Peroxisome Proliferator-activated Receptor Alpha Agonist Research Articles

Associations between Levels of Serum Perfluorinated Chemicals and Adiponectin in a Young Hypertension Cohort in Taiwan

In animals, perfluorinated chemicals (PFCs), specifically perfluorooctanoic acid (PFOA) and perfluorooctane sulfate (PFOS), function as peroxisome proliferator-activated receptor (PPAR) alpha agonists. However, the relevance of animal (primarily rodent) data to humans is unresolved. While plasma adiponectin level is very responsive to PPAR gamma agonist drugs, it has not been determined whether adiponectin level is related to serum PFCs concentrations. In the present study, 287 subjects (12-30 years of age) were recruited to determine the relationship between serum level of PFCs and serum level of adiponectin. The results showed males had higher serum PFOS concentrations than females and that those with metabolic syndrome had lower serum PFOA than controls. Besides, it showed regional elevations of the perfluoroundecanoic acid (PFUA) (median concentration: 7.11 ng/mL) in the study subjects. No relationship of PFOA, PFOS, PFUA, and the sum of all four PFCs was found to glucose homeostasis, adiponectin level, lipid profile, and inflammatory markers. The median and the range of perfluorononanoic acid (PFNA) concentration (in ng/mL; for four categories corresponding to the <50, 50-74, 75-89, and ≥90th percentiles) were 0.38 (0.38-1.68), 3.22 (1.73-4.65), 5.85 (4.75-8.29), 10.56 (8.40-25.40), respectively. After controlling for confounding factors, multiple linear regression analysis revealed that the mean natural log-transformed level of adiponectin increased significantly across categories of PFNA (in ng/mL; 8.78, 8.73, 9.06, 9.36; P for trend = 0.010 in the full model). In conclusion, higher serum PFNA concentration is associated with elevated serum adiponectin concentration.

The PPAR alpha agonist gemfibrozil is an ineffective treatment for spinal cord injured mice

Peroxisome Proliferator Activated Receptor (PPAR)-α is a key regulator of lipid metabolism and recent studies reveal it also regulates inflammation in several different disease models. Gemfibrozil, an agonist of PPAR-α, is a FDA approved drug for hyperlipidemia and has been shown to inhibit clinical signs in a rodent model of multiple sclerosis. Since many studies have shown improved outcome from spinal cord injury (SCI) by anti-inflammatory and neuroprotective agents, we tested the efficacy of oral gemfibrozil given before or after SCI for promoting tissue preservation and behavioral recovery after spinal contusion injury in mice. Unfortunately, the results were contrary to our hypothesis; in our first attempt, gemfibrozil treatment exacerbated locomotor deficits and increased tissue pathology after SCI. In subsequent experiments, the behavioral effects were not replicated but histological outcomes again were worse. We also tested the efficacy of a different PPAR-α agonist, fenofibrate, which also modulates immune responses and is beneficial in several neurodegenerative disease models. Fenofibrate treatment did not improve recovery, although there was a slight trend for a modest increase in histological tissue sparing. Based on our results, we conclude that PPAR-α agonists yield either no effect or worsen recovery from spinal cord injury, at least at the doses and the time points of drug delivery tested here. Further, patients sustaining spinal cord injury while taking gemfibrozil might be prone to exacerbated tissue damage.

Ammonium perfluorooctanoate may cause testosterone reduction by adversely affecting testis in relation to PPARα

