed in Transwell assays. In a three-dimensional culture system, H2122-PPAR(gamma) cells formed polarized spheroid structures similar to those observed with normal lung epithelial cells. H2122-LNCX cells formed nonpolarized aggregate structures and did not show any of these epithelial properties. These data indicate that inhibitory effects of PPAR(gamma) on lung tumorigenesis involve selective inhibition of invasive metastasis, and activation of pathways that promote a more differentiated epithelial phenotype.

Animals↗
PubMed2006

The role of the peroxisome proliferator-activated receptor-alpha (PPAR-alpha) in the regulation of acute inflammation.

The peroxisome proliferator-activated receptor-alpha (PPAR-alpha) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors related to retinoid, steroid, and thyroid hormone receptors. The aim of the present study was to evaluate the role of the PPAR-alpha receptor on the development of acute inflammation. To address this question, we used two animal models of acute inflammation (carrageenan-induced paw edema and carrageenan-induced pleurisy). We report here that when compared with PPAR-alpha wild-type mice, PPAR-alpha knockout mice (PPAR-alphaKO) mice experienced a higher rate of the extent and severity when subjected to carrageenan injection in the paw edema model or to carrageenan administration in the pleurisy model. In particular, the absence of a functional PPAR-alpha gene in PPAR-alphaKO mice resulted in a significant augmentation of various inflammatory parameters (e.g., enhancement of paw edema, pleural exudate formation, mononuclear cell infiltration, and histological injury) in vivo. Furthermore, the absence of a functional PPAR-alpha gene enhanced the staining (immunohistochemistry) for FAS ligand in the paw and in the lung and the expression of tumor necrosis factor alpha and interleukin-1beta in the lungs of carrageenan-treated mice. In conclusion, the increased inflammatory response observed in PPAR-alphaKO mice strongly suggests that a PPAR-alpha pathway modulates the degree of acute inflammation in the mice.

Acute Disease↗
PubMedDate not supplied

Inhibition of cell proliferation by potential peroxisome proliferator-activated receptor (PPAR) gamma agonists and antagonists.

This study was initiated to determine if potential PPAR gamma antagonists could block the inhibition of cell proliferation caused by 4-phenylbutyrate. The action of 4-phenylbutyrate differed from other PPAR gamma ligands examined in that it induces histone acetylation. Proliferation of DS19 mouse erythroleukemia cells was inhibited by PPAR gamma agonists (4-phenylbutyrate, rosiglitazone, ciglitazone and GW1929) and by potential PPAR gamma antagonists: BADGE (Biphenol A diglycidyl ether), GW9662, PD068235 and diclofenac. Combined incubations tended to exhibit additive inhibitory effects. Potential PPAR gamma agonists and antagonists inhibited the incorporation of thymidine into DNA of human prostate (PC3), colon (Caco-2) and breast (T47D) cancer cells but also affected NIH3T3 cells that have little or no expression of PPAR gamma. Lipid accumulation in T47D cells was seen after incubation with 4-phenylbutyrate and both potential PPAR gamma agonists and antagonists. The extent to which the effects of 4-phenylbutyrate on cell proliferation are mediated through PPAR gamma or induction of histone acetylation remains an open question. We conclude that potential PPAR gamma antagonists may fail to reverse the growth inhibitory effect of PPAR gamma ligands and may themselves act as growth inhibitory agents.

Acetylation↗
PubMed2001

Effects of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) on the expression of inflammatory cytokines and apoptosis induction in rheumatoid synovial fibroblasts and monocytes.

