Effects Of Peroxisome Proliferator-activated Receptor Research Articles

PPARα activator fenofibrate modulates angiotensin II-induced inflammatory responses in vascular smooth muscle cells via the TLR4-dependent signaling pathway

Angiotensin II (Ang II) is a crucial contributor to inflammatory processes involved in development and progression of atherosclerotic lesion. Toll-like receptor 4 (TLR4) signaling responsible for the initiation of inflammation also participates in pathogenesis of atherosclerosis. The protective effect of peroxisome proliferator-activated receptor α (PPARα) activators on atherosclerosis may be due to their impact on vascular inflammation, plaque instability and thrombosis. However, mechanisms underlying the inhibitory effects of PPARα activators on Ang II-induced vascular inflammation and the TLR4-dependent signaling pathway involved in vascular smooth muscle cells (VSMCs) remain unclear. The present study demonstrated that PPARα activator fenofibrate decreased Ang II-induced generation of pro-inflammatory mediators such as TLR4, MMP-9 and TNF-α, but enhanced production of anti-inflammatory molecules like PPARα and 6-keto-PGF 1α both in vivo and in vitro. Meanwhile, treatment of VSMCs with the TLR4 inhibitor or TLR4 siRNA showed that the inhibitory effects of fenofibrate on Ang II-induced inflammatory responses in VSMCs were dependent on TLR4. Furthermore, fenofibrate depressed Ang II-induced inflammatory responses in VSMCs by intervening the downstream effector molecules of the TLR4-dependent signaling pathway, including interferon-gamma inducible protein 10 (IP-10), protein kinases C (PKC) and nuclear factor κB (NF-κB). Thus, these findings provide the evidence for beneficial effects of PPARα activator fenofibrate to counter-regulate vascular inflammation induced by Ang II. More importantly, anti-inflammatory action of fenofibrate via interfering with the TLR4-dependent signaling pathway (TLR4/IP-10/PKC/NF-κB) works in concert to protect against atherosclerosis.

Effect of the dual peroxisome proliferator-activated receptor-α/γ agonist aleglitazar on risk of cardiovascular disease in patients with type 2 diabetes (SYNCHRONY): a phase II, randomised, dose-ranging study

Despite previous reports of potential adverse cardiovascular effects of peroxisome proliferator-activated receptor (PPAR) agonists, the promise for PPAR agonists to positively affect risk of cardiovascular disease in patients with type 2 diabetes is of continued interest. The SYNCHRONY study aimed to establish the glucose-lowering and lipid-modifying effects, and safety profile, of the dual PPAR-alpha and PPAR-gamma agonist aleglitazar. In this double-blind study, patients with type 2 diabetes (either drug-naive or pre-treated with </=two oral agents) were enrolled from 47 sites in seven countries. After a single-blind, 4-5-week placebo run-in period, 332 patients were randomised double-blind (via an interactive voice-response system) to 16 weeks' treatment with aleglitazar at once-daily doses of 50 mug, 150 mug, 300 mug, or 600 mug, or matching placebo (n=55 in each group), or to open-label pioglitazone 45 mg once daily (n=57) as a reference. The primary efficacy endpoint was the change in glycosylated haemoglobin (HbA(1c)) concentration from baseline to the end of treatment. Patients who received at least one dose of study drug and had at least one evaluable post-baseline HbA(1c) measurement were included in the efficacy analysis. This study is registered with ClinicalTrials.gov, number NCT00388518. The efficacy analysis excluded six patients (n=0 in pioglitazone group; n=1 in each of placebo, 50 mug, 150 mug, and 600 mug aleglitazar groups; and n=2 in 300 mug aleglitazar group). Aleglitazar significantly reduced baseline HbA(1c) versus placebo in a dose-dependent manner, from -0.36% (95% CI 0.00 to -0.70, p=0.048) with 50 mug to -1.35% (-0.99 to -1.70, p<0.0001) with 600 mug. The trend of changes over time suggests that the maximum effect of aleglitazar on HbA(1c) concentration was not yet reached after 16 weeks of treatment. Oedema, haemodilution, and weight gain occurred in a dose-dependent manner. However, at aleglitazar doses less than 300 mug, no patients had congestive heart failure, frequency of oedema was similar to placebo (one case at 50 mug, two at 150 mug, and three with placebo) and less than with pioglitazone (four cases), and bodyweight gain was less than with pioglitazone (0.52 kg at 150 mug vs 1.06 kg). The favourable balance in the safety and efficacy profile of aleglitazar represents encouraging short-term clinical data for this agent and provides good evidence to enter phase III investigation. F Hoffmann-La Roche AG (Switzerland).

