All the peroxisome proliferator activated receptors (PPARs) are found to be expressed in bone cells. The PPARγ agonist rosiglitazone has been shown to decrease bone mass in mice and thiazolidinediones (TZDs) have recently been found to increase bone loss and fracture risk in humans treated for type 2 diabetes mellitus. The aim of the study was to examine the effect of the PPARα agonist fenofibrate (FENO) and the PPARγ agonist pioglitazone (PIO) on bone in intact female rats.
Rats were given methylcellulose (vehicle), fenofibrate or pioglitazone (35 mg/kg body weight/day) by gavage for 4 months. BMC, BMD, and body composition were measured by DXA. Histomorphometry and biomechanical testing of excised femurs were performed. Effects of the compounds on bone cells were studied.
The FENO group had higher femoral BMD and smaller medullary area at the distal femur; while trabecular bone volume was similar to controls. Whole body BMD, BMC, and trabecular bone volume were lower, while medullary area was increased in PIO rats compared to controls. Ultimate bending moment and energy absorption of the femoral shafts were reduced in the PIO group, while similar to controls in the FENO group. Plasma osteocalcin was higher in the FENO group than in the other groups. FENO stimulated proliferation and differentiation of, and OPG release from, the preosteoblast cell line MC3T3-E1.
We show opposite skeletal effects of PPARα and γ agonists in intact female rats. FENO resulted in significantly higher femoral BMD and lower medullary area, while PIO induced bone loss and impairment of the mechanical strength. This represents a novel effect of PPARα activation.
This study explores the skeletal effects of the peroxisome proliferator activated receptor (PPAR)pan agonist tetradecylthioacetic acid (TTA). Rats, without (Study I) and with ovariectomy (OVX) or sham operation (Study II), were given TTA or vehicle daily for 4 months. Bone markers in plasma, whole body and femoral bone mineral density and content (BMD and BMC), and body composition were examined. Histomorphometric and biomechanical analyses (Study I) and biomechanical and μCT analyses (Study II) of the femur were performed. Normal rats fed TTA had higher femoral BMD and increased total and cortical area in femur compared to controls. The ovariectomized groups had decreased BMD and impaired microarchitecture parameters compared to SHAM. However, the TTA OVX group maintained femoral BMC, trabecular thickness in the femoral head, and cortical volume in the femoral metaphysis as SHAM. TTA might increase BMD and exert a light preventive effect on estrogen-related bone loss in rats.
The ob gene product, leptin, is a signaling factor regulating body weight and energy balance. ob gene expression in rodents is increased in obesity and is regulated by feeding patterns and hormones, such as insulin and glucocorticoids. In humans with gross obesity, ob mRNA levels are higher, but other modulators of human ob expression are unknown. In view of the importance of peroxisome proliferator-activated receptor gamma (PPARgamma) in adipocyte differentiation, we analyzed whether ob gene expression is subject to regulation by factors activating PPARs. Treatment of rats with the PPARalpha activator fenofibrate did not change adipose tissue and body weight and had no significant effect on ob mRNA levels. However, administration of the thiazolidinedione BRL49653, a PPARgamma ligand, increased food intake and adipose tissue weight while reducing ob mRNA levels in rats in a dose-dependent manner. The inhibitory action of the thiazolidinedione BRL49653 on ob mRNA levels was also observed in vitro. Thiazolidinediones reduced the expression of the human ob promoter in primary adipocytes, however, in undifferentiated 3T3-L1 preadipocytes lacking endogenous PPARgamma, cotransfection of PPARgamma was required to observe the decrease. In conclusion, these data suggest that PPARgamma activators reduce ob mRNA levels through an effect of PPARgamma on the ob promoter.
