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PubMed2002

PPAR and immune system--what do we know?

Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear steroid receptor superfamily. Originally, the receptors were identified as critical controllers for several key enzymes that catalyze the oxidation of fatty acids. PPARs consist of three members: PPAR-alpha, PPAR-beta/delta, and PPAR-gamma. Among them, PPAR-gamma is essential for controlling thermogenesis and adipocyte differentiation. The ligands for PPAR-gamma include 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2)--a metabolite from the prostaglandin synthesis pathway, and "glitazones"--drugs utilized in the treatment of patients with diabetes. The precursors for prostaglandins are fatty acids consumed from diet and these precursors have long been postulated to have a regulatory role in immune functions. Emerging evidence indicates that PPAR-gamma and its ligands are indeed important for the modulation of immune and inflammatory reactions. In this review, we will spotlight the molecular mechanisms of receptor/ligand function and how they may regulate immune and inflammatory reactions. We also propose that PPAR-gamma and its endogenous ligands are participating factors for Type 1/Type 2 T and NK cell differentiation and development. Deciphering the mechanism of action of PPAR-gamma and its ligands may lead to a new therapeutic regiment for treatment of diseases involving dysfunction of the immune system.

Animals↗
PubMed2004

Activation of PPAR gamma and delta by conjugated linoleic acid mediates protection from experimental inflammatory bowel disease.

BACKGROUND & AIMS: The molecular targets for the protective actions of conjugated linoleic acid (CLA) on experimental inflammatory bowel disease (IBD) are unknown. We used a loss-of-function approach to investigate whether CLA ameliorated colitis through a peroxisome proliferator-activated receptor gamma (PPAR gamma)-dependent mechanism. METHODS: The expression of PPAR gamma, delta, and their target genes in the colon of mice fed control or CLA-supplemented diets was assayed after a 7-day dextran sodium sulfate (DSS) challenge by quantitative real-time polymerase chain reaction (PCR). Additionally, nuclear factor-kappa B (NF-kappaB) p65 activation was quantified in the colon. To determine the involvement of PPAR gamma in the mechanism of action of CLA directly, specific deletions of PPAR gamma in the colon were performed in mice by using the Cre-lox recombination system. Colonic PPAR gamma null mice and wild-type littermates were fed either a CLA-supplemented or a control diet for 42 days and challenged with 2.5% DSS. The therapeutic efficacy of CLA also was examined by using the CD4 + CD45RB hi transfer colitis model. RESULTS: CLA induced PPAR gamma and delta, transcriptionally modulated PPAR gamma and delta-responsive gene clusters involved in lipid metabolism (uncoupling protein [UCP]1, UCP3, PPAR gamma coactivator 1alpha [PGC-1alpha], and CD36) and epithelial cell maturation (Gob-4 and Keratin 20). Additionally, CLA repressed tumor necrosis factor alpha (TNF-alpha) expression and NF-kappaB activation while inducing the immunoregulatory cytokine transforming growth factor beta 1 (TGF-beta 1 ). Clinically, CLA ameliorated DSS- and CD4 + -induced colitis. Loss of the PPAR gamma gene in the colon abrogated the beneficial effects of CLA in DSS colitis. CONCLUSIONS: Our studies provide molecular evidence in vivo, suggesting that CLA ameliorates colitis through a PPAR gamma-dependent mechanism.

Animals↗
PubMed2003

The 15-lipoxygenase-1 product 13-S-hydroxyoctadecadienoic acid down-regulates PPAR-delta to induce apoptosis in colorectal cancer cells.

