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PubMed2006

Agonists of peroxisome proliferators-activated receptors (PPAR) alpha, beta/delta or gamma reduce transforming growth factor (TGF)-beta-induced proteoglycans' production in chondrocytes.

OBJECTIVE: To investigate the potency of selective agonists of peroxisome proliferators-activated receptors' (PPAR) isotypes (alpha, beta/delta or gamma) to modulate the stimulating effect of transforming growth factor-beta1 (TGF-beta1) on proteoglycans' (PGs) synthesis in chondrocytes. METHOD: Rat chondrocytes embedded in alginate beads and cultured under low serum conditions were exposed to TGF-beta1 (10 ng/ml), alone or in combination with the following agonists: Wy14643 for PPARalpha, GW501516 for PPARbeta/delta, rosiglitazone (ROSI) for PPARgamma, in the presence or absence of PPAR antagonists (GW6471 for PPARalpha, GW9662 for PPARgamma). PGs' synthesis was evaluated by radiolabelled sulphate incorporation and glycosaminoglycans' (GAGs) content by Alcian blue staining of beads and colorimetric 1.9 dimethyl-methylene blue assay after beads' solubilization. Phosphorylation of Extracellular Signal-related Kinase1/2 (ERK1/2), Smad2/3 and p38-MAPK was assessed by Western Blot and production of prostaglandin E2 (PGE2) by Enzyme immuno-assay (EIA). Levels of mRNA for PPAR target genes [acyl-CoA oxidase (ACO) for PPARalpha; mitochondrial carnitin palmitoyl transferase-1 (CPT-1) for PPARbeta/delta and adiponectin for PPARgamma], aggrecan, TGF-beta1 and genes controlling GAGs' side chains' synthesis were quantified by real time polymerase chain reaction and normalized over RP29 housekeeping gene. RESULTS: ACO was selectively up-regulated by 100 microM of Wy14643, CPT-1 by 100 nM of GW501516 and adiponectin by 10 microM of ROSI without cell toxicity. TGF-beta1 increased PGs' synthesis by four-fold, GAGs' content and deposition by 3.5-fold and six-fold, respectively, while inducing aggrecan expression around 10-fold without modifying mRNA levels of GAGs' controlling enzymes. PPAR agonists inhibited the stimulating effect of TGF-beta1 by 24-44% on PGs' synthesis and over 75% on aggrecan, GAGs' content and deposition with the following rank order of potency: ROSI>GW501516> or =Wy14643. TGF-beta1-induced phosphorylation of Smad2/3 and ERK1/2 was reduced by ROSI over GW501516 but not by Wy14643 whereas stimulated PGE2 production was inhibited by Wy14643 over GW501516 but not by ROSI. The effect of PPAR agonists on PPAR target genes and TGF-beta1-induced aggrecan expression was reversed selectively by PPAR antagonists. CONCLUSION: In chondrocytes' beads, PPAR agonists reduced the stimulating effect of TGF-beta1 on PGs by inhibiting TGF-beta1-induced aggrecan expression in an isotype-selective manner. Thus, PPAR agonists could be deleterious in situation of cartilage repair although being protective in situation of cartilage degradation.

Animals↗
PubMed2003

Oleylethanolamide regulates feeding and body weight through activation of the nuclear receptor PPAR-alpha.

Oleylethanolamide (OEA) is a naturally occurring lipid that regulates satiety and body weight. Although structurally related to the endogenous cannabinoid anandamide, OEA does not bind to cannabinoid receptors and its molecular targets have not been defined. Here we show that OEA binds with high affinity to the peroxisome-proliferator-activated receptor-alpha (PPAR-alpha), a nuclear receptor that regulates several aspects of lipid metabolism. Administration of OEA produces satiety and reduces body weight gain in wild-type mice, but not in mice deficient in PPAR-alpha. Two distinct PPAR-alpha agonists have similar effects that are also contingent on PPAR-alpha expression, whereas potent and selective agonists for PPAR-gamma and PPAR-beta/delta are ineffective. In the small intestine of wild-type but not PPAR-alpha-null mice, OEA regulates the expression of several PPAR-alpha target genes: it initiates the transcription of proteins involved in lipid metabolism and represses inducible nitric oxide synthase, an enzyme that may contribute to feeding stimulation. Our results, which show that OEA induces satiety by activating PPAR-alpha, identify an unexpected role for this nuclear receptor in regulating behaviour, and raise possibilities for the treatment of eating disorders.