Thiazolidinediones in prediabetes and early type 2 diabetes: What can be learned about that disease’s pathogenesis

Several clinical trials have shown a high success rate of thiazolidinediones (TZDs) in prediabetes and early type 2 diabetes. The presumed mechanism of this effect has shifted from the best known effect of these agents to improve insulin sensitivity, to preservation of beta-cell function. The common explanation for this effect is unloading of the islet beta cell from the insulin resistance-induced hyperstimulation that eventually leads to beta-cell failure, so-called beta-cell rest. However, a recent finding is powerful biological effects of peroxisome proliferator-activated receptor (PPAR)gamma signaling in islet beta cells. This article reviews this topic by first describing the TZD intervention studies. Then it provides an overview of the current concepts regarding the beta-cell overwork and rest hypotheses, and the recent information about PPARgamma signaling effects in beta cells.

Peroxisome Proliferator-Activated Receptor γ (PPAR-γ) Agonist Rosiglitazone (RGZ) Inhibits HL-60 Cell Growth by Induction of Apoptosis

Objective To investigate the apoptotic effects of peroxisome proliferator-activated receptor γ (PPAR-γ) agonist rosiglitazone (RGZ) on leukemia HL-60 cells. Methods Cell apoptosis was measured by flow cytometry, Hoechst 33258 staining, and DNA fragmentation assay. The expression of caspase-3 and apoptosis-related gene Bax and Bcl-2 as well as survivin expression were analyzed by Western blotting. Results Rosiglitazone (over 40 μmol/L) could inhibit the growth of HL-60 cells and substantially cause apoptosis. Apoptotic cells were observed clearly by Hoechst staining, especially after the cells were treated with RGZ for 72 h, and a DNA fragmentation assay showed a typical DNA ladder. Western blotting showed cleavage of the caspase-3 zymogen protein (32-kD) with the appearance of its 17-kD cleavage and down-regulation of anti-apoptotic protein Bcl-2 and survivin as well as up-regulaton of pro-apoptotic protein Bax . Conclusion Rosiglitazone can inhibit HL-60 cell growth by the induction of apoptosis. Activation of caspase-3 and down-regulation of Bcl-2 and survivin as well as up-regulation of Bax expression may be one of its most important mechanisms.

Pan-PPAR agonist beneficial effects in overweight mice fed a high-fat high-sucrose diet

Objective We analyzed the effect of peroxisome proliferator-activated receptor (PPAR) agonists on adipose tissue morphology, adiponectin expression, and its relation to glucose and insulin levels in C57BL/6 mice fed a high-fat high-sucrose (HFHS) diet. Methods Male C57BL/6 mice received one of five diets: standard chow, HFHS chow, or HFHS plus rosiglitazone (PPAR-γ agonist), fenofibrate (PPAR-α agonist), or bezafibrate (pan-PPAR agonist). Diets were administered for 11 wk and medications from week 6 to week 11. Glucose intolerance (GI) and insulin resistance were evaluated by oral glucose tolerance testing and homeostasis model assessment for insulin resistance, respectively. Adipocyte diameter was analyzed in epididymal, inguinal, and retroperitoneal fat pads and by adiponectin immunostain. Results Mice fed the HFHS chow had hyperglycemia, GI, insulin resistance, increased fat pad weight, adipocyte hypertrophy, and decreased adiponectin immunostaining. Rosiglitazone improved GI, insulin sensitiveness, and adiponectin immunostaining, but it resulted in body weight gain, hyperphagia, and adipocyte and heart hypertrophy. Fenofibrate improved all parameters except for fasting glucose and GI. Bezafibrate was the most efficient in decreasing body weight and glucose intolerance. Conclusion Activation of PPAR-α, -δ, and -γ together is better than the activation of PPAR-α or -γ alone, because bezafibrate showed a wider range of action on metabolic, morphologic, and biometric alterations due to an HFHS diet in mice.