Perfluorooctanoate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, has the potential to lower testosterone levels as a result of testicular toxicity. To elucidate the mechanism and impact of PPARα on this reproductive toxicity, ammonium perfluorooctanoate (APFO) at doses of 0, 1.0 (low) mg/kg/day, or 5.0 (high) mg/kg/day was orally given daily to 129/sv wild-type ( mPPARα), Pparα-null and PPARα-humanized ( hPPARα) mice for 6 weeks. Both low- and high-dose APFO significantly reduced plasma testosterone concentrations in mPPARα and hPPARα mice, respectively. These decreases may, in part, be associated with decreased expression of mitochondrial cytochrome P450 side-chain cleavage enzyme, steroidogenic acute regulatory protein or peripheral benzodiazepine receptor as well as microsomal cytochrome P450 17α involved in the steroidogenesis. Additionally, both doses increased abnormalities in sperm morphology and vacuolated cells in the seminiferous tubules of both mouse lines. In contrast, APFO caused only a marginal effect either on the testosterone synthesis system or sperm and testis morphology in Pparα-null mice. These results suggest that APFO may disrupt testosterone biosynthesis by lowering the delivery of cholesterol into the mitochondria and decreasing the conversion of cholesterol to pregnenolone and androstandione in the testis of mPPARα and hPPARα mice, which may, in part, be related to APFO-induced mitochondrial damage.

APOA5 gene expression in the human intestinal tissue and its response to in vitro exposure to fatty acid and fibrate

Background and aimsAPOA5, a key gene regulating triglyceride (TG) levels, is reported to be expressed exclusively in the liver where it may regulate TG-rich particle synthesis and secretion. Since the same lipoprotein processing occurs in the intestine, we have postulated that this organ would also express APOA5. Methods and resultsWe have detected the APOA5 gene expression in C57BL/6J mouse and in human small intestine samples. In humans, it is expressed mainly in the duodenum and colon, with messenger RNA (mRNA) levels four orders of magnitude lower than in the liver, and the protein product being one-sixth of the liver equivalent. Subsequently, we carried out in vitro experiments in TC-7/CaCo2 human intestinal cells to analyse the expression of APOA5, APOC3, APOB and MTP genes after the incubation with long- and short-chain fatty acids, and a peroxisome proliferator-activated receptor alpha (PPARα) agonist (Wy 14643, a fibrate therapeutic agent). In the TC-7 cell line, APOA5 expression was significantly upregulated by saturated fatty acids. The short-chain fatty acid butyrate increased APOA5 expression almost fourfold while APOB was downregulated by increasing butyrate concentrations. When TC-7 cells were incubated with PPARα agonist, the APOA5 expression was increased by 60%, while the expression of APOB, MTP and APOC3 was decreased by 50%, 30% and 45%, respectively. ConclusionOur results demonstrate that APOA5 is expressed in the intestine, albeit at a much lower concentration than in the liver. While it remains to be determined whether intestinal apo A-V is functional, our in vitro experiments show that its expression is modifiable by dietary and pharmacological stimuli.

The effects of diet-induced obesity on hepatocyte insulin signaling pathways and induction of non-alcoholic liver damage

The prevalence of diet-induced obesity is increasing amongst adults and children worldwide, predisposing millions of people to an array of health problems that include metabolic syndrome, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. In this study we used experimental animals to investigate the effects of dietary obesity on markers of hepatic insulin signaling as well as structural changes in hepatocytes. Adult male Wistar rats were randomized and assigned to either a control group or a test group. Controls were fed standard laboratory pelleted diet (chow-fed), while the test group had free access to a highly-palatable diet (HPD). After eight weeks, the HPD-fed animals were subdivided into three subgroups and their diets altered as follows: HPD-to-chow, HPD with the addition of fenofibrate given by oral gavage for a further seven weeks, or HPD with vehicle (1% carboxymethylcellulose at 1 mL/kg body weight) given by oral gavage for a further seven weeks, respectively. Untreated diet-fed animals had significantly higher body weight, liver weight, and all measured metabolic profiles compared with chow-fed and treated diet-fed groups. Expression of kinases IRβ, IRS-1, AKt, eNOS, Shc and ERK1/2 were unaffected by obesity, while IRS-2 and P I3 kinase levels were significantly reduced in untreated HPD animals. Compared with chow-fed animals, steatosis and steatohepatitis were almost doubled in animals from untreated HPD, while removal of HPD and fenofibrate-treatment reduced steatosis by 40% and 80% respectively. These data suggest that diet-induced obesity affects intracellular insulin signaling mechanisms, namely IRS-2 and PI 3-kinase, leading to hepatic insulin resistance. Moreover, diet-induced obesity induces fatty liver, an effect which can be reversed by either removal of the source of obesity or treatment with fenofibrate, a peroxisome proliferator-activated receptor alpha agonist.