Diminished apoptosis, a critical event in tumorigenesis, is linked to down-regulated 15-lipoxygenase-1 (15-LOX-1) expression in colorectal cancer cells. 13-S-hydroxyoctadecadienoic acid (13-S-HODE), which is the primary product of 15-LOX-1 metabolism of linoleic acid, restores apoptosis. Nonsteroidal antiinflammatory drugs (NSAIDs) transcriptionally up-regulate 15-LOX-1 expression to induce apoptosis. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors for linoleic and arachidonic acid metabolites. PPAR-delta promotes colonic tumorigenesis. NSAIDs suppress PPAR-delta activity in colon cancer cells. The mechanistic relationship between 15-LOX-1 and PPAR-delta was previously unknown. Our current study shows that (i) 13-S-HODE binds to PPAR-delta, decreases PPAR-delta activation, and down-regulates PPAR-delta expression in colorectal cancer cells; (ii) the induction of 15-LOX-1 expression is a critical step in NSAID down-regulation of PPAR-delta and the resultant induction of apoptosis; and (iii) PPAR-delta is an important signaling receptor for 13-S-HODE-induced apoptosis. The in vivo relevance of these mechanistic findings was demonstrated in our tumorigenesis studies in nude mouse xenograft models. Our findings indicate that the down-regulation of PPAR-delta by 15-LOX-1 through 13-S-HODE is an apoptotic signaling pathway that is activated by NSAIDs.

Animals↗
PubMed2003

Compensation by the muscle limits the metabolic consequences of lipodystrophy in PPAR gamma hypomorphic mice.

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor, which controls adipocyte differentiation. We targeted with homologous recombination the PPAR gamma 2-specific exon B, resulting in a white adipose tissue knockdown of PPAR gamma. Although homozygous (PPAR gamma hyp/hyp) mice are born with similar weight as the WT mice, the PPAR gamma hyp/hyp animals become growth retarded and develop severe lipodystrophy and hyperlipidemia. Almost half of these PPAR gamma hyp/hyp mice die before adulthood, whereas the surviving PPAR gamma hyp/hyp animals overcome the growth retardation, yet remain lipodystrophic. In contrast to most lipodystrophic models, the adult PPAR gamma hyp/hyp mice only have mild glucose intolerance and do not have a fatty liver. These metabolic consequences of the lipodystrophy are relatively benign because of the induction of a compensatory gene expression program in the muscle that enables efficient oxidation of excess lipids. The PPAR gamma hyp/hyp mice unequivocally demonstrate that PPAR gamma is the master regulator of adipogenesis in vivo and establish that lipid and glucose homeostasis can be relatively well maintained in the absence of white adipose tissue.

Adipose Tissue↗
PubMed2001

PPAR gamma/RXR alpha heterodimers are involved in human CG beta synthesis and human trophoblast differentiation.

Recent studies performed with null mice suggested a role of either RXR alpha or PPAR gamma in murine placental development. We report here that both PPAR gamma and RXR alpha are strongly expressed in human villous cytotrophoblasts and syncytiotrophoblasts. Moreover, specific ligands for RXRs or PPAR gamma (but not for PPAR alpha or PPAR delta) increase both human CG beta transcript levels and the secretion of human CG and its free beta-subunit. When combined, these ligands have an additive effect on human CG secretion. Pan-RXR and PPAR gamma ligands also have an additive effect on the synthesis of other syncytiotrophoblast hormones such as human placental lactogen, human placental GH, and leptin. Therefore, in human placenta, PPAR gamma/RXR alpha heterodimers are functional units during cytotrophoblast differentiation into the syncytiotrophoblast in vitro. Elements located in the regulatory region of the human CG beta gene (beta 5) were found to bind RXR alpha and PPAR gamma from human cytotrophoblast nuclear extracts, suggesting that PPAR gamma/RXR alpha heterodimers directly regulate human CG beta transcription. Altogether, these data show that PPAR gamma/RXR alpha heterodimers play an important role in human placental development.

Cell Differentiation↗
PubMed2002

Expression of PAX8-PPAR gamma 1 rearrangements in both follicular thyroid carcinomas and adenomas.

