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PubMed2006

Aspirin and PPAR-alpha activators inhibit monocyte chemoattractant protein-1 expression induced by high glucose concentration in human endothelial cells.

Activated endothelial cells express monocyte chemoattractant protein-1 (MCP-1), a chemokine which is reportedly involved in the recruitment of plasma monocytes in the early stages of atherosclerosis. Since accelerated atherosclerosis is the main complication of diabetes and both diseases encompass an inflammatory reaction, we hypothesized that the anti-inflammatory drugs, aspirin and peroxisome proliferator-activated receptor (PPAR-alpha) activators (fenofibrate and clofibrate), could have an effect on the high glucose-induced MCP-1 expression in endothelial cells. To test this assumption, as well as the possible mechanisms involved, the MCP-1 expression and secretion, the reactive oxygen species levels, nuclear factor-kB (NF-kB) and activator protein-1 (AP-1) expression were determined in human endothelial cells exposed to high glucose concentrations in the presence of aspirin, fenofibrate and clofibrate. Human endothelial cells kept in normal glucose concentration in the absence of drugs were used as control. The results showed that (i) aspirin, fenofibrate and clofibrate decrease significantly the MCP-1 expression and secretion in human endothelial cells; (ii) the high glucose up-regulated expression of MCP-1 in endothelial cells was significantly reduced by inhibitors of NF-kB and reactive oxygen species; (iii) all drugs notably decrease the level of the reactive oxygen species and activation of NF-kB and AP-1. Together, the findings indicate that in endothelial cells aspirin and PPAR-alpha activators reduce the high glucose-increased expression of MCP-1 by a mechanism that includes the inhibition of reactive oxygen species, and decrease of AP-1 and NF-kB activation.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2005

Isoform specific changes in PPAR alpha and beta in colon and breast cancer with differentiation.

To investigate the role of peroxisome proliferator-activated receptors (PPARs) alpha and beta in the differentiation of colon cancer cells, we differentiated HT-29 cells using sodium butyrate (NaB) and culturing post-confluence and assessed differentiation using the marker intestinal alkaline phosphatase. While PPARalpha levels only changed with culturing post confluence, PPARbeta levels increased independent of the method of differentiation. To explore further the differences induced by NaB, we assessed changes in both PPAR isoforms in MCF-7 breast cancer cells cultured in the presence of NaB over 48h. Again a very different expression pattern was observed with PPARalpha increasing after 4h and remaining elevated, while PPARbeta increased transiently. Our studies suggest that the expression of PPARs is dependent upon both the method of differentiation and on time. Moreover, these studies show that changes in PPARalpha levels are not required for the differentiation of colon cancer cell lines, whereas changes in PPARbeta are more closely associated with differentiation.

Breast Neoplasms↗
PubMed2001

The role of PPAR alpha in obesity.

Obesity is a rapidly increasing health problem in all developed countries. Overweight rarely occurs in isolation but as part of a complex pattern of metabolic abnormalities ("metabolic syndrome" or "syndrome X") consisting of hyperlipidemia, hypoalphalipoproteinemia, type II diabetes and atherosclerosis. The disorder is considerably influenced by genetic, behavioural and nutritional factors. Recent data indicate that a group of closely related nuclear receptors, the peroxisome proliferator-activated receptors (PPARs), may be involved in the metabolic changes ultimately leading to obesity. This review summarises the latest developments in the PPAR field, with particular emphasis being placed on the physiological function of PPAR alpha during various nutritional states, and the possible role of PPAR alpha in obesity.

Animals↗
PubMed2005

Peroxisome proliferator-activated receptor (PPAR)alpha activation increases adiponectin receptors and reduces obesity-related inflammation in adipose tissue: comparison of activation of PPARalpha, PPARgamma, and their combination.