Animals↗
PubMed1994

Dexamethasone and insulin demonstrate marked and opposite regulation of the steady-state mRNA level of the peroxisomal proliferator-activated receptor (PPAR) in hepatic cells. Hormonal modulation of fatty-acid-induced transcription.

Fatty acids and the peroxisomal proliferator, 3-tetradecylthioacetic acid (TTA) stimulate transcription of peroxisomal beta-oxidation enzymes. Recently, we have shown that their actions are markedly modulated by dexamethasone and insulin which show synergistic and inhibitory effects, respectively. In this study, we describe the regulation of the peroxisomal proliferator-activated receptor (PPAR), a member of the steroid-hormone-receptor superfamily, in a similar manner by hormones and fatty acids, supporting the hypothesis that PPAR may act as a ligand-activated transcription factor. Northern-blot analysis of steady-state mRNA levels revealed three different specific transcripts for PPAR of 10.2, 4.6 and 1.8 kb, and the former two being regulated in hepatic tissue, hepatocytes and hepatoma cells. Dexamethasone produced a pronounced overall stimulatory effect (15.3-fold) in rat hepatocytes, while insulin blocked this action completely. Minor inductions of PPAR mRNA (up to twofold induction) were observed when different fatty acids were administrated alone. However, in combination with dexamethasone, additive or synergistic actions, mounting to 24-fold stimulation, were observed, while insulin always exerted an over-riding down-regulatory effect. In non-fasting rats receiving dexamethasone, elevation of serum insulin, a slight increase in serum free fatty acids accompanied by PPAR mRNA level increases of 2.4-fold and stimulation of liver peroxisomal acyl-CoA oxidase mRNA were observed. Our results suggest that PPAR mRNA expression is under strict hormonal control and that the fatty acids and hormones affect PPAR mRNA levels in a manner analogous to the regulation of the peroxisomal beta-oxidation enzymes. The PPAR gene-regulating unit apparently contains hormone-response elements (HRE) for dexamethasone and insulin, which are thus functionally important for PPAR transcription in liver cells, making a significant enhancement or inhibition of the physiological actions of fatty acids possible.

Acyl-CoA Oxidase↗
PubMed2003

Role of PPAR-gamma ligands in neuroprotection against glutamate-induced cytotoxicity in retinal ganglion cells.