Potential effects of peroxisome proliferator-activated receptor activator on LPS-induced lung injury in rats

Multiple factors contribute to the pathogenesis and prognosis of chronic obstructive pulmonary disease (COPD), still requiring new therapeutic strategies and medications for the disease. The aim of the present study is to investigate the model of lipopolysaccharide (LPS)-induced chronic lung injury and hyperinflation and test therapeutic effects of peroxisome proliferator-activated receptor (PPAR)-γ agonist. Wister rats were challenged with intra-tracheal instillation of LPS at concentrations of 0.006, 0.060, 0.600, and 6.000 mg/ml per kg, twice a week, for 1, 2, 4 and 6 weeks. PPAR activator, 15-deoxy-Δ 12,14-prostaglandin J2 (15D-PGJ2), or vehicle (PBS) was administered orally and daily at the dose of 1 and 10 mg/ml per kg in animals challenged with LPS or PBS at the dose of 0.060 mg/ml per kg body weight twice a week for 4 weeks. We found that intra-tracheal exposure of LPS resulted in a dose-dependent pattern of chronic lung hyperinflation and hypertrophy, increased alveolar enlargement, reduced vascular endothelial growth factor (VEGF) and elevated tissue inhibitor of metalloproteinases (TIMP)-1 levels in bronchoalveolar lavage (BAL) fluid, and early changes of leukocyte influx and interferon (IFN)-γ levels in bronchoalveolar lavage (BAL) fluid. PPAR-γ agonist ameliorated these changes related with the dose used. LPS-induced lung disease model shows some similarities with human disease, and PPAR-γ agonist may be an alternative for COPD therapy.

Overexpression of Jab1 in Hepatocellular Carcinoma and Its Inhibition by Peroxisome Proliferator-Activated Receptorγ Ligands In vitro and In vivo

Jun activation domain-binding protein 1 (Jab1) is the fifth subunit of the COP9 signalosome and exhibits oncogenic activity. We investigated Jab1 expression in hepatocellular carcinoma (HCC) tissues and cell lines and tested the effect of peroxisome proliferator-activated receptor gamma (PPARgamma) ligands on Jab1 expression. Jab1 expression in HCC tissues and cell lines was studied by real-time reverse transcription-PCR, immunohistochemical staining, and Western blotting. Promoter activity and chromatin immunoprecipitation assays were done to address the inhibition of Jab1 promoter by PPARgamma ligands. RNA interference was used to clarify PPARgamma ligand-induced inhibition of Jab1. Anticancer and Jab1-suppressing activity of PPARgamma ligands was tested in nude mice. Jab1 was detected in the nucleus and cytoplasm of HCC tissues and 37% (37 of 99) of tissues exhibited Jab1 overexpression. Jab1 expression correlated with sex and hepatitis C virus infection, whereas it was negatively associated with hepatitis B virus infection. Additionally, Jab1 was overexpressed in HCC cell lines. PPARgamma ligands troglitazone and rosiglitazone down-regulated Jab1 expression in HCC cells, and troglitazone directly suppressed Jab1 promoter activity by inhibiting Sp1- and Tcf4-mediated transcription. This suppression was mediated via both PPARgamma-dependent and PPARgamma-independent mechanisms. Ectopic expression of Jab1 counteracted troglitazone-induced growth inhibition. Animal studies verified that intratumor or i.p. injection of troglitazone attenuated HCC growth and reduced Jab1 expression in tumor tissues. Our results indicate that Jab1 is overexpressed in HCC and PPARgamma ligands may suppress Jab1 to inhibit the proliferation of HCC cells.