We examined the effects of activation of peroxisome proliferator-activated receptor (PPAR)alpha, PPARgamma, and both of them in combination in obese diabetic KKAy mice and investigated the mechanisms by which they improve insulin sensitivity. PPARalpha activation by its agonist, Wy-14,643, as well as PPARgamma activation by its agonist, rosiglitazone, markedly improved insulin sensitivity. Interestingly, dual activation of PPARalpha and -gamma by a combination of Wy-14,643 and rosiglitazone showed increased efficacy. Adipocyte size in Wy-14,643-treated KKAy mice was much smaller than that of vehicle- or rosiglitazone-treated mice, suggesting that activation of PPARalpha prevents adipocyte hypertrophy. Moreover, Wy-14,643 treatment reduced inflammation and the expression of macrophage-specific genes in white adipose tissue (WAT). Importantly, Wy-14,643 treatment upregulated expression of the adiponectin receptor (AdipoR)-1 and AdipoR2 in WAT, which was decreased in WAT of KKAy mice compared with that in nondiabetic control mice. Furthermore, Wy-14,643 directly increased expression of AdipoRs and decreased monocyte chemoattractant protein-1 expression in adipocytes and macrophages. Rosiglitazone increased serum adiponectin concentrations and the ratio of high molecular weight multimers of adiponectin to total adiponectin. A combination of rosiglitazone and Wy-14,643 increased both serum adiponectin concentrations and AdipoR expression in WAT. These data suggest that PPARalpha activation prevents inflammation in WAT and that dual activation of PPARalpha and -gamma enhances the action of adiponectin by increasing both adiponectin and AdipoRs, which can result in the amelioration of obesity-induced insulin resistance.

Animals↗
PubMed2003

Reduction of all-trans-retinal in the mouse liver peroxisome fraction by the short-chain dehydrogenase/reductase RRD: induction by the PPAR alpha ligand clofibrate.

The mouse liver 16,000 g fraction, which contains peroxisomes, reduces all-trans-retinal, but has limited ability to dehydrogenate retinol enzymatically. Feeding mice for 2 weeks with a diet containing clofibrate (0.5%, w/w), a PPAR alpha ligand and peroxisome proliferator, increased the 16,000 g fraction approximately 2-fold in protein, approximately 2-fold in specific activity of retinal reduction, and approximately 4-fold in retinal reductase units compared to controls, and caused a 50% decrease in liver retinol. An increase in both reductase specific activity and units indicates that clofibrate/PPAR alpha induced expression of retinal-reducing enzymes(s), in addition to increasing reductase(s) content. We expressed a cDNA from the NCBI data bank that encodes a peroxisome short-chain dehydrogenase/reductase. The enzyme, mouse retinal reductase (RRD, also known as human 2,4-dienoyl-CoA reductase), reduces all-trans-retinal [V(m) = 40 nmol min(-1) (mg of protein)(-1); K(0.5) = 2.3 microM] and has 4- and 60-fold less activity with 13-cis-retinal and 9-cis-retinal, respectively. Recombinant RRD functions with both unbound and CRBP(I) (cellular retinol-binding protein)-bound retinal, but apo-CRBP(I) inhibits the reductase. RRD mRNA expression was initiated on embryo day 7. Most adult tissues assayed expressed the mRNA. Liver, kidney, and heart had the most intense expression, with much less intense expression in brain, spleen, and lung. Clofibrate feeding increased the amount of RRD protein in the 16,000 g fraction of liver, consistent with the clofibrate-induced increase in reductase activity. These data relate retinoid metabolism, PPAR alpha, peroxisomes, and RRD, and are consistent with a further function of CRBP(I) in retinoid metabolism.

Aldehyde Oxidoreductases↗
PubMed2004

PGC-1 promotes insulin resistance in liver through PPAR-alpha-dependent induction of TRB-3.

Insulin resistance is a major hallmark in the development of type 2 diabetes, which is characterized by an impaired ability of insulin to inhibit glucose output from the liver and to promote glucose uptake in muscle. The nuclear hormone receptor coactivator PGC-1 (peroxisome proliferator-activated (PPAR)-gamma coactivator-1) has been implicated in the onset of type 2 diabetes. Hepatic PGC-1 expression is elevated in mouse models of this disease, where it promotes constitutive activation of gluconeogenesis and fatty acid oxidation through its association with the nuclear hormone receptors HNF-4 and PPAR-alpha, respectively. Here we show that PGC-1-deficient mice, generated by adenoviral delivery of PGC-1 RNA interference (RNAi) to the liver, experience fasting hypoglycemia. Hepatic insulin sensitivity was enhanced in PGC-1-deficient mice, reflecting in part the reduced expression of the mammalian tribbles homolog TRB-3, a fasting-inducible inhibitor of the serine-threonine kinase Akt/PKB (ref. 6). We show here that, in the liver, TRB-3 is a target for PPAR-alpha. Knockdown of hepatic TRB-3 expression improved glucose tolerance, whereas hepatic overexpression of TRB-3 reversed the insulin-sensitive phenotype of PGC-1-deficient mice. These results indicate a link between nuclear hormone receptor and insulin signaling pathways, and suggest a potential role for TRB-3 inhibitors in the treatment of type 2 diabetes.