PURPOSE: The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is the target of the insulin sensitizing thiazolidinediones (TZDs), a class of drugs used in the treatment of type 2 diabetes mellitus. Glaucoma and other retinal disorders are some of the major complications in diabetes. In the present study, the role that PPAR-gamma ligands play in protecting retinal ganglion cells (RGC-5) against glutamate insult was explored. METHODS: Transformed rat RGC (RGC-5 cells) and two PPAR-gamma agonists, 15-deoxy-D(12,14)-prostaglandin J2 (15d-PGJ2) and troglitazone were used. RGC-5 cells were incubated with either of the PPAR-gamma ligands and were exposed to either L-glutamic acid or buthionine sulfoximine (BSO). Cell viability was determined with the neutral red dye uptake assay. Levels of PPAR-gamma receptor proteins were monitored by immunoblot analysis. RESULTS: Glutamate treatment resulted in RGC-5 cell death, and both 15d-PGJ2 and troglitazone protected the RGC-5 cells from glutamate cytotoxicity. The neuroprotective concentrations of both compounds ranged from approximately 1 to 5 micro M. Troglitazone further protected against BSO toxicity, whereas 15d-PGJ2 did not. Glutamate treatment appears to exert its cytotoxicity through oxidative damage, because pretreatment of RGC-5 cells with the antioxidants N-acetyl cysteine (NAC) and thiourea resulted in the reversal of glutamate cytotoxicity. Furthermore, the glutamate effect was not reversed by pretreatment with MK801 or DL-threo-betabenzyloxyaspartate (DL-TBOA), suggesting that glutamate cytotoxicity is not mediated through the NMDA receptor and/or glutamate transporter, respectively. Levels of PPAR-gamma receptor protein did not show any appreciable change in response to glutamate exposure, with or without 15d-PGJ2 or troglitazone. CONCLUSIONS: Two PPAR-gamma ligands, 15d-PGJ2 and troglitazone, protect RGC-5, an established transformed rat retinal ganglion cell line, against glutamate cytotoxicity. The neuroprotective effects of the two compounds appear to be mediated through an antioxidant rather than a PPAR-gamma-dependent pathway. These results suggest that PPAR-gamma agonists, in addition to improving insulin sensitivity, may also provide a valuable antioxidant benefit that could prove valuable in targeting ocular complications including glaucoma.

Animals↗
PubMed2000

Improved insulin-sensitivity in mice heterozygous for PPAR-gamma deficiency.

The thiazolidinedione class of insulin-sensitizing, antidiabetic drugs interacts with peroxisome proliferator-activated receptor gamma (PPAR-gamma). To gain insight into the role of this nuclear receptor in insulin resistance and diabetes, we conducted metabolic studies in the PPAR-gamma gene knockout mouse model. Because homozygous PPAR-gamma-null mice die in development, we studied glucose metabolism in mice heterozygous for the mutation (PPAR-gamma(+/-) mice). We identified no statistically significant differences in body weight, basal glucose, insulin, or FFA levels between the wild-type (WT) and PPAR-gamma(+/-) groups. Nor was there a difference in glucose excursion between the groups of mice during oral glucose tolerance test, but insulin concentrations of the WT group were greater than those of the PPAR-gamma(+/-) group, and insulin-induced increase in glucose disposal rate was significantly increased in PPAR-gamma(+/-) mice. Likewise, the insulin-induced suppression of hepatic glucose production was significantly greater in the PPAR-gamma(+/-) mice than in the WT mice. Taken together, these results indicate that - counterintuitively - although pharmacological activation of PPAR-gamma improves insulin sensitivity, a similar effect is obtained by genetically reducing the expression levels of the receptor.

Animals↗
PubMed2003

Anti-inflammatory and antiproliferative actions of PPAR-gamma agonists on T lymphocytes derived from MS patients.

Peroxisomal proliferator-activated receptors (PPARs) belong to a nuclear receptor superfamily of ligand-activated transcription factors. The PPAR-gamma isoform is expressed in human T lymphocytes, and oral administration of PPAR-gamma agonists ameliorates the clinical course and histopathological features in experimental autoimmune encephalomyelitis, an animal model for multiple sclerosis, suggesting a potential role for PPAR-gamma agonists in the treatment of autoimmune diseases. To assess a potential therapeutic role of PPAR-gamma agonists in multiple sclerosis, we compared the immunomodulatory effects of the thiazolidinedione (TZD) drugs pioglitazone (PIO) and ciglitazone and the non-TZD PPAR-gamma agonist GW347845 on human T leukemia cells (Jurkat cells) and phytohemagglutinin (PHA)-stimulated peripheral blood mononuclear cells (PBMCs) derived from 21 multiple sclerosis patients and 12 healthy donors. PIO, ciglitazone, and GW347845 suppressed PHA-induced T cell proliferation by 40-50% and secretion of interferon-gamma and tumor necrosis factor alpha, by 30-50%. Inhibition of proliferation was increased to approximately 80% and that of proinflammatory cytokine secretion, to 80-90% when PBMCs were first preincubated with PPAR-gamma agonists and re-exposed at the time of PHA stimulation, indicating a sensitizing effect of PPAR-gamma agonists. Inhibition of proliferation was also observed in the tetanus toxoid-specific T cell line KHS.TT2, albeit to a lesser extent. The antiproliferative effects of PIO and GW347845 were accompanied by a decrease of cell viability. Electron microscopy and Western blot analysis revealed DNA condensation and down-regulation of bcl-2, suggesting the induction of apoptosis in activated T lymphocytes. In summary, the data support the potential use of PPAR-gamma agonists as immunomodulatory, therapeutic agents for autoimmune diseases.