Recently, a translocation t(2;3)(q13;p25), leading to the formation of a chimeric PAX8-peroxisome proliferator-activated receptor (PPAR)gamma 1 oncogene, was detected in follicular thyroid carcinomas (FTC), but not in follicular thyroid adenomas (FTA), papillary thyroid carcinomas (PTC), or multinodular hyperplasias. However, previous cytogenetic studies have identified the t(2;3)(q13;p25) translocation also in some cases of FTA. In this study, we have combined RT-PCR with primers in exons 4-8 of PAX8 and in exon 1 of PPAR gamma 1 with PPAR gamma immunohistochemistry to study PAX8-PPAR gamma 1 oncogene activation in FTC (n = 9), FTA (n = 16), PTC (n = 9), anaplastic thyroid carcinomas (n = 4), and multinodular hyperplasias (n = 2). PAX8-PPAR gamma 1 rearrangements were detected by RT-PCR in 5 of 9 (56%) FTC and in 2 of 16 (13%) FTA. By contrast, all cases of PTC, anaplastic thyroid carcinomas, and multinodular hyperplasia were RT-PCR-negative. Diffuse nuclear immunoreactivity for PPAR gamma was observed in 7 of 9 (78%) FTC, 5 of 16 FTA (31%), and 1 of 9 PTC (11%). Positivity was focal in 3 cases (1 FTC, 1 PTC, and 1 multinodular hyperplasia). Diffuse nuclear staining for PPAR gamma was present in RT-PCR- negative cases of FTC (n = 3), FTA (n = 3), and PTC (n = 1), suggesting that a different PAX8-PPAR gamma 1 breakpoint, a rearrangement between PPAR gamma 1 and a non-PAX8 partner, or overexpression of the native protein might be present. Our findings that PAX8-PPAR gamma 1 rearrangements are present in both follicular carcinomas and adenomas suggest that this oncogene is not a reliable marker to differentiate between FTC and FTA in fine-needle aspiration biopsies of follicular neoplasms of the thyroid.

Adenoma↗
PubMed2002

Selective intranuclear redistribution of PPAR isoforms by RXR alpha.

The intracellular localization of transcriptionally active green fluorescent protein (GFP) chimeras linked to PPARs for human PPAR alpha (GFP-PPARh alpha) and mouse PPAR alpha, beta, and gamma 1 (GFP-PPARm alpha, GFP-PPARm beta, and GFP-PPARm gamma, respectively) was examined in the mouse hepatoma cell line, Hepa-1, using fluorescence microscopy. A predominantly nuclear and diffuse distribution of each isoform was found in both the presence and absence of specific ligands for each receptor. GFP-PPARm alpha-G (containing a Glu282Gly substitution of PPARm alpha) and a phosphorylation mutant, GFP-PPARm gamma-A (containing a Ser82Ala substitution of PPARm gamma), exhibited altered transcriptional activities, but displayed similar intracellular localization patterns compared with their respective wild-type receptors. Coexpression of nuclear receptor corepressor suppressed, whereas steroid receptor coactivator-1 enhanced the transcriptional activity of each of the GFP-PPAR isoforms, but did not discernibly alter their intracellular distributions, both in the presence and absence of PPAR ligands. Interestingly, coexpression of the obligate heterodimeric partner of PPARs, RXR alpha, resulted in an intranuclear redistribution of the GFP-PPARm gamma isoform characterized by a reticulated pattern of the green fluorescent label for PPAR gamma within the nucleus, but not in nucleoli, and a heightened concentration of the fluorescent label surrounding nucleolar structures and at the nuclear membrane. Conversely, coexpression of yellow fluorescent protein-RXR alpha and native PPARm gamma resulted in a similar distribution of the yellow fluorescent tag. This localization pattern was not discernibly altered by PPAR gamma or RXR alpha-specific ligands. These results implicate RXR alpha in the nuclear reorganization of PPAR gamma and suggest that PPAR gamma colocalizes with RXR alpha at specific locations within the nucleus independent of added ligand.