Effects of peroxisome proliferator-activated receptor α (PPARα) agonists on leucine-induced phosphorylation of translational targets in C2C12 cells

Effect of peroxisome proliferator-activated receptor α (PPARα) agonists, WY-14,643 (WY) and/or clofibrate, on the leucine-induced phosphorylation of translational targets in C2C12 myoblasts was studied. C2C12 cells were treated with WY or clofibrate for 24 h prior to stimulation with leucine. Western blot analyses revealed that the leucine-induced phosphorylation of p70 S6 kinase (p70S6K), a key regulator of translation initiation, was significantly higher in WY-treated cells than in control and clofibrate-treated cells. Phosphorylation of extracellular-regulated kinase (ERK1/2) was higher in WY-treated cells. WY treatment also increased the leucine-induced phosphorylation of ribosomal protein S6 and eukaryotic initiation factor 4B. In contrast, eukaryotic elongation factor 2, a marker for peptide chain elongation process, was significantly activated (dephosphorylated) only in leucine-stimulated control cells. Pre-treatment of the cells with PD98059 (ERK1/2 kinase inhibitor) prevented the phosphorylation of ERK1/2 and decreased the leucine-induced phosphorylation of p70S6K. It is concluded that WY increased the leucine-induced phosphorylation of target proteins involving in translation initiation via ERK/p70S6K pathway, but impaired the signaling for elongation process, suggesting that p70S6K phosphorylation may be essential, but not sufficient for the activation of entire targets for protein translation in WY-treated cells.

Effects of peroxisome proliferator-activated receptor γ on the maintenance of quiescent phenotype of hepatic stellate cells

Effects of peroxisome proliferator-activated receptor γ on the maintenance of quiescent phenotype of hepatic stellate cells

Activation of peroxisome proliferator-activated receptor γ inhibits TNF-α-mediated osteoclast differentiation in human peripheral monocytes in part via suppression of monocyte chemoattractant protein-1 expression

Tumor necrosis factor-α (TNF-α) plays critical roles in bone resorption at the site of inflammatory joints. The aim of this study is to evaluate the effect of peroxisome proliferator-activated receptor γ (PPAR-γ) agonists, a new class of anti-inflammatory compounds, on TNF-α-mediated osteoclastogenesis in human monocytes. Human monocytes were differentiated into osteoclasts in the presence of TNF-α and macrophage colony-stimulating factor. Tartrate-resistant acid phosphatase (TRAP) staining and a pit formation assay using dentin were used for the identification of activated osteoclasts. The protein and gene expressions of transcription factors were determined by immunofluorescence and real-time RT-PCR analysis, respectively. TNF-α-induced osteoclast generation from human peripheral monocytes in a dose-dependent manner, and the induction was not inhibited by osteoprotegerin, a decoy receptor for receptor activator of NF-κB ligand. The addition of PPAR-γ agonists, 15-deoxy-Δ 12,14-prostaglandin J 2 (15d-PGJ 2) or ciglitazone, to the culture resulted in a remarkably reduced number of generated osteoclasts. In addition, both agonists inhibited the protein and gene expressions of nuclear factor of activated T-cell isoform c1 (NFATc1), c-Fos, c-Jun and NF-κB p65, which are known to be associated with osteoclastogenesis. GW9662, an antagonist of PPAR-γ, fully rescued ciglitazone-induced inhibition, but did not affect 15d-PGJ 2-induced inhibition. Monocyte chemoattractant protein-1 (MCP-1), a CC chemokine related to osteoclastogenesis, was induced during TNF-α-mediated osteoclast differentiation, and the neutralizing antibody to MCP-1 reduced osteoclast formation by about 40%. 15d-PGJ 2 and ciglitazone blocked the induction of MCP-1 by TNF-α. Moreover, the addition of MCP-1 rescued the inhibition of TRAP-positive multinucleated cell (TRAP-MNCs) formation by 15d-PGJ 2 and ciglitazone, although generated TRAP-MNCs had no capacity to resorb dentin slices. Our data demonstrate that 15d-PGJ 2 and ciglitazone down-regulate TNF-α-mediated osteoclast differentiation in human cells, in part via suppression of the action of MCP-1. These PPAR-γ agonists may be a promising therapeutic application for rheumatoid arthritis and inflammatory bone-resorbing diseases.