Adjuvants, Immunologic↗
PubMed2002

The activity of PPAR gamma in primary human trophoblasts is enhanced by oxidized lipids.

The ligand-dependent nuclear receptor PPAR gamma plays an important role in murine and human trophoblast differentiation. Oxidized lipids, which are implicated in the pathophysiology of placental dysfunction, have recently been identified as ligands for PPAR gamma. We therefore hypothesized that oxidized lipids activate PPAR gamma in human trophoblasts and influence placental function. To test our hypothesis, we examined the effect of 9S-hydroxy-10E,12Z-octadecadienoic acid (9-HODE), 13S-hydroxy-9Z,11E-octadecadienoic acid (13-HODE), and 15S-hydroxy-5Z,8Z,11Z,13E-eicosatetraenoic acid (15-HETE) on PPAR gamma activity in cultured term human trophoblasts. Our results demonstrate that these lipids stimulate PPAR gamma activity and that the AF-2 fragment, which harbors the ligand-binding domain of PPAR gamma, mediates this effect. Furthermore, we assessed the consequences of PPAR gamma activation by the oxidized lipids, and we found that these lipids stimulate human CG production, a measure of trophoblast differentiation. In contrast, the expression of syncytin, a marker for syncytium formation as well as the expression of the cell cycle modulators cyclin E and p27 are unchanged by the oxidized lipids. We concluded that 9-HODE, 13-HODE, and 15-HETE activate PPAR gamma in primary human trophoblasts. These PPAR gamma ligands may play a role in placental differentiation, yet they are unlikely to contribute to trophoblast dysfunction.

Cell Differentiation↗
PubMed2002

Experimental approaches to study PPAR gamma agonists as antidiabetic drugs.

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors that are related to retinoid, steroid and thyroid hormone receptors. Since PPARs appear to be closely involved in the regulation of dietary fat storage and catabolism, they have been established as an important target for the treatment of type 2 diabetes and other disorders associated with the high intake of dietary fat. Thiazolidinediones (TZDs) were the first class of compounds to be identified as PPAR gamma-ligands, constituting a new class of antidiabetic drugs that have recently been introduced as therapeutic agents for the treatment of type 2 diabetes mellitus by acting as insulin sensitizers. These compounds improve insulin resistance by increasing cell sensitivity to insulin. In fact, PPAR gamma agonists increase peripheral insulin sensitivity by increasing the transcription of genes, which, in turn, increase glucose uptake, also improving insulin-stimulated glucose disposal in muscle. PPAR gamma agonists increase insulin signaling, reduce circulating levels of free fatty acids and stimulate adipocyte differentiation, thus favoring the formation of smaller, more insulin-sensitive adipocytes. TZDs have been proven effective in different experimental models to evaluate their effectiveness as an antidiabetic agent, and the involvement of PPAR gamma in the pharmacological effects of these compounds has been supported by studies showing an excellent correlation between the hypoglycemic action of these drugs and their affinity for PPAR gamma. Despite this evidence, the site of action and the molecular mechanism of TZDs remain unclear. The aim of the present article was to review and discuss the most relevant pharmacological studies performed in the search for establishing the mechanism of action of antidiabetic TZDs and related compounds acting as PPAR gamma agonists, as well as to summarize those representative experimental approaches currently used to evaluate PPAR gamma agonists as therapeutic agents for the treatment of insulin-resistant type 2 diabetes mellitus.