Role of Peroxisome Proliferator-Activated Receptor α in Diabetic Nephropathy

With a developing worldwide epidemic of diabetes mellitus, the renal complications associated with diabetes have become a serious health concern. Primary therapy for treating diabetic nephropathy is a multifactorial process. Peroxisome proliferator-activated receptor alpha (PPARα) agonists have been used primarily in clinical practice for the treatment of dyslipidemia and insulin resistance. Given that PPARα expression and regulation of metabolic pathways are involved in oxidative stress, inflammation, blood pressure regulation, and the renin-angiotensin aldosterone system, PPARα likely influences the development and pathogenesis of diabetic nephropathy via indirect effects on glucose and lipid homeostasis and also by direct action on the kidneys. These findings suggest that PPARα may become an important therapeutic target for treating diabetic renal complications.

Systems Analysis of Small Signaling Modules Relevant to Eight Human Diseases

Using eight newly generated models relevant to addiction, Alzheimer’s disease, cancer, diabetes, HIV, heart disease, malaria, and tuberculosis, we show that systems analysis of small (4–25 species), bounded protein signaling modules rapidly generates new quantitative knowledge from published experimental research. For example, our models show that tumor sclerosis complex (TSC) inhibitors may be more effective than the rapamycin (mTOR) inhibitors currently used to treat cancer, that HIV infection could be more effectively blocked by increasing production of the human innate immune response protein APOBEC3G, rather than targeting HIV’s viral infectivity factor (Vif), and how peroxisome proliferator-activated receptor alpha (PPARα) agonists used to treat dyslipidemia would most effectively stimulate PPARα signaling if drug design were to increase agonist nucleoplasmic concentration, as opposed to increasing agonist binding affinity for PPARα. Comparative analysis of system-level properties for all eight modules showed that a significantly higher proportion of concentration parameters fall in the top 15th percentile sensitivity ranking than binding affinity parameters. In infectious disease modules, host networks were significantly more sensitive to virulence factor concentration parameters compared to all other concentration parameters. This work supports the future use of this approach for informing the next generation of experimental roadmaps for known diseases.Electronic supplementary materialThe online version of this article (doi:10.1007/s10439-010-0208-y) contains supplementary material, which is available to authorized users.

Evaluation of in vivo genotoxic potential of fenofibrate in rats subjected to two-week repeated oral administration

Fenofibrate (FF), a peroxisome proliferator-activated receptor-alpha agonist, has been used as one of the hypolipidemic drugs in man and induces oxidative stress and promotes hepatocarcinogenesis in the liver of rodents. This chemical belongs to a class of non-genotoxic carcinogens, but DNA damage secondary to oxidative stress resulting from reactive oxygen species (ROS) generation is suspected in rodents given this chemical. To examine whether FF has genotoxic potential, partially hepatectomized F344 male rats were treated orally with 0, 1,000 or 2,000 mg/kg of FF for 2 weeks, followed by diet containing 0.15% 2 acetyl aminofluorene (2 AAF) for enhancement the tumor-promoting effect for 10 days and a single oral dose of carbon tetrachloride (CCl4) as the first experiment (liver initiation assay). As the second experiment, the in vivo liver comet assay was performed in hepatectomized rats, and the expression of some DNA repair genes was examined. In the liver initiation assay, the number and area of glutathione S-transferase placental form (GST-P)-positive single cells and foci did not increase in the FF treated groups. In the comet assay, positive results were obtained after 3 h of the last treatment of FF, and the expression of some DNA repair genes such as Apex1, Ogg1 and Mlh1 were upregulated in rats given the high dose of FF at 3 h after the treatment but not in 24 h after the treatment. The results of the present study suggest that FF causes some DNA damage in livers of rats, but is not a strong genotoxic substance leading to a DNA mutation since such DNA damage was repaired by the increased activity of some DNA repair genes.