Peroxisome proliferator-activated receptor γ agonists inhibit the proliferation and invasion of human colon cancer cells

Background and aims: Data regarding the effect of peroxisome proliferator-activated receptor γ (PPAR-γ) ligands on the invasive ability of colon cancer cells are currently limited. This study was designed to...

The peroxisome proliferator-activated receptor-γ agonist troglitazone inhibits transforming growth factor-β–mediated glioma cell migration and brain invasion

Gliomas are the most common primary tumors of the central nervous system, with glioblastomas as the most malignant entity. Rapid proliferation and diffuse brain invasion of these tumors are likely to determine the unfavorable prognosis. Considering its promigratory properties, the transforming growth factor-beta (TGF-beta) signaling pathway has become a major therapeutic target. Analyses of resected glioma tissues revealed an intriguing correlation between tumor grade and the expression of TGF-beta(1-3) as well as their receptors I and II. Here, we analyzed the effects of peroxisome proliferator-activated receptor gamma (PPAR-gamma) agonists on glioma proliferation, migration, and brain invasion. Using an organotypic glioma invasion model, we show that micromolar doses of the PPAR-gamma activator troglitazone blocked glioma progression without neurotoxic damage to the organotypic neuronal environment observed. This intriguing antiglioma property of troglitazone seems to be only partially based on its moderate cytostatic effects. We identified troglitazone as a potent inhibitor of glioma cell migration and brain invasion, which occurred in a PPAR-gamma-independent manner. The antimigratory property of troglitazone was in concordance with the transcriptional repression of TGF-beta(1-3) and their receptors I and II and associated with reduced TGF-beta release. Due to its capacity to counteract TGF-beta release and glioma cell motility and invasiveness already at low micromolar doses, troglitazone represents a promising drug for adjuvant therapy of glioma and other highly migratory tumor entities.

Effects of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ agonists on glucose and lipid metabolism in patients with type 2 diabetes mellitus

The aim of the study was to examine the effects of pioglitazone (PIO), a peroxisome proliferator-activated receptor (PPAR)-gamma agonist, and fenofibrate (FENO), a PPAR-alpha agonist, as monotherapy and in combination on glucose and lipid metabolism. Fifteen type 2 diabetic patients received FENO (n = 8) or PIO (n = 7) for 3 months, followed by the addition of the other agent for 3 months in an open-label study. Subjects received a 4 h hyperinsulinaemic-euglycaemic clamp and a hepatic fat content measurement at 0, 3 and 6 months. Following PIO, fasting plasma glucose (FPG) (p < 0.05) and HbA(1c) (p < 0.01) decreased, while plasma adiponectin (AD) (5.5 +/- 0.9 to 13.8 +/- 3.5 microg/ml [SEM], p < 0.03) and the rate of insulin-stimulated total-body glucose disposal (R (d)) (23.8 +/- 3.8 to 40.5 +/- 4.4 micromol kg(-1) min(-1), p < 0.005) increased. After FENO, FPG, HbA(1c), AD and R (d) did not change. PIO reduced fasting NEFA (784 +/- 53 to 546 +/- 43 micromol/l, p < 0.05), triacylglycerol (2.12 +/- 0.28 to 1.61 +/- 0.22 mmol/l, p < 0.05) and hepatic fat content (20.4 +/- 4.8 to 10.2 +/- 2.5%, p < 0.02). Following FENO, fasting NEFA and hepatic fat content did not change, while triacylglycerol decreased (2.20 +/- 0.14 to 1.59 +/- 0.13 mmol/l, p < 0.01). Addition of FENO to PIO had no effect on R (d), FPG, HbA(1c), NEFA, hepatic fat content or AD, but triacylglycerol decreased (1.61 +/- 0.22 to 1.00 +/- 0.15 mmol/l, p < 0.05). Addition of PIO to FENO increased R (d) (24.9 +/- 4.4 to 36.1 +/- 2.2 micromol kg(-1) min(-1), p < 0.005) and AD (4.1 +/- 0.8 to 13.1 +/- 2.5 microg/ml, p < 0.005) and reduced FPG (p < 0.05), HbA(1c) (p < 0.05), NEFA (p < 0.01), hepatic fat content (18.3 +/- 3.1 to 13.5 +/- 2.1%, p < 0.03) and triacylglycerol (1.59 +/- 0.13 to 0.96 +/- 0.9 mmol/l, p < 0.01). Muscle adenosine 5'-monophosphate-activated protein kinase (AMPK) activity did not change following FENO; following the addition of PIO, muscle AMPK activity increased significantly (phosphorylated AMPK:total AMPK ratio 1.2 +/- 0.2 to 2.2 +/- 0.3, p < 0.01). We conclude that PPAR-alpha therapy has no effect on NEFA or glucose metabolism and that addition of a PPAR-alpha agonist to a PPAR-gamma agent causes a further decrease in plasma triacylglycerol, but has no effect on NEFA or glucose metabolism.