Hepatoprotective potential of peroxisome proliferator activator receptor (PPAR)-α and -γ agonists, fenofibrate (FEN), and pioglitazone (PIO), respectively, against cyclophosphamide (CP)-induced toxicity has been investigated in rat. FEN and PIO (150 and 10 mg/kg/day, resp.) were given orally for 4 weeks. In separate groups, CP (150 mg/kg, i.p.) was injected as a single dose 5 days before the end of experiment, with or without either PPAR agonist. CP induced hepatotoxicity, as it caused histopathological alterations, with increased serum alanine and aspartate transaminases, total bilirubin, albumin, alkaline phosphatase and lactate dehydrogenase. CP caused hepatic oxidative stress, indicated by decrease in tissue reduced glutathione, with increase in malondialdehyde and nitric oxide levels. CP also caused decrease in hepatic antioxidant enzyme levels, including catalase, superoxide dismutase, glutathione peroxidase, and glutathione S-transferase. Furthermore, CP increased serum and hepatic levels of the inflammatory marker tumor necrosis factor (TNF)-α, evaluated using ELISA. Preadministration of PIO, but not FEN, prior to CP challenge improved hepatic function and histology, and significantly reversed oxidative and inflammatory parameters. In conclusion, activation of PPAR-γ, but not PPAR-α, conferred protection against CP-induced hepatotoxicity, via activation of antioxidant and anti-inflammatory mechanisms, and may serve as supplement during CP chemotherapy.
Metformin has been reported to increase the expression of the glucagon-like peptide-1 (GLP-1) receptor in pancreatic beta cells in a peroxisome proliferator-activated receptor (PPAR)-α-dependent manner. We investigated whether a PPARα agonist, fenofibrate, exhibits an additive or synergistic effect on glucose metabolism, independent of its lipid-lowering effect, when added to metformin. Non-obese diabetic Goto-Kakizaki (GK) rats were divided into four groups and treated for 28 days with metformin, fenofibrate, metformin plus fenofibrate or vehicle. The random blood glucose levels, body weights, food intake and serum lipid profiles were not significantly different among the groups. After 4 weeks, metformin, but not fenofibrate, markedly reduced the blood glucose levels during oral glucose tolerance tests, and this effect was attenuated by adding fenofibrate. Metformin increased the expression of the GLP-1 receptor in pancreatic islets, whereas fenofibrate did not. During the intraperitoneal glucose tolerance tests with the injection of a GLP-1 analog, metformin and/or fenofibrate did not alter the insulin secretory responses. In conclusion, fenofibrate did not confer any beneficial effect on glucose homeostasis but reduced metformin's glucose-lowering activity in GK rats, thus discouraging the addition of fenofibrate to metformin to improve glycemic control.
fenofibrate; glucagon-like peptide-1; Goto-Kakizaki rats; metformin; peroxisome proliferator-activated receptor alpha
We sought to determine the effects of activation of peroxisome proliferator-activated receptor-γ (PPAR-γ) on multilocularization of adipocytes in adult white adipose tissue (WAT). Male C57BL/6 normal, db/db, and ob/ob mice were treated with agonists of PPAR-γ, PPAR-α, or β3-adrenoceptor for 3 weeks. To distinguish multilocular adipocytes from unilocular adipocytes, whole-mounted adipose tissues were co-immunostained for perilipin and collagen IV. PPAR-γ activation with rosiglitazone or pioglitazone induced a profound change of unilocular adipocytes into smaller, multilocular adipocytes in adult WAT in a time-dependent, dose-dependent, and reversible manner. PPAR-α activation with fenofibrate did not affect the number of locules or remodeling. db/db and ob/ob obese mice exhibited less multilocularization in response to PPAR-γ activation compared to normal mice. Nevertheless, all adipocytes activated by PPAR-γ contained a single nucleus regardless of locule number. Multilocular adipocytes induced by PPAR-γ activation contained substantially increased mitochondrial content and enhanced expression of uncoupling protein-1, PPAR-γ coactivator-1-α , and perilipin. Taken together, PPAR-γ activation induces profound multilocularization and enhanced mitochondrial biogenesis in the adipocytes of adult WAT. These changes may affect the overall function of WAT.
mitochondria; mitochondrial uncoupling protein; pioglitazone; receptors, adrenergic, β-3; rosiglitazone
Expression of ATP binding cassette transporter A1 (ABCA1), a major regulator of high density lipoprotein (HDL) biogenesis, is known to be up-regulated by the transcription factor liver X receptor (LXR) α, and expression is further enhanced by activation of the peroxisome proliferator activated receptors (PPARs). We investigated this complex regulatory network using specific PPAR agonists: four fibrates (fenofibrate, bezafibrate, gemfibrozil and LY518674), a PPAR δ agonist (GW501516) and a PPAR γ agonist (pioglitazone). All of these compounds increased the expression of LXRs, PPARs and ABCA1 mRNAs, and associated apoA-I-mediated lipid release in THP-1 macrophage, WI38 fibroblast and mouse fibroblast. When mouse fibroblasts lacking expression of PPAR α were examined, the effects of fenofibrate and LY518674 were markedly diminished while induction by other ligands were retained. The PPAR α promoter was activated by all of these compounds in an LXR α-dependent manner, and partially in a PPAR α-dependent manner, in mouse fibroblast. The LXR responsive element (LXRE)-luciferase activity was enhanced by all the compounds in an LXR α-dependent manner in mouse fibroblast. This activation was exclusively PPAR α-dependent by fenofibrate and LY518674, but nonexclusively by the others. We conclude that PPARs and LXRs are involved in the regulation of ABCA1 expression and HDL biogenesis in a cooperative signal transduction pathway.