Animals↗
PubMed2001

Control of vascular cell proliferation and migration by PPAR-gamma: a new approach to the macrovascular complications of diabetes.

Compared with nondiabetic subjects, type 2 diabetic individuals are at an increased risk for coronary artery disease and coronary restenosis after angioplasty or stenting. Increased proliferation and migration of vascular smooth muscle cells (VSMCs) contribute importantly to the formation of both atherosclerotic and restenotic lesions. Therefore, pharmaceutical interventions targeting proteins that regulate VSMC growth or movement are a promising new approach to treat diabetes-associated cardiovascular disease. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a member of the nuclear receptor superfamily that, when activated by thiazolidinedione (TZD) insulin sensitizers, regulates a host of target genes. All of the major cells in the vasculature express PPAR-gamma, including endothelial cells, VSMCs, and monocytes/macrophages. PPAR-gamma is present in intimal macrophages and VSMCs in early human atheromas. In an animal model of vascular injury; PPAR-gamma levels are substantially elevated in the neointima that forms after mechanical injury of the endothelium. Recent experimental studies provide evidence that PPAR-gamma may function to protect the vasculature from injury. Cell culture studies have shown that TZD PPAR-gamma ligands inhibit both the proliferation and migration of VSMCs. These antiatherogenic activities of PPAR-gamma may also occur in vivo, because TZDs inhibit lesion formation in several animal models. PPAR-gamma ligands may also protect the vasculature indirectly by normalizing metabolic abnormalities of the diabetic milieu that increase cardiovascular risk. Activation of PPAR-gamma, newly defined in vascular cells, may be a useful approach to protect the vasculature in diabetes.

Blood Vessels↗
PubMed2001

Effect of a pharmacological activation of PPAR on the expression of RAR and TR in rat liver.

It has recently been shown that high-fat diets induce the expression of peroxisome proliferator-activated receptor (PPAR) with a concomitant decrease in expression of retinoic acid (RAR) and triiodothyronine (TR) receptors in rat liver. The authors have suggested that PPAR activation may be responsible for these modifications in nuclear receptor expression. With the aim of gaining further insight into a possible relationship between the patterns of expression of these receptors, we have examined, using a pharmacological model, the effect of a strong and specific PPAR activation induced by bezafibrate, a peroxisome proliferator agent. Activation of PPAR was evaluated by quantifying PPAR alpha mRNA and acyl-CoA oxidase mRNA. The expression of RAR and TR was determined by assaying the binding properties of these nuclear receptors and by quantifying the mRNA level of RAR beta and TR alpha1,beta1 isoforms. After a 10 day treatment of young rats, induction of PPAR (PPAR alpha mRNA was increased by 40% [P< 0.05 and acyl-CoA oxidase mRNA by 411% [P<0.001]) and a concomitant decrease of RAR and TR expression (Maximal Binding Capacity was decreased by 21 and 26%, respectively [P<0.05]) in the liver was observed. RXR alpha mRNA expression was unchanged by treatment. Cross-talk between RAR, TR and PPAR signalling pathways may be implicated in the new patterns of nuclear receptor expression observed. The decreased expression of RAR and TR reported here could provide a novel element for the understanding of the link between PPAR and tumorigenesis in rat liver.

Acyl-CoA Oxidase↗
PubMed2005

[Nuclear Receptor PPARs and magnesium].