Effects of Peroxisome Proliferator-Activated Receptor Ligands in Modulating Tissue Factor and Tissue Factor Pathway Inhibitor in Acutely Symptomatic Carotid Atheromas

Severely stenotic, symptomatic carotid atheromas are associated with a high risk of stroke in the short term. Although carotid endarterectomy is effective in reducing this stroke risk, it is frequently not applied within the time window for significant benefit. We investigated the effect of peroxisome proliferator-activated receptor (PPAR) -alpha and -gamma ligands in acutely modifying tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in unstable carotid atheromas. During a 3-year period, 64 patients who had experienced a transient ischemic attack or stroke with good recovery within 6 weeks before surgery and 12 asymptomatic patients with a >70% carotid stenosis were recruited. The expression of PPAR-alpha and -gamma was investigated in endarterectomy samples. The effects of the PPAR-alpha and -gamma ligands fenofibrate and rosiglitazone were investigated in cell culture experiments. Targeted biopsy specimens from endarterectomy samples (n=48) were incubated with medication for 4 days. TF and TFPI were assessed by immunohistochemistry, Western blot analysis, flow cytometry, and activity assays. PPAR-gamma1 but not -alpha was downregulated in atheromas removed from patients with recent symptoms and no evidence of diabetes. Fenofibrate but not rosiglitazone impaired the induction of TF in human endothelial cells and reduced resting levels of TF activity in vascular smooth muscle cells. Rosiglitazone but not fenofibrate increased TFPI secretion from human endothelial cells. Both fenofibrate (100+/-18.7% to 56.6+/-8.8%, P=0.005; 0.2664+/-0.0696 to 0.1771+/-0.0310, P=0.02) and rosiglitazone (100+/-22% to 88.3+/-20%, P=0.02; 0.3113+/-0.0729 to 0.2287+/-0.0415, P=0.04) reduced TF expression and activity, respectively, in atheroma biopsy specimens. A low expression of TFPI was found in atheroma biopsy specimens with little evidence of TFPI activity. This study suggests that both PPAR-alpha and -gamma ligands have beneficial effects in acutely reducing TF in unstable carotid atheromas.

Hypoxia reduces the expression and anti-inflammatory effects of peroxisome proliferator-activated receptor- in human proximal renal tubular cells

Peroxisome proliferator-activated receptor (PPAR)-gamma may counteract tissue fibrosis via its anti-inflammatory actions, while hypoxia, a new pro-fibrotic factor, reportedly modifies PPAR-gamma expression. However, the effects of hypoxia on the expression and anti-inflammatory actions of PPAR-gamma have yet remained to be clarified in renal tubular cells. Confluent human proximal renal tubular epithelial cells (HPTECs) were exposed to hypoxia (1% O2) and/or TNF-alpha at 10 ng/ml for up to 48 h. The cells were incubated with PPAR-gamma agonists, 15d-PGJ2 or pioglitazone, for 30 min before stimulation. Precise amounts of PPAR-gamma and MCP-1 mRNA and protein were measured by TaqMan quantitative PCR and immunoblot or ELISA, respectively. A cDNA array analysis identified PPAR-gamma as one of the hypoxia-affected genes in HPTECs. Hypoxia reduced mRNA levels of PPAR-gamma at 24 and 48 h and protein levels at 6 and 48 h. Knockout of hypoxia-inducible factor-1alpha (HIF-1alpha) with its dominant negative form did not block the hypoxia-induced reduction in PPAR-gamma expression. PPAR-gamma's activation with 15d-PGJ2 or pioglitazone reduced basal and TNF-alpha-stimulated MCP-1 expression at mRNA and protein levels at 24 h under normoxia. MCP-1 reduction rates at basal mRNA and protein levels were slightly but significantly lower during hypoxia than normoxia (9 vs 69% and 36 vs 42%, respectively, for 15d-PGJ2, and 0 vs 34% and 12 vs 21%, respectively, for pioglitazone). Finally, a specific inhibitor for PPAR-gamma, GW9662, weakened the MCP-1-decreasing effect of 15d-PGJ2 by about 30%, under basal conditions, while it abolished the effect of pioglitazone almost completely. Hypoxia-induced loss of function of PPAR-gamma reduces anti-inflammatory effects of PPAR-gamma activation, possibly modulating inflammatory responses in the diseased kidney.