Active Transport, Cell Nucleus↗
PubMed2000

A new thiazolidinedione, NC-2100, which is a weak PPAR-gamma activator, exhibits potent antidiabetic effects and induces uncoupling protein 1 in white adipose tissue of KKAy obese mice.

Thiazolidinediones (TZDs) reduce insulin resistance in type 2 diabetes by increasing peripheral uptake of glucose, and they bind to and activate the transcriptional factor peroxisome proliferator-activated receptor-gamma (PPAR-gamma). Studies have suggested that TZD-induced activation of PPAR-gamma correlates with antidiabetic action, but the mechanism by which the activated PPAR-gamma is involved in reducing insulin resistance is not known. To examine whether activation of PPAR-gamma directly correlates with antidiabetic activities, we compared the effects of 4 TZDs (troglitazone, pioglitazone, BRL-49653, and a new derivative, NC-2100) on the activation of PPAR-gamma in a reporter assay, transcription of the target genes, adipogenesis, plasma glucose and triglyceride levels, and body weight using obese KKAy mice. There were 10- to 30-fold higher concentrations of NC-2100 required for maximal activation of PPAR-gamma in a reporter assay system, and only high concentrations of NC-2100 weakly induced transcription of the PPAR-gamma but not PPAR-alpha target genes in a whole mouse and adipogenesis of cultured 3T3L1 cells, which indicates that NC-2100 is a weak PPAR-gamma activator. However, low concentrations of NC-2100 efficiently lowered plasma glucose levels in KKAy obese mice. These results strongly suggest that TZD-induced activation of PPAR-gamma does not directly correlate with antidiabetic (glucose-lowering) action. Furthermore, NC-2100 caused the smallest body weight increase of the 4 TZDs, which may be partly explained by the finding that NC-2100 efficiently induces uncoupling protein (UCP)-2 mRNA and significantly induces UCP1 mRNA in white adipose tissue (WAT). NC-2100 induced UCP1 efficiently in mesenteric WAT and less efficiently in subcutaneous WAT, although pioglitazone and troglitazone also slightly induced UCP1 only in mesenteric WAT. These characteristics of NC-2100 should be beneficial for humans with limited amounts of brown adipose tissue.

Adipose Tissue↗
PubMed2006

CLA and n-3 PUFA differentially modulate clinical activity and colonic PPAR-responsive gene expression in a pig model of experimental IBD.

BACKGROUND AND AIMS: Conjugated linoleic acid (CLA) and n-3 polyunsaturated fatty acids (PUFA) have been proposed as important pharmaco-nutrients for modulating mucosal immunity and therapeutic responses in patients with inflammatory bowel disease (IBD). We evaluated the ability of CLA and n-3 PUFA alone or in combination to modulate IBD in a pig model of dextran sodium sulfate (DSS)-induced colitis. METHODS: Sixty-four, 15-day-old pigs were used to evaluate the effect of CLA, n-3 PUFA and a 50:50 mixture of CLA and n-3 PUFA on growth, clinical activity and colonic PPAR-responsive gene expression. Diets were formulated to contain: 1.33% soybean oil (control); 1.33% CLA; 1.33% fish oil; or 1.33% of a 50:50 mixture of CLA and fish oil. Intestinal inflammation was induced by an intragastric challenge with DSS on day 42 of dietary supplementation. The colonic expression of peroxisome proliferator-activated receptor-gamma (PPAR-gamma), PPAR gamma- and delta-responsive genes, keratinocyte growth factor (KGF) and tumor necrosis factor (TNF-alpha) were assayed by quantitative RT-PCR. RESULTS: The onset of IBD was delayed, colitis less severe and growth suppression attenuated in pigs fed CLA, which correlated with induction of colonic PPAR gamma and its responsive gene PPAR gamma-coactivator-1alpha (PGC1-alpha) and downregulation of TNF-alpha. However, dietary supplementation with n-3 PUFA alone or in combination with CLA resulted in an early onset of disease (i.e., day 2) and faster recovery on days 6 and 7, which correlated with a marked induction of the PPAR delta-responsive gene uncoupling protein 3 (UCP3). CLA and n-3 PUFA acted synergistically to upregulate colonic KGF expression in DSS-challenged pigs but n-3 PUFA blocked CLA-induced PPAR gamma activation. CONCLUSION: Dietary CLA-supplementation upregulated colonic PPAR gamma expression and contributed to delaying the onset of experimental IBD, whereas n-3 PUFA failed to protect from IBD, although it accelerated colonic regeneration and clinical remission by activating PPAR delta.