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors that are activated by fatty acids and their derivatives. PPARs consist of three isotypes named PPAR alpha (NR1C1), PPAR beta/delta (NR1C2) and PPAR gamma (NR1C3) in vertebrates. Each of them is encoded in a separate gene and binds fatty acids and eicosanoids. Although each isotype fulfills distinct functions, PPARs function not only as an important fatty acid sensor that regulate lipid, carbohydrate and amino acid metabolism but also play an important role in various signaling pathways (immunity, inflammation, apoptosis and cell differentiation). Dysfunction of PPAR-mediated signals leads to various diseases such as diabetes, obese, hyperlipidemia, inflammation and cancer. Importantly, magnesium appears to play a pivotal role in regulating the PPAR-mediated signaling pathways as a key cofactor in the protein phosphorylation. Therefore, restrict control of magnesium concentration in the body appears to be very important for protection for these diseases. In this review, I focus on emerging knowledge about relationship between PPAR-mediated signals and magnesium.

Animals↗
PubMed1996

Role of the peroxisome proliferator-activated receptor (PPAR) in mediating the effects of fibrates and fatty acids on gene expression.

The three types of peroxisome proliferator-activated receptors (PPAR), termed alpha, delta (or beta), and gamma, belong to the nuclear receptor superfamily. 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 that also binds thiazolidinedione antidiabetic agents with high affinity. PPARs heterodimerize with retinoic X receptor (RXR) and alter the transcription of target genes after binding to response elements or PPREs, consisting of a direct repeat of the nuclear receptor hexameric DNA recognition motif (PuGGTCA) spaced by 1 nucleotide (DR-1). Upon activation by fatty acids (FAs) and drugs that affect lipid metabolism, PPARs control the expression of genes implicated in intra- and extracellular lipid metabolism, most notably those involved in peroxisomal beta-oxidation. PPARs partially mediate the inductive effects of fibrates and fatty acids on high density lipoprotein (HDL) cholesterol levels by regulating the transcription of the major HDL apolipoproteins, apoA-I and apoA-II. The hypotriglyceridemic action of fibrates and certain fatty acids also involves PPAR and is constituted of: 1) increased hydrolysis of plasma triglycerides due to induction of LPL and reduction of apoC-III expression; 2) stimulation of cellular fatty acid uptake and conversion to acyl-CoA derivatives due to increased expression of genes for fatty acid transport protein and acyl-CoA synthetase; 3) increased peroxisomal and mitochondrial beta-oxidation; and 4) decreased synthesis of fatty acids and triglycerides and decreased production of very low density lipoprotein (VLDL). Hence, both enhanced catabolism of triglyceride-rich particles and reduced secretion of VLDL particles contribute to the hypolipidemic effect of fibrates and fatty acids. Finally, PPARs appear to be involved in differentiation processes because activation of PPAR gamma 2 triggers adipocyte differentiation and stimulates expression of several genes critical to adipogenesis. It is suggested that PPARs are key messengers responsible for the translation of nutritional and pharmacological stimuli into changes in gene expression and differentiation pathways.

Adipocytes↗
PubMed2006

Functions of the peroxisome proliferator-activated receptor (PPAR) alpha and beta in skin homeostasis, epithelial repair, and morphogenesis.

The three peroxisome proliferator-activated receptors (PPAR alpha, PPAR beta, and PPAR gamma) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. They are regarded as being sensors of physiological levels of fatty acids and fatty acid derivatives. In the adult mouse skin, they are found in hair follicle keratinocytes but not in interfollicular epidermis keratinocytes. Skin injury stimulates the expression of PPAR alpha and PPAR beta at the site of the wound. Here, we review the spatiotemporal program that triggers PPAR beta expression immediately after an injury, and then gradually represses it during epithelial repair. The opposing effects of the tumor necrosis factor-alpha and transforming growth factor-beta-1 signalling pathways on the activity of the PPAR beta promoter are the key elements of this regulation. We then compare the involvement of PPAR beta in the skin in response to an injury and during hair morphogenesis, and underscore the similarity of its action on cell survival in both situations.

Animals↗
PubMed2004

Mitochondrial dysfunction by synthetic ligands of peroxisome proliferator activated receptors (PPARs).