ABCA1; PPAR; LXR; ABCA1; HDL; Cholesterol
Inhibitor of DNA binding (Id2) is a helix-loop-helix (HLH) transcription factor that participates in cell differentiation and proliferation. Id2 has been linked to the development of cardiovascular diseases since thiazolidinediones, antidiabetic agents and peroxisome proliferator-activated receptor (PPAR) gamma agonists, have been reported to diminish Id2 expression in human cells. We hypothesized that PPARα activators may also alter Id2 expression. Fenofibrate diminished hepatic Id2 expression in both late pregnant and unmated rats. In 24 hour fasted rats, Id2 expression was decreased under conditions known to activate PPARα. In order to determine whether the fibrate effects were mediated by PPARα, wild-type mice and PPARα-null mice were treated with Wy-14,643 (WY). WY reduced Id2 expression in wild-type mice without an effect in PPARα-null mice. In contrast, fenofibrate induced Id2 expression after 24 hours of treatment in human hepatocarcinoma cells (HepG2). MK-886, a PPARα antagonist, did not block fenofibrate-induced activation of Id2 expression, suggesting a PPARα-independent effect was involved. These findings confirm that Id2 is a gene responsive to PPARα agonists. Like other genes (apolipoprotein A-I, apolipoprotein A-V), the opposite directional transcriptional effect in rodents and a human cell line further emphasizes that PPARα agonists have different effects in rodents and humans.
To compare the molecular and biologic signatures of a balanced dual peroxisome proliferator-activated receptor (PPAR)-α/γ agonist, aleglitazar, with tesaglitazar (a dual PPAR-α/γ agonist) or a combination of pioglitazone (Pio; PPAR-γ agonist) and fenofibrate (Feno; PPAR-α agonist) in human hepatocytes.
Methods and Results
Gene expression microarray profiles were obtained from primary human hepatocytes treated with EC50-aligned low, medium and high concentrations of the three treatments. A systems biology approach, Causal Network Modeling, was used to model the data to infer upstream molecular mechanisms that may explain the observed changes in gene expression. Aleglitazar, tesaglitazar and Pio/Feno each induced unique transcriptional signatures, despite comparable core PPAR signaling. Although all treatments inferred qualitatively similar PPAR-α signaling, aleglitazar was inferred to have greater effects on high- and low-density lipoprotein cholesterol levels than tesaglitazar and Pio/Feno, due to a greater number of gene expression changes in pathways related to high-density and low-density lipoprotein metabolism. Distinct transcriptional and biologic signatures were also inferred for stress responses, which appeared to be less affected by aleglitazar than the comparators. In particular, Pio/Feno was inferred to increase NFE2L2 activity, a key component of the stress response pathway, while aleglitazar had no significant effect. All treatments were inferred to decrease proliferative signaling.
Aleglitazar induces transcriptional signatures related to lipid parameters and stress responses that are unique from other dual PPAR-α/γ treatments. This may underlie observed favorable changes in lipid profiles in animal and clinical studies with aleglitazar and suggests a differentiated gene profile compared with other dual PPAR-α/γ agonist treatments.
The peroxisome proliferator-activated receptor alpha (PPARalpha) is a nuclear receptor implicated in the control of cellular lipid utilization. To test the hypothesis that PPARalpha is activated as a component of the cellular lipid homeostatic response, the expression of PPARalpha target genes was characterized in response to a perturbation in cellular lipid oxidative flux caused by pharmacologic inhibition of mitochondrial fatty acid import. Inhibition of fatty acid oxidative flux caused a feedback induction of PPARalpha target genes encoding fatty acid oxidation enzymes in liver and heart. In mice lacking PPARalpha (PPARalpha-/-), inhibition of cellular fatty acid flux caused massive hepatic and cardiac lipid accumulation, hypoglycemia, and death in 100% of male, but only 25% of female PPARalpha-/- mice. The metabolic phenotype of male PPARalpha-/- mice was rescued by a 2-wk pretreatment with beta-estradiol. These results demonstrate a pivotal role for PPARalpha in lipid and glucose homeostasis in vivo and implicate estrogen signaling pathways in the regulation of cardiac and hepatic lipid metabolism.