Animals↗
PubMed2005

Netoglitazone is a PPAR-gamma ligand with selective effects on bone and fat.

Thiazolidinediones are effective anti-diabetic drugs that improve insulin sensitivity through the activation of the nuclear receptor and adipocyte-specific transcription factor, peroxisome proliferator-activated receptor gamma (PPAR-gamma). Recent evidence suggests that PPAR-gamma also controls bone cell development and bone homeostasis. In mice, PPAR-gamma insufficiency results in increased bone mass, whereas administration of the specific PPAR-gamma agonist rosiglitazone leads to bone loss and increased bone marrow adiposity. Although the pro-adipocytic and anti-osteoblastic activities of PPAR-gamma can be separated in vitro using ligands with distinct chemical structures, little evidence exists supporting this functional separation in vivo. Netoglitazone (MCC-555, RWJ-241947) is a thiazolidinedione, which acts as either a full or partial PPAR-gamma agonist, or antagonist, in a cell type specific manner. In this study, the pro-adipocytic and anti-osteoblastic activities of netoglitazone were evaluated in vitro, using both U-33/gamma2 cells as a model of marrow mesenchymal cell differentiation under the control of PPAR-gamma2 and primary bone marrow cultures, and in vivo in C57BL/6 mice. In vitro, netoglitazone induced adipocyte and inhibited osteoblast formation in a PPAR-gamma2-dependent manner; however, it was 100-fold less effective than rosiglitazone. In vivo, the administration of netoglitazone at an effective hyperglycemic dose (10 microg/g body weight/day) did not result in trabecular bone loss. Bone quality parameters such as bone mineral density and bone microarchitecture were not affected in netoglitazone-treated animals. The observed lack of an in vivo effect of netoglitazone on bone was entirely consistent with its low anti-osteoblastic activity in vitro. In contrast to the observed in vitro effects, netoglitazone in vivo effectively induced marrow adipocyte formation and induced changes in the weights of extramedullary fat depots. Consistent with these cell type-specific effects, expression of the adipocyte-specific gene marker FABP4/aP2 was increased, whereas the expression of osteoblast-specific gene markers, Runx2, Dlx5, osteocalcin, and collagen were not affected by netoglitazone. In conclusion, netoglitazone is a member of a new class of PPAR-gamma ligands with distinct anti-diabetic, anti-osteoblastic, and pro-adipocytic activities in vivo.

Adipocytes↗
PubMed2005

Impaired expression of PPAR gamma protein contributes to the exaggerated growth of vascular smooth muscle cells in spontaneously hypertensive rats.

Peroxisome proliferator-activated receptor gamma (PPAR gamma), a member of the nuclear receptor family, has been implicated in the regulation of vascular smooth muscle cell (VSMC) growth; however, the underlying mechanisms are still not fully understood. We hypothesized that PPAR gamma functional deficiency may contribute to the enhanced proliferation of VSMC associated with hypertension in spontaneously hypertensive rats (SHR). We observed that PPAR gamma mRNA level in SHR VSMC was 3 approximately 4 fold higher than that from Wistar-Kyoto rats (WKY), but the protein expression levels of PPAR gamma are significantly lower in SHR than WKY VSMC, suggesting an impaired control of PPAR gamma protein expression in SHR VSMC. The deficiency of PPAR gamma protein expression in SHR VSMC was demonstrated by PPAR gamma reporter gene assays. Furthermore, the exaggerated growth of SHR VSMC was markedly attenuated by adenoviral PPAR gamma overexpression. Taken together, our results provided the first direct evidence that impaired expression of PPAR gamma protein contributes to the exaggerated growth of SHR VSMC.