PPAR.ALPHA. Agonists Positively and Negatively Regulate the Expression of Several Nutrient/Drug Transporters in Mouse Small Intestine

A systematic analysis to examine the effects of peroxisome proliferator-activated receptor (PPAR)alpha agonists on the expression levels of all the nutrient/drug plasma-membrane transporters in the mouse small intestine was performed. Transporter mRNAs that were induced or repressed by two independent PPARalpha-specific agonists were identified by a genome-wide microarray method, and the changes were confirmed by real-time PCR using RNA isolated from the intestines and livers of wild-type and PPARalpha-null mice. Expression levels of seven nutrient/drug transporters (Abcd3, Octn2/Slc22a5, FATP2/Slc27a2, Slc22a21, Mct13/Slc16a13, Slc23a1 and Bcrp/Abcg2) in the intestine were up-regulated and the expression level of one (Mrp1/Abcc1) was down-regulated by PPARalpha; although the previously report that the H(+)/peptide co-transporter 1 (Pept1) is up-regulated by PPARalpha was not replicated in our study. We propose that the transport processes can be coordinately regulated with intracellular metabolism by nutrient nuclear receptors.

Effects of Peroxisome Proliferator-Activated Receptor γ and Its Ligand on Blood–Retinal Barrier in a Streptozotocin-Induced Diabetic Model

To clarify whether endogenous peroxisome proliferator-activated receptor gamma (PPARgamma) and its ligand, rosiglitazone, affect retinal leukostasis and the associated vascular leakage using an experimental diabetic model. Diabetes was induced in heterozygous PPARgamma+/- mice and Brown Norway rats with an intraperitoneal streptozotocin (STZ) injection. Retinal leukostasis and leakage, quantified by concanavalin A (Con A) lectin perfusion labeling combined with a fluorophotometric dextran leakage assay, were investigated at 120 days in diabetic PPARgamma+/- and wild-type mice and at 21 days in diabetic rats receiving rosiglitazone or the vehicle. The retinal protein expression levels of vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF)-alpha, and the intercellular adhesion molecule (ICAM)-1 were investigated by means of the ELISA assay. In the diabetic PPARgamma+/- mice, retinal leukostasis and leakage were greater than in the diabetic wild-type mice. In addition retinal leukostasis and leakage were suppressed by treatment with rosiglitazone in experimental diabetic rats. ELISA analysis revealed that the upregulated ICAM-1 expression in the diabetic rat retina was reduced by rosiglitazone treatment. An endogenous pathway involving PPARgamma provides protection against retinal leukostasis and retinal leakage in diabetes and treatment with PPARgamma specific ligands inhibits retinal leukostasis and retinal leakage in diabetic rats.