Activation of peroxisome proliferator-activated receptor (PPAR)-γ, a nuclear transcription factor, has been shown to inhibit the production of proinflammatory cytokines and, in peripheral tissues, to down-regulate the renin-angiotensin system (RAS). PPAR-γ is expressed in key brain areas involved in cardiovascular and autonomic regulation. We hypothesized that activation of central PPAR-γ would reduce sympathetic excitation and ameliorate peripheral manifestations of heart failure (HF) by inhibiting central inflammation and brain RAS activity. Two weeks after coronary artery ligation, HF rats received an intracerebroventricular (ICV) infusion of the PPAR-γ agonist pioglitazone or vehicle for another 2 weeks. PPAR- expression in the paraventricular nucleus of hypothalamus (PVN), an important cardiovascular region, was unchanged in HF compared with sham-operated (SHAM) rats. However, PPAR-γ DNA binding activity was reduced, nuclear factor-kB activity was increased, and expression of proinflammatory cytokines and angiotensin II type-1 receptor was augmented in the HF rats. Mean blood pressure response to ganglionic blockade was greater, plasma norepinephrine levels, lung/body weight, right ventricle/body weight, and left ventricular end-diastolic pressure were increased and maximal left ventricular dP/dt was decreased. All these findings were ameliorated in HF rats treated with ICV pioglitazone, which increased PPAR-γ expression and DNA binding activity in PVN. The results demonstrate that cardiovascular and autonomic mechanisms leading to heart failure after myocardial infarction can be modulated by activation of PPAR-γ in the brain. Central PPAR-γ may be a novel target for treatment of sympathetic excitation in myocardial infarction-induced HF.
peroxisome proliferator-activated receptor-γ; proinflammatory cytokines; renin-angiotensin system; nuclear factor-kB; autonomic regulation
Osteopontin (OPN) is associated with human abdominal aortic aneurysms (AAA) and in vitro studies suggest that this cytokine is downregulated by peroxisome proliferator-activated receptor (PPAR) ligation. We examined the effect of two PPAR ligands within a mouse model of aortic aneurysm.
At 11 weeks of age apolipoprotein E deficient (ApoE−/−) mice were given pioglitazone (n=27), fenofibrate (n=27) or vehicle (n=27) in their drinking water. From 13 weeks of age mice received angiotensin II (1μg/kg/min) infusion via subcutaneous pumps until death or 17 weeks when the aortas were harvested and maximum aortic diameters were recorded. Suprarenal aortic segments were assessed for OPN concentration and macrophage accumulation. Saline infused mice served as negative controls (n=22).
Angiotensin II induced marked dilatation in the suprarenal aorta (>2-fold increase compared to controls) associated with upregulation of the cytokines OPN and macrophage infiltration. Suprarenal aortic expansion was significantly reduced by administration of pioglitazone (mean diameter 1.61±0.11mm, p=.011) and fenofibrate (mean diameter 1.51±0.13mm, p=.001) compared to the vehicle control group (mean diameter 2.10±0.14mm). Immunostaining for macrophages was reduced in mice treated with pioglitazone (median staining area 6.2%, interquartile range 4.1–7.2, p<.001) and fenofibrate (median staining area 4.0%, interquartile range 2.2–6.1, p<.001) compared to mice receiving vehicle control (median staining area 13.2%, interquartile range 8.4–20.0).
These findings suggest the potential value of peroxisome proliferator-activated receptor ligation as a therapy for human AAAs.
Aortic aneurysm; medication; treatment
Trials of peroxisome proliferator-activated receptor (PPAR) agonists have shown mixed results for cardiovascular prevention. Fibrates are PPAR-α agonists that act primarily to improve dyslipidemia. Based on low- and high-density
lipoprotein cholesterol (LDL and HDL) effects, gemfibrozil may be of greater cardiovascular benefit than expected, fenofibrate performed about as expected, and bezafibrate performed worse than expected. Increases in both cardiovascular and noncardiovascular serious adverse events have been observed with some fibrates. Thiazolidinediones (TZDs) are PPAR-γ agonists used to improve impaired glucose metabolism but also influence lipids.