Adenoviridae↗
PubMed2006

Role of PPAR-gamma on the pathogenesis and vascular changes in glycerol-induced acute renal failure.

Peroxisome proliferator activated receptor-gamma (PPAR-gamma), a nuclear transcription factor, modulates angiotensin II (AII) or thromboxane A(2) (TxA(2)) response in the vasculature via transcriptional regulation of their gene or receptor expression. Increased AII or TxA(2) vasoconstriction and deteriorating renal function observed in glycerol-induced acute renal failure (ARF) may be attributed to a down-regulated PPAR-gamma expression/activity probably via an increased free radical generation. In this study, we investigated the effect of PPAR-gamma induction in glycerol-induced ARF by examining renal vascular reactivity to AII and TxA(2) and by renal expression/activity of PPAR-gamma. Vascular responses to AII or U46619, a TxA(2) mimetic were determined in rat isolated perfused kidney following induction of ARF with glycerol (50%, v/v, i.m.). Extent of renal damage and function were assessed with or without pre-treatment with ciglitazone (9 nmol kg(-1) x 21 days), a PPAR-gamma inducer. In ARF, vasoconstriction was enhanced to AII (three-fold; p<0.05) and U46619 (82%; p<0.05). Ciglitazone reduced AII and U46619 vasoconstriction by 59+/-1% (p<0.05) and 56+/-1% (p<0.05), respectively. Ciglitazone reduced proteinuria (38+/-3%) which was two-fold higher in ARF. Similarly, ciglitazone enhanced Na(+) excretion by 1.5 times while reducing BUN by 49+/-6%. On the contrary, ciglitazone did not change plasma creatinine which was significantly higher in ARF rats. Ciglitazone reduced free radical generation by 30+/-3% while elevating nitrite excretion approximately 2-fold. PPAR-gamma expression and activity were significantly lower in ARF rats and ciglitazone enhanced PPAR-gamma protein expression and activity by 45+/-3% and 52+/-4%, respectively. Data from this study suggest that reduced PPAR-gamma expression and activity may be involved in the pathology of glycerol-induced ARF and induction of PPAR-gamma by ciglitazone confers protection through reduced AII and TxA(2) vasoconstriction and/or enhanced renal function via reducing free radical generation.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2006

Effects of PPAR gamma agonists on cardiovascular function in obese, non-diabetic patients.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors, and when activated by their ligands, they induce perixosome proliferation. Three receptors have been identified: PPAR gamma, PPAR delta, and PPAR alpha, all with different tissue expression. PPAR gamma is predominantly expressed in adipose tissue and regulates the formation of fat cells and their function. The effect of PPAR gamma activation is to enhance the action of insulin in insulin-sensitive tissue by increasing peripheral glucose disposal and decreasing hepatic glucose production. The thiazolidinediones (TZDs) are a class of medications used for treatment and possibly the prevention of type 2 diabetes, which are potent agonists for the PPAR gamma receptor. Because the thiazolidinediones target insulin resistance, these agents may improve many of the risk factors associated with obesity and insulin resistance including dyslipidemia, hypertension, impaired fibrinolysis, and atherosclerosis. The impact of the thiazolidinediones on cardiovascular mortality is currently unclear but it appears that the thiazolidinediones exert numerous non-glycemic effects that may improve cardiovascular outcomes. Several non-TZD PPAR gamma agonists and combined PPAR gamma/alpha effect on cardiovascular disease are also being evaluated. These drugs have anti-inflammatory and vascular properties and are currently the subject of numerous studies targeting the primary and secondary prevention of macrovascular disease in patients with diabetes and insulin resistance and might be developed as anti-atherogenic agents on the basis of their actions.