Animals↗
PubMed2004

Involvement of PPAR gamma co-activator-1, nuclear respiratory factors 1 and 2, and PPAR alpha in the adaptive response to endurance exercise.

Endurance exercise training induces an increase in the respiratory capacity of muscle, resulting in an increased capacity to generate ATP as well as improved efficiency of muscle contraction. Such adaptations are largely the result of a coordinated genetic response that increases mitochondrial proteins, fatty acid oxidation enzymes and the exercise- and insulin-stimulated glucose transporter GLUT4, and shifts the contractile and regulatory proteins to their more efficient isoforms. In recent years a number of the transcriptional regulators involved in this genetic response have been identified and these factors can be classified into two different groups. The first group comprises transcription factors such as nuclear respiratory factors (NRF) 1 and 2 and PPAR alpha that bind DNA in a sequence-specific manner. The second group, referred to as transcriptional co-activators, alter transcription without directly binding to DNA. The PPAR gamma co-activator (PGC) family of proteins have been identified as the central family of transcriptional co-activators for induction of mitochondrial biogenesis. PGC-1 alpha is activated by exercise, and is sufficient to produce the endurance phenotype through direct interactions with NRF-1 and PPAR alpha, and potentially NRF-2. Furthering the understanding of the activation of PGC proteins following exercise has implications beyond improving athletic performance, including the possibility of providing targets for the treatment of frailty in the elderly, obesity and diseases such as mitochondrial myopathies and diabetes.

Adaptation, Physiological↗
PubMedDate not supplied

Recent update on the PPAR alpha-null mouse.

Short-term treatment of rats and mice with peroxisome proliferators (PP) results in an increase in liver peroxisome number, marked hepatomegaly and induction of several genes encoding peroxisomal and other microsomal and mitochondrial enzymes involved in fatty acid metabolism. Chronic treatment of rodents with PP results in hepatocellular carcinoma. Species differences in PP responses have been found. For example, PP such as clofibrate and gemfibrozil, are highly effective lipid and cholesterol lowering drugs in humans but do not cause peroxisome proliferation and there is no evidence for increased liver cancers in patients receiving these drugs. A receptor, designated PP-activated receptor alpha (PPAR alpha) is capable of trans-activating reporter genes containing a PP response (PPRE), but requires the presence of both PP, 9-cis retinoic acid and another receptor called RXR alpha. However, PP may not directly bind to PPAR alpha but probably indirectly disturb cellular metabolism to liberate an endogenous ligand. Subsequent to the first identification of a PPAR alpha, other members of this receptor family were found and designated PPAR alpha, PPAR beta (also called NUC1 and PPAR delta) and PPAR gamma. The alpha form is most abundant in liver and kidney, sites of peroxisome proliferation while the other two receptors are not significantly expressed in these tissues. On the basis of tissue-specific localization and spectrum of target gene activation, the physiological function of PPAR alpha and PPAR gamma appear to be related to fatty acid metabolism and regulation of adipogenesis, respectively. To gain insight into the function of PPAR alpha and its role in the peroxisome proliferator response and hepatocellular carcinogenesis, gene targeting was used to develop a PPAR alpha-deficient mouse. These animals are resistant to the pleiotropic effects of PP and no induction of any known target gene has been found. Recent studies on the phenotypes of these mice have led to an understanding of the mechanism of action of PP. They have also provided a useful model to establish the physiological role of PPAR alpha in fatty acid homeostasis and inflammation.