PPARs are a class of nuclear receptors involved in lipid and glucidic metabolism, immune regulation and cell differentiation. This spectrum of biological activities stimulated pharmacological research to synthetize different molecules with PPARs binding activity with beneficial therapeutic effects. As a matter of fact, some synthetic PPAR-ligands have been already employed in pharmacotherapy: PPAR-alpha ligands, such as fibrates, are used in hyperlipidemias and thiazolidinediones, mainly PPAR-gamma ligands, are employed as insulin sensitizers. However, both classes of drugs showed pharmacotoxicological profiles which cannot be fully ascribed to activation of their specific receptors and which are causing a growing incidence of dramatic side effects (rhabdomyolysis, acute liver failure, heart failure, etc.). A re-evaluation of the biological activities of PPAR synthetic ligands, in particular of the mitochondrial dysfunction based on a rotenone-like Complex I partial inhibition and of its consequent metabolic adaptations, seems to explain some of the pathophysiologic aspects of PPARs allowing a better definition of the therapeutic properties of the so-called PPAR-ligands.

Animals↗
PubMed2004

PPAR-gamma overexpression selectively suppresses insulin secretory capacity in isolated pancreatic islets through induction of UCP-2 protein.

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) regulates several cellular functions, but its physiological role in pancreatic islet cells remains to be investigated. In this study, we confirmed the presence of PPAR-gamma in rat isolated islets and examined its role on insulin and glucagon secretion by using PPAR-gamma-overexpressed islets. PPAR-gamma overexpression significantly suppressed insulin secretion induced by stimulatory concentration of glucose (p<0.05). In addition, insulin secretion evoked by high potassium depolarization also was significantly decreased from PPAR-gamma-overexpressed islets (p<0.05). On the other hand, no significant change in glucagon release was observed after high potassium depolarization between PPAR-gamma-overexpressed and control islets. Insulin and glucagon content in islets was not statistically different between the two groups. In addition, the expression of uncoupling protein-2 (UCP-2) was found to be induced in PPAR-gamma-overexpressed islets. This result clearly indicates that the deteriorative effect of PPAR-gamma overexpression on the secretory machinery is selective for pancreatic beta-cells. And it is possible that its site of action can be located in the energy-consuming exocytotic process of insulin secretory granules, and that the reduction of ATP production through increased UCP-2 reduces insulin exocytosis.

Adenosine Triphosphate↗
PubMed2004

Peroxisome proliferator-activated receptor (PPAR)-alpha: a pharmacological target with a promising future.

Peroxisome proliferator-activated receptor (PPAR)-alpha is a ligand-activated transcriptional factor that belongs to the family of nuclear receptors. PPAR-alpha regulates the expression of genes involved in fatty acid beta-oxidation and is a major regulator of energy homeostasis. Fibrates are PPAR-alpha agonists and have been used to treat dyslipidemia for several decades because of their triglyceride (TG) lowering and high-density lipoprotein cholesterol (HDL-C) elevating effects. More recent research has demonstrated anti-inflammatory and anti-thrombotic actions of PPAR-alpha agonists in the vessel wall as well. Thus, PPAR-alpha agonists decrease the progression of atherosclerosis by modulating metabolic risk factors and by their anti-inflammatory actions on the level of the vascular wall. This is confirmed by several clinical studies, in which fibrates have shown to reduce atherosclerotic plaque formation and the event rate of coronary heart disease (CHD), especially in patients suffering from metabolic syndrome (MS). MS is characterized by a group of metabolic risk factors that include obesity, raised blood pressure, dyslipidemia, insulin resistance or glucose intolerance, and a prothrombotic state, and its incidence in the Western world is rising to epidemic proportions. This review paper will focus on the functions of PPAR-alpha in fatty acid beta-oxidation, lipid metabolism, and vascular inflammation. Furthermore, PPAR-alpha genetics, the clinical use of PPAR-alpha activators and their future perspective will be discussed.

Arteriosclerosis↗
PubMed2005

EPA and DHA reduce LPS-induced inflammation responses in HK-2 cells: evidence for a PPAR-gamma-dependent mechanism.