Effect of peroxisome proliferator-activated receptor γ ligand. Rosiglitazone on left ventricular remodeling in rats with myocardial infarction

Background Recent studies have demonstrated that PPARγ ligands have anti-inflammatory effect which is involved in ventricular remodeling. So we hypothesized that PPARγ ligand may have beneficial effects on post-infarct ventricular remodeling. Methods Experimental myocardial infarction (MI) was induced in SD rats by ligation of the left coronary artery. Twenty-four hours after surgery, survival rats were randomly divided into MI group and Rosiglitazone (MI + Ros) group which would take rosiglitazone 3 mg/kg day for 8 weeks. After 8 weeks treatment, left ventricular hemodynamics were measured and organs were weighed. Myocardial collagen analysis was determined in Van Gieson staining by quantitative morphometry. Myocardial angiotensin II and aldosterone were detected by radioimmunoassay. Myocardial AT1 and AT2 mRNA expression were determined by RT-PCR. Results Only 1 rat in MI group died of anesthesia at the 8th week. Rosiglitazone treatment could improve left ventricular ± d p/d t max, collagen volume fraction and perivascular circumferential area; reduce lung/body mass ratio and liver/body mass ratio; inhibit myocardial angiotensin II and aldosterone; and had no significant effects on myocardial AT1 and AT2 mRNA. Plasma insulin and blood glucose were comparable between two groups. Conclusions PPARγ ligand has neutral effect on mortality and beneficial effect on post-infarct ventricular remodeling, partly by suppressing myocardial angiotensin II and aldosterone, irrespective of plasma insulin and blood glucose level.

Effects of PPAR and RXR ligands in semaphorin 6B gene expression of human MCF-7 breast cancer cells

This study tests the hypothesis that the activators of peroxisome proliferator-activated receptors (PPARs) and 9-cis-retinoic acid receptor (RXR) regulate human semaphorin 6B (Sema6B) gene expression. The human MCF-7 breast adenocarcinoma cell line was chosen because it expresses Sema6B at a high level. The Sema6B mRNA level was analyzed by RT-PCR and the semaphorin 6B protein content was determined using a polyclonal antibody that we have produced and characterized. Treatments with fenofibrate (a PPARalpha activator) and troglitazone (a PPARgamma ligand) strongly decreased the Sema6B mRNA. The drop in Sema6B mRNA level and in protein content was more important when the treatment combined the action of fenofibrate or troglitazone and 9-cis-retinoic acid. On the other hand, no significant change was observed in the Sema6B mRNA and protein levels when the cells were exposed to the combined action of GW610742 (a PPARbeta activator) and 9-cis-retinoic acid. These data suggest that PPARalpha/RXR and PPARgamma/RXR heterodimers are involved in the regulation of Sema6B gene expression and open new perspectives concerning the participation of these nuclear receptors in cell recognition and migration.

Activation of Peroxisome Proliferator-Activated Receptor-γ Decreases Pancreatic Cancer Cell Invasion through Modulation of the Plasminogen Activator System

Cancer cell invasion and metastasis require the concerted action of several proteases that degrade extracellular matrix proteins and basement membranes. Recent reports suggest the plasminogen activator system plays a critical role in pancreatic cancer biology. In the present study, we determined the contribution of the plasminogen activator system to pancreatic cancer cell invasion in vitro. Moreover, the effect of peroxisome proliferator-activated receptor (PPAR)-gamma ligands, which are currently in clinical use as antidiabetic drugs and interestingly seem to display antitumor activities, on pancreatic cancer cell invasion and the plasminogen activator system was assessed. Expression of components of the plasminogen activator system [i.e., urokinase-type plasminogen activator (uPA), plasminogen activator inhibitor-1, and uPA receptor] was detected in six human pancreatic cancer cell lines. Inhibition of urokinase activity by specific synthetic compounds reduced baseline pancreatic cancer cell invasion. The PPAR-gamma ligands 15-deoxy-Delta12,14-prostaglandin J2 and ciglitazone also attenuated pancreatic cancer cell invasion. This effect was abrogated by dominant-negative PPAR-gamma receptors and pharmacologic PPAR-gamma inhibitors. Moreover, activation of PPAR-gamma by ligands increased plasminogen activator inhibitor-1 and decreased uPA levels in pancreatic cancer cells, and this was accompanied by a reduction in total urokinase activity. The present study shows that the plasminogen activator system plays an integral role in pancreatic cancer cell invasion in vitro. Activation of the nuclear receptor PPAR-gamma by ligands reduced pancreatic cancer cell invasion, which was largely mediated by modulation of the plasminogen activator system. These findings further underscore the potential role of PPAR-gamma ligands as therapeutic agents in pancreatic cancer.