Pioglitazone reduces atherosclerotic events in diabetic subjects, but has no net cardiovascular benefit due to increased congestive heart failure risk. Rosiglitazone may increase the risk of atherosclerotic events, and has a net harmful effect on the cardiovascular system when congestive heart failure is included. The primary benefit of TZDs appears to be the prevention of diabetic microvascular complications. Dual PPAR-α/γ agonists have had unacceptable adverse effects but more selective agents are in development. PPAR-δ and pan-agonists are also in development. It will be imperative to prove that future PPAR agonists not only prevent atherosclerotic events but also result in a net reduction on total cardiovascular events without significant noncardiovascular adverse effects with long-term use.
Peroxisome proliferators-activated receptor alpha (PPARα) activation modulates cholesterol metabolism and suppresses bile acid synthesis. This study aims to evaluate the effect of short-term administration of fenofibrate, a PPARα agonist, on proinflammatory cytokines, apoptosis, and hepatocellular damage in cholestasis.
Forty male Wistar rats were randomly divided into four groups: I = sham operated, II = bile duct ligation (BDL), III = BDL + vehicle (gum Arabic), IV = BDL + fenofibrate (100 mg/kg/day). All rats were sacrificed on 7th day after obtaining blood samples and liver tissue. Total bilirubin, aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP), gamma-glutamyl transferase, (GGT), tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1 β), and total bile acid (TBA) in serum, and liver damage scores; portal inflammation, necrosis, bile duct number, in liver tissue were evaluated. Apoptosis in liver was also assessed by immunohistochemical staining.
Fenofibrate administration significantly reduced serum total bilirubin, AST, ALT, ALP, and GGT, TNF-α, IL-1 β levels, and TBA (P < 0.01). Hepatic portal inflammation, hepatic necrosis, number of the bile ducts and apoptosis in rats with BDL were more prominent than the sham-operated animals (P < 0.01). PPARα induction improved all histopathologic parameters (P < 0.01), except for the number of the bile duct, which was markedly increased by fenofibrate therapy (P < 0.01).
Short-term administration of fenofibrate to the BDL rats exerts beneficial effects on hepatocellular damage and apoptosis.
Traumatic spinal cord injury (SCI) is accompanied by a dramatic inflammatory response, which escalates over the first week post-injury and is thought to contribute to secondary pathology after SCI. Peroxisome proliferator-activated receptors (PPAR) are widely expressed nuclear receptors whose activation has led to diminished pro-inflammatory cascades in several CNS disorders. Therefore, we examined the efficacy of the PPARγ agonist Pioglitazone in a rodent SCI model. Rats received a moderate mid-thoracic contusion and were randomly placed into groups receiving vehicle, low dose or high dose Pioglitazone. Drug or vehicle was injected i.p. at 15 min post-injury and then every 12h for the first 7d post-injury. Locomotor function was followed for 5 weeks using the BBB scale. BBB scores were greater in treated animals at 7d post-injury and significant improvements in BBB subscores were noted, including better toe clearance, earlier stepping and more parallel paw position. Stereological measurements throughout the lesion revealed a significant increase in rostral spared white matter in both Pioglitazone treatment groups. Spinal cords from the high dose group also had significantly more gray matter sparing and motor neurons rostral and caudal to epicenter. Thus, our results reveal that clinical treatment with Pioglitazone, an FDA-approved drug used currently for diabetes, may be a feasible and promising strategy for promoting anatomical and functional repair after SCI.