Animals↗
PubMed2003

Cross-talk between peroxisome proliferator-activated receptor (PPAR) alpha and liver X receptor (LXR) in nutritional regulation of fatty acid metabolism. II. LXRs suppress lipid degradation gene promoters through inhibition of PPAR signaling.

Fatty acid metabolism is transcriptionally regulated by two reciprocal systems: peroxisome proliferator-activated receptor (PPAR) alpha controls fatty acid degradation, whereas sterol regulatory element-binding protein-1c activated by liver X receptor (LXR) regulates fatty acid synthesis. To explore potential interactions between LXR and PPAR, the effect of LXR activation on PPARalpha signaling was investigated. In luciferase reporter gene assays, overexpression of LXRalpha or beta suppressed PPARalpha-induced peroxisome proliferator response element-luciferase activity in a dose-dependent manner. LXR agonists, T0901317 and 22(R)-hydroxycholesterol, dose dependently enhanced the suppressive effects of LXRs. Gel shift assays demonstrated that LXR reduced binding of PPARalpha/retinoid X receptor (RXR) alpha to peroxisome proliferator response element. Addition of increasing amounts of RXRalpha restored these inhibitory effects in both luciferase and gel shift assays, suggesting the presence of RXRalpha competition. In vitro protein binding assays demonstrated that activation of LXR by an LXR agonist promoted formation of LXR/RXRalpha and, more importantly, LXR/PPARalpha heterodimers, leading to a reduction of PPARalpha/RXRalpha formation. Supportively, in vivo administration of the LXR ligand to mice and rat primary hepatocytes substantially decreased hepatic mRNA levels of PPARalpha-targeted genes in both basal and PPARalpha agonist-induced conditions. The amount of nuclear PPARalpha/RXR heterodimers in the mouse livers was induced by treatment with PPARalpha ligand, and was suppressed by superimposed LXR ligand. Taken together with data from the accompanying paper (Yoshikawa, T., T. Ide, H. Shimano, N. Yahagi, M. Amemiya-Kudo, T. Matsuzaka, S. Yatoh, T. Kitamine, H. Okazaki, Y. Tamura, M. Sekiya, A. Takahashi, A. H. Hasty, R. Sato, H. Sone, J. Osuga, S. Ishibashi, and N. Yamada, Endocrinology 144:1240-1254) describing PPARalpha suppression of the LXR-sterol regulatory element-binding protein-1c pathway, we propose the presence of an intricate network of nutritional transcription factors with mutual interactions, resulting in efficient reciprocal regulation of lipid degradation and lipogenesis.

ATP Binding Cassette Transporter 1↗
PubMed2004

PPAR alpha, fibrates, lipid metabolism and inflammation.

Peroxisome proliferator-activated receptors (PPARs) are lipid-activated transcription factors belonging to the nuclear receptor superfamily. Three PPAR isotypes have been characterised: alpha, beta/delta and gamma. Identification of selective ligands and gene targeting studies have allowed determination of subtype-specific functions and the therapeutic potential of these receptors. Thus, PPAR alpha plays a prominent role in several physiological processes including the control of lipid and lipoprotein metabolism, glucose homoeostasis and the inflammatory response. Here, we update the potential of PPAR alpha activation in the treatment of metabolic disorders and related cardiovascular complications.

Arteriosclerosis↗
PubMed2005

Isohumulones modulate blood lipid status through the activation of PPAR alpha.

Isohumulones derived from hops are the major bitter compounds in beer. It was recently reported that isohumulones activated peroxisome proliferator-activated receptors (PPARs) alpha and gamma in vitro and modulated glucose and lipid metabolism in vivo. In this study, we examined the effects of isomerized hop extract (IHE) primarily containing isohumulones in C57BL/6N male mice and found that such treatment increased their liver weight and reduced their plasma triglyceride and free fatty acid levels. Microarray analysis and quantitative real time PCR (QPCR) showed that IHE dose-dependently upregulated the expression of a battery of hepatic genes that are involved in microsomal omega-oxidation and peroxisomal and mitochondrial beta-oxidation. These effects were common in both genders and very similar to those found with the PPARalpha agonist, fenofibrate (FF). Moreover, these effects were not found in PPARalpha-deficient mice. Thus, our results strongly suggest that IHE intake upregulates the expression of key genes that are involved in hepatic fatty acid oxidation, and that it ameliorates the blood lipid profile by activating PPARalpha.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed2006

In vitro screening of 200 pesticides for agonistic activity via mouse peroxisome proliferator-activated receptor (PPAR)alpha and PPARgamma and quantitative analysis of in vivo induction pathway.

Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors and key regulators of lipid metabolism and cell differentiation. However, there have been few studies reporting on a variety of environmental chemicals, which may interact with these receptors. In the present study, we characterized mouse PPARalpha and PPARgamma agonistic activities of 200 pesticides (29 organochlorines, 11 diphenyl ethers, 56 organophosphorus pesticides, 12 pyrethroids, 22 carbamates, 11 acid amides, 7 triazines, 8 ureas and 44 others) by in vitro reporter gene assays using CV-1 monkey kidney cells. Three of the 200 pesticides, diclofop-methyl, pyrethrins and imazalil, which have different chemical structures, showed PPARalpha-mediated transcriptional activities in a dose-dependent manner. On the other hand, none of the 200 pesticides showed PPARgamma agonistic activity at concentrations <or =10(-5) M. To investigate the in vivo effects of diclofop-methyl, pyrethrins and imazalil, we examined the gene expression of PPARalpha-inducible cytochrome P450 4As (CYP4As) in the liver of female mice intraperitoneally injected with these compounds (< or =300 mg/kg). RT-PCR revealed significantly high induction levels of CYP4A10 and CYP4A14 mRNAs in diclofop-methyl- and pyrethrins-treated mice, whereas imazalil induced almost no gene expressions of CYP4As. In particular, diclofop-methyl induced as high levels of CYP4A mRNAs as WY-14643, a potent PPARalpha agonist. Thus, most of the 200 pesticides tested do not activate PPARalpha or PPARgamma in in vitro assays, but only diclofop-methyl and pyrethrins induce PPARalpha agonistic activity in vivo as well as in vitro.

Animals↗
PubMed2005

Skeletal muscle glycogen synthase subcellular localization: effects of insulin and PPAR-alpha agonist (K-111) administration in rhesus monkeys.

Insulin covalently and allosterically regulates glycogen synthase (GS) and may also cause the translocation of GS from glycogen-poor to glycogen-rich locations. We examined the possible role of subcellular localization of GS and glycogen in insulin activation of GS in skeletal muscle of six obese monkeys and determined whether 1) insulin stimulation during a hyperinsulinemic euglycemic clamp and/or peroxisome proliferator-activated receptor (PPAR)-alpha agonist treatment (K-111, 3 mg.kg(-1).day(-1); Kowa) induced translocation of GS and 2) translocation of GS was associated with insulin activation of GS. GS and glycogen were present in all fractions obtained by differential centrifugation, except for the cytosolic fraction, under both basal and insulin-stimulated conditions. We found no evidence for translocation of GS by insulin. GS total (GST) activity was strongly associated with glycogen content (r = 0.70, P < 0.001). Six weeks of treatment with K-111 increased GST activity in all fractions, except the cytosolic fraction, and mean GST activity, GS independent activity, and glycogen content were significantly higher in the insulin-stimulated samples compared with basal samples, effects not seen with vehicle. The increase in GST activity was strongly related to the increase in glycogen content during the hyperinsulinemic euglycemic clamp after K-111 administration (r = 0.74, P < 0.001). Neither GS protein expression nor GS gene expression was affected by insulin or by K-111 treatment. We conclude that 1) in vivo insulin does not cause translocation of GS from a glycogen-poor to a glycogen-rich location in primate skeletal muscle and 2) the mechanism of action of K-111 to improve insulin sensitivity includes an increase in GST activity without an increase in GS gene or protein expression.

Adipose Tissue↗
PubMed2004

Biochemical and morphological effects of K-111, a peroxisome proliferator-activated receptor (PPAR)alpha activator, in non-human primates.