Adipocytes↗
PubMed2006

Absence of peroxisome proliferators-activated receptors (PPAR)alpha enhanced the multiple organ failure induced by zymosan.

The peroxisome proliferator-activated receptor (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 is to evaluate the role of PPAR-alpha receptor on the development of multiple-organ dysfunction syndrome (MODS) induced by zymosan. MODS was induced by peritoneal injection of zymosan (dose, 500 mg/kg i.p. as a suspension in saline) in PPAR-alpha wild-type (PPAR-alphaWT) and PPAR-alpha knockout (PPAR-alphaKO) mice, was assessed 18 h after the administration of zymosan, and was monitored for 12 days (for loss of body weight and mortality). A severe inflammatory process, induced by zymosan administration in wild-type mice, coincided with the damage of liver, kidney, pancreas, and small intestine. Myeloperoxidase activity, indicative of neutrophil infiltration, and lipid peroxidation were significantly increased in zymosan-treated wild-type mice. Zymosan in the wild-type mice also induced a significant increase in the plasma levels of nitrite/nitrate. Immunohistochemical examination demonstrated a marked increase in the immunoreactivity to nitrotyrosine and Fas ligand in the intestine of zymosan-treated wild-type mice. In contrast, the degree of (1) peritoneal inflammation and tissue injury, (2) nitrotyrosine formation and Fas ligand expression, and (3) neutrophil infiltration were markedly enhanced in intestinal tissue obtained from zymosan-treated PPAR-alphaKO mice. Zymosan-treated PPAR-alphaKO mice also showed a significantly increased mortality. Taken together, the present study clearly demonstrates that PPAR-alpha pathway modulates the degree of MODS associated with zymosan-induced nonseptic shock.

Animals↗
PubMed2006

PPAR-gamma agonists as regulators of microglial activation and brain inflammation.

The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) belongs to a large group of nuclear receptors controlling reproduction, metabolism, development and immune response. Upon activation by specific agonists, these receptors form dimers and translocate to the nucleus, where they act as agonist-dependent transcription factors and regulate gene expression by binding to specific promoter regions of target genes. The observation that PPAR-gamma is involved in the regulation of macrophage differentiation and activation in the peripheral organs has prompted the investigation of the functional role of PPAR-gamma in microglial cells, the main macrophage population of the CNS. The present review summarizes the several lines of evidence supporting that PPAR-gamma natural and synthetic agonists may control brain inflammation by inhibiting several functions associated to microglial activation, such as the expression of surface antigens and the synthesis of nitric oxide, prostaglandins, inflammatory cytokines and chemokines. Moreover, one of the major natural PPAR-gamma agonist, 15d-prostaglandin J(2) may contribute to the safe elimination of activated microglia by inducing apoptosis. Synthetic PPAR-gamma agonists do not entirely reproduce the range of 15d-prostaglandin J(2) effects, suggesting that PPAR-gamma independent mechanisms are also involved in the action of this prostaglandin. In addition to microglia, PPAR-gamma agonists affect functions and survival of other neural cells, including astrocytes, oligodendrocytes and neurons. Although most of the evidence comes from in vitro observations, an increasing number of studies in animal models further supports the potential therapeutic use of PPAR-gamma agonists in human brain diseases including multiple sclerosis, Parkinson's disease and Alzheimer's disease.

Animals↗
PubMed2005

[PPAR-gamma receptors, new therapeutic target in metabolic and cardiovascular diseases].