inflammation; locomotion; motor neurons; white matter sparing; gray matter; spinal contusion
Peroxisome proliferator-activated receptor (PPAR) agonists are used as adjunct therapy in the treatment of diabetes mellitus. Fibrates, including fenofibrate, gemfibrozil, benzafibrate, ciprofibrate, and clofibrate act on PPAR alpha to reduce the level of hypertriglyceridemia. However, agonists (ligands) of PPAR-beta/delta receptors, such as tesaglitazar, muraglitazar, ragaglitazar, imiglitazar, aleglitazar, alter the body's energy substrate preference from glucose to lipids and hence contribute to the reduction of blood glucose level. Glitazones or thiazolidinediones on the other hand, bind to PPAR-gamma receptors located in the nuclei of cells. Activation of PPAR-gamma receptors leads to a decrease in insulin resistance and modification of adipocyte metabolism. They reduce hyperlipidaemia by increasing the level of ATP-binding cassette A1, which modifies extra-hepatic cholesterol into HDL. Dual or pan PPAR ligands stimulate two or more isoforms of PPAR and thereby reduce insulin resistance and prevent short- and long-term complications of diabetes including micro-and macroangiopathy and atherosclerosis, which are caused by deposition of cholesterol. This review examines the chemical structure, actions, side effects and future prospects of dual and pan PPAR agonists.
Diabetes mellitus; PPAR agonists; thiazolidinediones; fibrates; medicinal chemistry.
Peroxisome proliferator-activated receptor (PPAR) α ligands (Wy-14,643, and fenofibrate) and PPARγ ligands (troglitazone and ciglitazone) inhibit antigen-induced cysteinyl leukotriene production in immunoglobulin E-treated mast cells. The inhibitory effect of these ligands on cysteinyl leukotriene production is quite strong and is almost equivalent to that of the anti-asthma compound zileuton. To develop new aspects for anti-asthma drugs the pharmacological target of these compounds should be clarified. Experiments with bone-marrow-derived mast cells from PPARα knockout mice and pharmacological inhibitors of PPARγ suggest that the inhibitory effects of these ligands are independent of PPARs α and γ. The mechanisms of the PPAR-independent inhibition by these agents on cysteinyl leukotriene production are discussed in this review.
AMP-dependent protein kinase (AMPK) and peroxisome proliferator-activated receptor (PPAR) α facilitate fatty acid oxidation. We have shown that treatment of hepatoma cells with ethanol or feeding ethanol-containing diets to mice inhibited both PPARα and AMPK activity. Importantly, WY-14,643 reversed the development of fatty liver in alcohol-fed mice. Whether WY-14,643, a PPARα agonist, has any effects on AMPK is not known. The aim of this study was to investigate the effect of WY-14,643 on AMPK activity.
The effect of WY-14,643 on AMPK phosphorylation and activity were examined in rat hepatoma cells (H4IIEC3). The effect of WY-14,643 on upstream kinases of AMPK, PKC-ζ/LKB1, intracellular AMP:ATP ratio, oxidative stress, and AMPK gene expression were studied.
Treatment of the H4IIEC3 cells with WY-14,643 for 24 h led to 60% increase in the phosphorylation of AMPK. The effect of WY-14,643 on AMPK phosphorylation is PKC-ζ/LKB1 independent. WY-14,643 did not alter the levels of intracellular AMP:ATP ratio and it did not increase the levels of reactive oxygen species at 24-h of treatment. WY-14,643-induced AMPK α subunit expression by 2- to 2.5-fold, but there was no change in AMPKα subunit protein at 24 h. The effect of WY-14,643 on AMPK phosphorylation did not altered by the presence of an NADPH oxidase inhibitor.
WY-14,643 induced AMPKα subunit phosphorylation and the activity of the enzyme. This was associated with induction of AMPKα1 and α2 mRNA, but the mechanism for this activation is uncertain.
WY-14,643; PPARα agonist; AMPKα
The incidence of diabetes is directly related to the incidence of obesity, which is at epidemic proportions in the US. Cardiovascular disease is a common complication of diabetes, which results in high morbidity and mortality. Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear hormone receptors that regulate lipid and glucose metabolism. PPAR-α agonists such as fenofibrate and PPAR-γ agonists such as the thiozolidinediones have been used to treat dyslipidemia and insulin resistance in diabetes. Over the past few years research has discovered the role of PPARs in the regulation of inflammation, proliferation, and angiogenesis. Clinical trials looking at the effect of PPAR agonists on cardiovascular outcomes have produced controversial results. Studies looking at angiogenesis and proliferation in various animal models and cell lines have shown a wide variation in results. This may be due to the differential effects of PPARs on proliferation and angiogenesis in various tissues and pathologic states. This review discusses the role of PPARs in stimulating angiogenesis. It also reviews the settings in which stimulation of angiogenesis may be either beneficial or harmful.