This study was performed to investigate whether peroxisome proliterator-activated receptor-gamma (PPAR-gamma) exerted an anti-inflammatory effect on rheumatoid synovial cells and inhibited dysregulated proliferation. The expression of PPAR-gamma mRNA in cultured human synoviocytes and THP-1 cells was analysed by RT-PCR. PPAR-gamma was expressed in normal, osteoarthritis (OA), rheumatoid arthritis (RA) synovial cells as well as a human monocytic cell line, THP-1. In RA and OA synoviocytes, the induction of inflammatory cytokine mRNA expression such as TNF-alpha and IL-1beta was significantly inhibited by the natural PPAR-gamma agonist, 15 deoxy-Delta(12,14)prostaglandin J(2)(15d-PGJ(2)). The effect of PPAR-gamma on the nuclear factor (NF)-kappaB activity was tested by electrophoretic mobility shift assay (EMSA). Both troglitazone and 15d-PGJ(2)markedly inhibited TNF-alpha-induced NF-kappaB activation at 30 microM. However, PPAR-gamma agonist neither reduced proliferation nor induced apoptosis in RA synoviocytes when measured by XTT assay and fluorescence activated cell sorter (FACS) analysis. In contrast, it induced apoptosis in a dose-dependent manner in THP-1 cells and augmented TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis as well. In conclusion, these data demonstrate that PPAR-gamma is expressed in human synoviocytes and THP-1 cells, and the PPAR-gamma activation inhibits expression of inflammatory cytokines in RA synoviocytes. Furthermore, PPAR-gamma activation induces apoptosis by itself and augments TRAIL/Apo2L-induced apoptosis in THP-1 cells. These results suggest that PPAR-gamma agonists may provide a new therapeutic approach for RA.

Apoptosis↗
PubMedDate not supplied

The effects of fibrates and thiazolidinediones on plasma triglyceride metabolism are mediated by distinct peroxisome proliferator activated receptors (PPARs).

The hypolipidemic fibrates and antidiabetic thiazolidinediones display potent triglyceride-lowering activities. Studies on the molecular action mechanisms of these compounds indicate that thiazolidinediones and fibrates exert their action by activating distinct transcription factors of the peroxisome proliferator activated receptor (PPAR) family, resulting in increased expression of lipoprotein lipase (LPL) and decreased expression of apolipoprotein (apo) C-III, both key-players in plasma triglyceride metabolism. Fibrates, on the one hand, are PPAR alpha activators, which selectively induce LPL mRNA levels and activity in the liver. Furthermore, hepatic apo C-III mRNA levels and protein production strongly decrease after fibrate treatment. On the other hand, thiazolidinediones, which are high affinity ligands for PPAR gamma, have no effect in the liver, but act primarily on adipose tissue, where they induce LPL mRNA levels and activity. The modulation of the expression of the LPL and apo C-III genes in liver and adipose tissue is correlated with the tissue-specific distribution of the respective PPARs (PPAR gamma expression being restricted to adipose tissue, whereas PPAR alpha is expressed predominantly in liver) confirming that fibrates and thiazolidinediones exert their effects primarily through PPAR alpha and PPAR gamma respectively. This distinct tissue-specific transcriptional regulation of genes involved in lipid metabolism by fibrates and thiazolidinediones indicates that research of compounds displaying combined PPAR alpha and PPAR gamma activation potential should lead to the discovery of more potent triglyceride-lowering drugs, which may be of use in the treatment of hypertriglyceridemia.

Adipose Tissue↗
PubMed2002

The role of PPARs in atherosclerosis.

Peroxisome proliferator-activated receptors (PPARs) are lipid-activated transcription factors that regulate lipid and lipoprotein metabolism, glucose homeostasis and inflammation. The PPAR family consists of three proteins, alpha, beta/delta and gamma. Recent data suggest that PPAR alpha and gamma activation decreases atherosclerosis progression not only by correcting metabolic disorders, but also through direct effects on the vascular wall. PPARs modulate the recruitment of leukocytes to endothelial cells, control the inflammatory response and lipid homeostasis of monocytes/macrophages and regulate inflammatory cytokine production by smooth muscle cells. Experiments using animal models of atherosclerosis and clinical studies in humans strongly support an anti-atherosclerotic role for PPAR alpha and gamma in vivo. Thus, PPARs remain attractive therapeutic targets for the development of drugs used in the treatment of chronic inflammatory diseases such as atherosclerosis. Future research will aim for the development of more potent drugs with co-agonist activity on PPAR alpha, PPAR beta/delta and/or PPAR gamma as well as tissue and target gene-selective PPAR receptor modulators (SPPARMs).

Acute-Phase Proteins↗