PPARs ("Peroxisome Proliferator-Activated Receptors") belong to a superfamily of nuclear receptors with several isoforms, among which PPAR-alpha mainly located in the liver and PPAR-gamma mainly located in the adipose tissue. These receptors are considered as major pharmacological targets since the discovery of their activation by specific agonists, which lead to various favourable metabolic effects. Improvement of lipid profile by fibrates is explained by the activation of liver PPAR-alpha receptors. However, PPAR-gamma receptors have focused most fundamental and clinical research in recent years after the demonstration of their activation by thiazolidinediones (pioglitazone, rosiglitazone), a new class of antidiabetic agents. Beyond their effects on insulin sensitivity, glitazones exert pleiotropic effects that may result in cardiovascular protection in high risk patients. It has been recently demonstrated that certain angiotensin AT1 receptor blockers (sartans) can also exert a partial agonist activity on PPAR-gamma. Among the molecules of this class, telmisartan appears to exert this effect at the lower concentrations. Thus, PPAR-y, as common pharmacological target, may, at least partially, explain some of the effects observed with both thiazolidinediones and inhibitors of the renin-angiotensin system, in particular the improvement in insulin sensitivity (in particular via an increase in adiponectin levels), the protection against type 2 diabetes, the reduction in arterial blood pressure and the prevention of cardiovascular complications. There is currently a major interest from the pharmaceutical industry in the development of new molecules able to activate both PPAR-alpha and PPAR-gamma.

Cardiovascular Diseases↗
PubMed2002

Expression of peroxisome proliferator-activated receptor (PPAR) in human prostate cancer.

BACKGROUND: Recent studies have demonstrated that peroxisome proliferator activator-receptors (PPAR)-gamma is expressed in some cancer cells such as breast, lung, and gastric cancer, and its ligand induces growth arrest of these cancer cells through apoptosis. However, the expression and localization of PPARs in prostate have not been examined. In this study, PPARs expression was investigated in human prostate cancer (PC), prostatic intraepithelial neoplasia (PIN), benign prostatic hyperplasia (BPH), and normal prostate (NP) tissues. METHODS: Tumor specimens were obtained from 156 patients with PC, 15 with PIN, 20 with BPH, and 12 patients with NP tissues. The expressions were investigated by RT-PCR and immunohistochemical methods. RESULTS: Immunoreactive PPAR-alpha and -beta were significantly apparent in PC tissues. Marked expressions of PPAR-alpha and -beta were also detected in PIN, BPH, and NP groups. However, very weak or no expression of immunoreactive PPAR-gamma was found in BPH and NP cases. In contrast, we found significant expression of immunoreactive PPAR-gamma in cancer cells in PC group and in PIN group. CONCLUSIONS: Our results demonstrated that PPAR-gamma is induced in PC, and suggest that PPAR-gamma ligands may mediate its own potent antiproliferative effect against PC cells through differentiation.

Aged↗
PubMed2000

PPAR-gamma is selectively upregulated in Caco-2 cells by butyrate.

The peroxisome proliferator-activated receptor (PPAR)-gamma is a nuclear lipid-activable receptor controlling the expression of genes involved in lipid metabolism and adipocyte differentiation. In order to investigate the possible role of PPAR-gamma in the differentiation of intestinal epithelial cells, we examined its expression in the human colon carcinoma cell line Caco-2, which undergoes rapid cell differentiation in the presence of butyrate. PPARs were quantified on mRNA level by RT competitive multiplex PCR, the corresponding proteins were determined by Western blot. In contrast to PPAR-alpha and PPAR-beta, PPAR-gamma mRNA and protein increased significantly in butyrate-treated Caco-2 cells in a dose- and time-dependent manner. This effect was butyrate-specific, since no change in PPAR-gamma expression could be observed after incubation with propionate or valerate. Activation of PPAR-gamma by ciglitazone further increased butyrate-induced cell differentiation dose-dependently. These data demonstrate a role for PPAR-gamma in the regulation of cell differentiation in Caco-2 cells.

Alkaline Phosphatase↗