PPAR; VEGF; angiogenesis; cardiovascular
We investigated effects on glucose and lipid metabolism in combination of JTT-130, a novel intestine-specific microsomal triglyceride transfer protein (MTP) inhibitor, and pioglitazone, peroxisome proliferator-activated receptor (PPAR) γ agonist. Male Zucker diabetic fatty rats were divided into 4 groups: control group, JTT-130 treatment group, pioglitazone treatment group, and combination group. The Zucker diabetic fatty rats were fed a regular powdered diet with JTT-130 and/or pioglitazone as a food admixture for 6 weeks. Effects on glucose and lipid metabolism were compared mainly between JTT-130 treatment group and combination group. JTT-130 treatment showed good glycemic control, while the plasma glucose and glycated hemoglobin levels in combination group were significantly decreased as compared with those JTT-130 treatment group. The reduction in the plasma triglyceride and free fatty acid levels in combination group was higher than that in JTT-130 treatment group, and glucose utilization was significantly elevated in adipose tissues. In Zucker diabetic fatty rats, combination treatment of JTT-130 and pioglitazone showed better glycemic control and a strong hypolipidemic action with an enhancement of insulin sensitivity. Combination therapy of MTP inhibitor and PPARγ agonist might be more useful in the treatment of type 2 diabetes accompanied with obesity and insulin resistance.
Synthetic peroxisome proliferator-activated receptor (PPAR) agonists are used to treat dyslipidemia and insulin resistance. In this study, we examined molecular mechanisms that explain differential effects of a PPARα agonist (fenofibrate) and a PPARγ agonist (rosiglitazone) on macrophages during obesity-induced atherogenesis. Twelve-week-old mice with combined leptin and LDL-receptor deficiency (DKO) were treated with fenofibrate, rosiglitazone or placebo for 12 weeks. Only rosiglitazone improved adipocyte function, restored insulin sensitivity, and inhibited atherosclerosis by decreasing lipid-loaded macrophages. In addition, it increased interleukin-1 receptor-associated kinase-3 (Irak3) and decreased monocyte chemoattractant protein-1 (Mcp1) expressions, indicative of a switch from M1 to M2 macrophages. The differences between fenofibrate and rosiglitazone were independent of Pparγ expression. In bone marrow-derived macrophages (BMDM), we identified the rosiglitazone-associated increase in adiponectin as cause of the increase in Irak3. Interestingly, the deletion of Irak3 in BMDM (IRAK3−/− BMDM) resulted in activation of the canonical NFκB signaling pathway and increased Mcp1 protein secretion. Rosiglitazone could not decrease the elevated Mcp1 secretion in IRAK3−/− BMDM directly and fenofibrate even increased the secretion, possibly due to increased mitochondrial reactive oxygen species production. Furthermore, aortic extracts of high-fat insulin-resistant LDL-receptor deficient mice, with lower adiponectin and Irak3 and higher Mcp1, showed accelerated atherosclerosis. In aggregate, our results emphasize an interaction between PPAR agonist-mediated increase in adiponectin and macrophage-associated Irak3 in the protection against atherosclerosis by PPAR agonists.
We created an inflammation-induced Parkinson’s disease model, where microglia activation leads to oxidative stress, mitochondrial dysfunction, and dopaminergic neurodegeneration in the substantia nigra. Pioglitazone, an agonist of peroxisome proliferator activated receptor–gamma (PPAR-γ), can prevent these deficits and protect dopaminergic neurons. To continue exploring the effects of pioglitazone in this model we focused on the expression of PPAR-γ, uncoupling protein 2 (UCP2), and mitoNEET. We report that intrastriatal lipopolysaccharide (LPS) increases striatal PPAR-γ, UCP2, and mitoNEET expression, and pioglitazone attenuates these LPS-induced changes.
Parkinson’s disease; PPAR-γ; UCP-2; mitoNEET; inflammation
The association between modulation of detailed lipoprotein profiles and cholesterol ester transfer (CET) activity by peroxisome proliferator-activated receptor (PPAR)-a agonists in patients with coronary artery disease remains unclear. We assessed lipid profiles, plasma CET activity, and in-stent intimal hyperplasia after fenofibrate treatment in patients who underwent elective coronary stenting.
Forty-three consecutive patients who underwent elective coronary stenting were randomized to the fenofibrate group (300 mg/day for 25 weeks, n = 22) or the control group (n = 21). At baseline and follow up, CET activity and lipoprotein profiles were measured, and quantitative coronary angiography was performed.