K-111 has been characterized as a potent peroxisome proliferator-activated receptor (PPAR)alpha activator. Antidiabetic potency and amelioration of disturbed lipid metabolism were demonstrated in rodents, which were accompanied by elevations of peroxisomal enzymes and liver weight. To examine the possible therapeutic application of K-111 we have now assessed its efficacy in non-human primates with high transferability to humans. For this purpose obese, hypertriglyceridaemic, hyperinsulinaemic prediabetic rhesus monkeys were dosed sequentially with 0, 1, 3 and 10mg/kg per day orally over a period of 4 weeks each. In addition, the effect of K-111 on the peroxisome compartment was analyzed in cynomolgus monkeys using liver samples obtained following a 13-week oral toxicity study. In prediabetic monkeys, the reduction of hyperinsulinaemia and improvement of insulin-stimulated glucose uptake rate indicated amelioration of insulin resistance. These effects were nearly maximal at a dose of 3mg/kg per day, while triglycerides and body weight were lowered significantly in a dose-dependent manner. This reduction of body weight contrasts sharply with the adipogenic response observed with thiazolidinediones, another family of insulin-sensitizing agents. In young cynomolgus monkeys at a dosage of 5mg/kg per day and more, K-111 induced an up to three-fold increase in lipid beta-oxidation enzymes with an 1.5- to 2-fold increase in peroxisome volume density. This moderate increase in peroxisomal activity by K-111 in monkeys is consistent with its role as an PPARalpha activator and corresponds to the observations with fibrates in other low responder mammalian species. The increase in beta-oxidation may explain, at least in part, the lipid modulating effect as well as the antidiabetic potency of K-111. This pharmacological profile makes K-111 a highly promising drug candidate for clinical applications in the treatment of type 2 diabetes, dyslipidaemia, obesity and the metabolic syndrome.

Acyl-CoA Oxidase↗
PubMed2003

Ragaglitazar: the pharmacokinetics, pharmacodynamics, and tolerability of a novel dual PPAR alpha and gamma agonist in healthy subjects and patients with type 2 diabetes.

Ragaglitazar is a novel dual peroxisome proliferator-activated receptor (PPAR) alpha and gamma agonist intended to restore insulin sensitivity and correct diabetic dyslipidemia. These studies assessed single-dose pharmacokinetics and tolerability of ragaglitazar in healthy subjects, as well as multiple-dose pharmacokinetics, pharmacodynamics, and tolerability of ragaglitazar in healthy subjects and in patients with type 2 diabetes. Healthy subjects received a single oral dose (1-120 mg), and healthy subjects and type 2 diabetic patients received a loading dose and thereafter once-daily doses (0.5-16 mg) of ragaglitazar for 6 and 20 days, respectively. Ragaglitazar was rapidly absorbed (tmax: 1.5-1.7 h), with mean AUC0-24 h and Cmax proportional to dose after single and multiple dosing; t1/2 was 80 hours following a single dose and 104 hours in healthy subjects and 122 hours in patients after multiple dosing. Administration of 4 mg ragaglitazar to patients (n = 4) for 21 days resulted in mean decreases from baseline in fasting levels of plasma glucose (18%), C-peptide (18%), fructosamine (6%), triglycerides (36%), free fatty acids (49%), total cholesterol (11%), low-density lipoprotein (LDL) cholesterol (21%), and very low-density lipoprotein (VLDL) cholesterol (15%), as well as an increase in high-density lipoprotein (HDL) cholesterol (33%). Overall, ragaglitazar was well tolerated; with multiple dosing, there was a higher incidence of adverse events for patients that, at the highest dose level (16 mg), included peripheral edema and anemia.

Adolescent↗
PubMed2000

Evidence for the presence of peroxisome proliferator-activated receptor (PPAR) alpha and gamma and retinoid Z receptor in cartilage. PPARgamma activation modulates the effects of interleukin-1beta on rat chondrocytes.