BACKGROUND: Recent studies have shown that fish oil, containing omega-3 polyunsaturated fatty acids (omega-3 PUFAs) eicosapentaenoic acid (EPA) (C20:5 omega 3), and docosahexaenoic acid (DHA) (C22:6 omega 3) retard the progression of renal disease, especially in IgA nephropathy (IgAN). Despite increasing knowledge of the beneficial effects of fish oils, little is known about the mechanisms of action of omega-3 PUFAs. It has been reported that activation of peroxisome proliferator-activated receptors (PPARs) inhibits production of proinflammatory cytokines. Both EPA and DHA have been shown to activate PPARs. The aim of this study was to examine if omega-3 PUFAs have anti-inflammatory effects via activation of PPARs in human renal tubular cells. METHODS: An immortalized human proximal tubular cell line [human kidney-2 (HK-2) cells] was used in all experiments. Conditioned media was collected from omega-3 PUFAs- treated cells and subjected to enzyme-linked immunosorbent assay (ELISA). Total cellular RNA was isolated from the above cells for real-time quantitative polymerase chain reaction (PCR). Nuclear Extracts were prepared from the HK-2 cells for transcription factor activation assay. RESULTS: Both EPA and DHA at 10 micromol/L and 100 micromol/L concentrations effectively decreased lipopolysaccharide (LPS)-induced nuclear factor-kappaB (NF-kappaB) activation and monocyte chemoattractant protein-1 (MCP-1) expression. EPA and DHA also increased both PPAR-gamma mRNA and protein activity (two- to threefold) in HK-2 cells. A dose of 100 micromol/L bisphenol A diglycidyl ether (BADGE) abolished the PPAR-gamma activation induced by both EPA and DHA and removed the inhibitory effect of EPA and DHA on LPS-induced NF-kappaB activation in HK-2 cells. Overexpression of PPAR-gamma further inhibited NF-kappaB activation compared to the control cells in the presence of EPA and DHA. CONCLUSION: Our data demonstrate that both EPA and DHA down-regulate LPS-induced activation of NF-kappaB via a PPAR-gamma-dependent pathway in HK-2 cells. These results suggest that PPAR-gamma activation by EPA and DHA may be one of the underlying mechanisms for the beneficial effects of fish oil.

Benzhydryl Compounds↗
PubMed2006

Troglitazone and pioglitazone interactions via PPAR-gamma-independent and -dependent pathways in regulating physiological responses in renal tubule-derived cell lines.

Troglitazone (Tro) and pioglitazone (Pio) activation of peroxisome proliferator-activated receptor (PPAR)-gamma and PPAR-gamma-independent pathways was studied in cell lines derived from porcine renal tubules. PPAR-gamma-dependent activation of PPAR response element-driven luciferase gene expression was observed with Pio at 1 microM but not Tro at 1 microM. On the other hand, PPAR-gamma-independent P-ERK activation was observed with 5 microM Tro but not with Pio (5-20 microM). In addition, Pio (1-10 microM) increased metabolic acid production and activated AMP-activated protein kinase (AMPK) associated with decreased mitochondrial membrane potential, whereas Tro (1-20 microM) did not. These results are consistent with three pathways through which glitazones may act in effecting metabolic processes (ammoniagenesis and gluconeogenesis) as well as cellular growth: 1) PPAR-gamma-dependent and PPAR-gamma-independent pathways, 2) P-ERK activation, and 3) mitochondrial AMPK activation. The pathways influence cellular acidosis and glucose and glutamine metabolism in a manner favoring reduced plasma glucose in vivo. In addition, significant interactions can be demonstrated that enhance some physiological processes (ammoniagenesis) and suppress others (ligand-mediated PPAR-gamma gene expression). Our findings provide a model both for understanding seemingly opposite biological effects and for enhancing therapeutic potency of these agents.

Animals↗