In the fenofibrate group, the levels of large very low-density lipoprotein cholesterol, and small low-density lipoprotein (LDL) cholesterol decreased and those of small high-density lipoprotein (HDL) cholesterol increased. Besides, CET activity decreased independent of the effect of fenofibrate on total and LDL cholesterol. The reduction of CET activity significantly correlated with the increase in LDL particle size (r = 0.47, P = 0.03) and the decrease of triglycerides in large HDL subclasses (r = 0.48, P = 0.03). Although there were no significant differences in restenosis parameters between the two groups, low CET activity significantly correlated with the inhibition of neointimal hyperplasia (r = 0.56, P = 0.01).
Fenofibrate inhibited CET activity and thereby improved atherogenic lipoprotein profiles, and reduced intimal hyperplasia after coronary stenting.
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of the nuclear hormone receptor superfamily. The 3 PPAR isoforms (alpha, delta/beta and gamma) are known to control many physiological functions including glucose absorption, lipid balance, and cell growth and differentiation. Of interest, PPAR-gamma activation was recently shown to mitigate the inflammation associated with chronic and acute neurological insults. Particular attention was paid to test the therapeutic potential of PPAR agonists in acute conditions like stroke, spinal cord injury (SCI) and traumatic brain injury (TBI), in which massive inflammation plays a detrimental role. While 15d-prostaglandin J2 (15d PGJ2) is the natural ligand of PPAR-gamma, the thiazolidinediones (TZDs) are potent exogenous agonists. Due to their insulin-sensitizing properties, 2 TZDs rosiglitazone and pioglitazone are currently FDA-approved for type-2 diabetes treatment. Recent studies from our laboratory and other groups have shown that TZDs induce significant neuroprotection in animal models of focal ischemia and SCI by multiple mechanisms. The beneficial actions of TZDs were observed to be both PPAR-gamma-dependent as well as - independent. The major mechanism of TZD-induced neuroprotection seems to be prevention of microglial activation and inflammatory cytokine and chemokine expression. TZDs were also shown to prevent the activation of pro-inflammatory transcription factors at the same time promoting the anti-oxidant mechanisms in the injured CNS. This review article discusses the multiple mechanisms of TZD-induced neuroprotection in various animal models of CNS injury with an emphasis on stroke.
Transcription Factor; Inflammation; Brain Damage; Nuclear Factor; Cerebral Ischemia; Stroke; Neuroprotection; Review
Rosiglitazone and fenofibrate, specific agonists of the peroxisome proliferator activated receptors-γ (PPARγ) and -α (PPARα), respectively, improve insulin sensitivity in diabetic animals and in patients with type 2 diabetes. Here we investigated how pre-diabetic Otsuka Long–Evans Tokushima Fatty (OLETF) rats fed with normal and high-fat diets respond to these PPAR agonists.
Pre-diabetic OLETF rats were subjected to high-fat or standard diets with or without rosiglitazone or fenofibrate for 2 weeks. The metabolism of the rats and the levels of malonyl-CoA and activities of malonyl-CoA decarboxylase (MCD), acetyl-CoA carboxylase (ACC), and AMP-activated protein kinase (AMPK) in metabolic tissues were assessed.
Rosiglitazone and fenofibrate significantly improved insulin sensitivity and reduced the levels of plasma triglycerides and free fatty acids in OLETF rats fed with a high-fat diet. Fenofibrate particularly reduced the body weight, fat, and total cholesterol in high fat diet OLETF rats. The highly elevated malonyl-CoA levels in the skeletal muscle and liver of OLETF rat were significantly reduced by rosiglitazone or fenofibrate due to, in part, the increased MCD activities and expression. On the other hand, ACC activities were unchanged in skeletal muscle and decreased in liver in high fat diet group. AMPK activities were dramatically decreased in OLETF rats and not affected by these agonists.
These results demonstrate that treatment of pre-diabetic OLETF rats–particularly those fed a high-fat diet–with rosiglitazone and fenofibrate significantly improves insulin sensitivity and fatty acid metabolism by increasing the activity of MCD and reducing malonyl-CoA levels in the liver and skeletal muscle.
PPARγ; PPARα agonists; Rosiglitazone; Fenofibrate; Malonyl-CoA; Malonyl-CoA decarboxylase; Acetyl-CoA carboxylase