Peroxisome proliferator-activated receptor (PPAR) alpha, PPARgamma, and retinoid acid receptor-related orphan receptor (ROR) alpha are members of the nuclear receptor superfamily of ligand-activated transcription factors. Although they play a key role in adipocyte differentiation, lipid metabolism, or glucose homeostasis regulation, recent studies suggested that they might be involved in the inflammation control and especially in the modulation of the cytokine production. This strongly suggests that these transcriptional factors could modulate the deleterious effects of interleukin-1 (IL-1) on cartilage. However, to date, their presence in cartilage has never been investigated. By quantitative reverse transcription-polymerase chain reaction, Western blot, and immunocytochemistry analysis, we demonstrated, for the first time, the presence of PPARalpha, PPARgamma, and RORalpha in rat cartilage, at both mRNA and protein levels. Comparatively, the PPARalpha mRNA content in cartilage was much lower than in the liver but not significantly different to that of the adipose tissue. PPARgamma mRNA expression in cartilage was weak, when compared with adipose tissue, but similar to that found in the liver. RORalpha mRNA levels were similar in the three tissues. mRNA expression of the three nuclear receptors was very differently modulated by IL-1 or mono-iodoacetate treatments. This indicates that they should be unequally involved in the effects of IL-1 on chondrocyte, which is in accordance with results obtained in other cell types. Indeed, we showed that 15d-PGJ2 mainly, but also the drug troglitazone, that are ligands of PPARgamma could significantly counteract the decrease in proteoglycan synthesis and NO production induced by IL-1. By contrast, PPARalpha ligands such as Wy-14,643 or clofibrate had no effect on this process. Therefore, the presence of PPARgamma in chondrocytes opens up new perspectives to modulate the effects of cytokines on cartilage by the use of specific ligands. The function of the two other transcription factors, PPARalpha and RORalpha identified in chondrocytes remains to be explored.

Alginates↗
PubMedDate not supplied

Left-ventricular diastolic dysfunction may be prevented by chronic treatment with PPAR-alpha or -gamma agonists in a type 2 diabetic animal model.

OBJECTIVES: The aim of this study was to determine whether the peroxisome proliferator-activated receptor (PPAR) ligands could prevent left-ventricular diastolic dysfunction (LVDD) in rats with advanced diabetes. In addition, this study examined whether the activity of malonyl-CoA decarboxylase (MCD), which is an enzyme related to the degradation of malonyl-CoA that is known to regulate the fatty acid metabolism, is changed by the diabetic state itself or by treatment with the PPAR ligands. METHODS: Male Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of type 2 diabetes, aged 28 weeks, were divided into 3 groups: the untreated, pioglitazone-treated (10 mg/kg/d), and fenofibrate-treated (150 mg/kg/d) groups. The rats were treated for 10 weeks. Male Long-Evans Tokushima Otsuka (LETO) rats were used as nondiabetic control. Doppler echocardiography and measurements of the MCD activity at the myocardium were performed. RESULTS: At the age of 38 weeks, the OLETF rats treated with either pioglitazone or fenofibrate showed an improvement in the plasma glucose levels after glucose loading as well as an improvement in the fasting plasma insulin, triglyceride, and FFA levels compared to the untreated OLETF rats. The untreated OLETF rats showed a prolonged deceleration time of the E-wave (DTE) (74.3 +/- 3.7 vs LETO, 56.3 +/- 3.8 ms, P < 0.05) and a reduced ratio of the peak early diastolic velocity wave to the late diastolic wave (E/A ratio) (1.25 +/- 0.06 vs LETO 1.54 +/- 0.08, P < 0.05). Pioglitazone treatment in the OLETF rats improved the DTE (51.6 +/- 1.7 ms, P < 0.05), and the fenofibrate treatment also improved the DTE (61.4 +/- 4.3 ms, P < 0.05) and E/A ratio (1.57 +/- 0.05, P < 0.05) compared to the untreated OLETF rats. The parameters related to the systolic function did not change among the groups at both pre- and post-treatments. The MCD activity of the myocardium was remarkably lower in the OLETF rats compared to the LETO rats (3.26 +/- 0.38 vs 7.76 +/- 0.84 nmol/min/mg protein, P < 0.05). The pioglitazone and fenofibrate treatments resulted in an increase in the MCD activity compared to that in the untreated rats (7.20 +/- 0.74 and 8.33 +/- 0.83 nmol/min/mg protein, P < 0.05, respectively). CONCLUSIONS: The PPAR-alpha or -gamma agonists prevented LVDD in the advanced diabetic rat hearts, possibly through an improvement in the fatty acid metabolism in the myocardium or a correction of the hyperglycemia and/or hyperlipidemia.

Animals↗