Natural peroxisome proliferator-activated receptor-alpha agonist cream demonstrates similar therapeutic response to topical steroids in atopic dermatitis

Background: Atopic dermatitis (AD) requires permanent skin care. Objective: A cream containing 2% SO (sunflower oleodistillate), with peroxisome proliferator-activated receptor-alpha (PPAR-α) agonist properties, has been compared to a topical steroid (hydrocortisone butyro-propionate 1 mg/g). Methods: An open, randomized study included two groups of 40 children (aged 3 months to 4 years). Group A applied the steroid and group B applied the 2% SO cream, twice a day. SCORAD (SCORing Atopic Dermatitis) was determined at D0, D7 and D21 and quality of life (QoL) at D0 and D21. Results: SCORAD was similar at D0 (37.2 versus 36.9), D7 (18.9 versus 19.2) (–49% and –48%) and D21 (11 versus 9.4) (–70% and –75%) (p < 0.01 versus D0). The Infant Dermatitis Quality of Life and Dermatitis Family Impact Questionnaire improved similarly by 65%/67% in group A and 72%/75% in group B at D21 (p < 0.01 versus D0). Conclusion: A 2% SO cream has demonstrated therapeutic properties, using clinical scores and QoL, comparable to those of a topical steroid.

Toxicological evaluation of ammonium 4,8-dioxa-3H-perfluorononanoate, a new emulsifier to replace ammonium perfluorooctanoate in fluoropolymer manufacturing

Ammonium 4,8-dioxa-3H-perfluorononanoate (ADONA) was developed to replace ammonium perfluorooctanoate (APFO) as an emulsifier in the manufacture of fluoropolymers. The toxicity of ADONA was evaluated in acute and repeat-dose studies of up to 90-days duration, and in eye and skin irritation, dermal sensitization, genotoxicity, and developmental toxicity studies. ADONA was also evaluated as a peroxisome proliferator-activated receptor alpha (PPARα) agonist in rats. ADONA was moderately toxic orally and practically non-toxic dermally in acute studies in rats. It was a mild skin irritant and a moderate to severe eye irritant in rabbits. It was a weak dermal sensitizer in local lymph node assays in mice. ADONA was not genotoxic based on the weight of evidence from five assays. It was not developmentally toxic in rats except at maternally toxic doses. ADONA was a possible PPARα agonist in male rats. The liver was the primary target organ in male rats and the kidney was the primary target organ in female rats. NOAELs in 28- and 90-day oral studies in rats were 10mg/kg/day for males and 100mg/kg/day for females. These findings demonstrate that the toxicity profile for ADONA is acceptable for its intended use and is superior to that of APFO.

Synthesis and structure-activity relationships of N-(2-oxo-3-oxetanyl)amides as N-acylethanolamine-hydrolyzing acid amidase inhibitors.

The fatty acid ethanolamides (FAEs) are a family of bioactive lipid mediators that include the endogenous agonist of peroxisome proliferator-activated receptor-alpha, palmitoylethanolamide (PEA). FAEs are hydrolyzed intracellularly by either fatty acid amide hydrolase or N-acylethanolamine-hydrolyzing acid amidase (NAAA). Selective inhibition of NAAA by (S)-N-(2-oxo-3-oxetanyl)-3-phenylpropionamide [(S)-OOPP, 7a] prevents PEA degradation in mouse leukocytes and attenuates responses to proinflammatory stimuli. Starting from the structure of 7a, a series of beta-lactones was prepared and tested on recombinant rat NAAA to explore structure-activity relationships (SARs) for this class of inhibitors and improve their in vitro potency. Following the hypothesis that these compounds inhibit NAAA by acylation of the catalytic cysteine, we identified several requirements for recognition at the active site and obtained new potent inhibitors. In particular, (S)-N-(2-oxo-3-oxetanyl)biphenyl-4-carboxamide (7h) was more potent than 7a at inhibiting recombinant rat NAAA activity (7a, IC(50) = 420 nM; 7h, IC(50) = 115 nM) in vitro and at reducing carrageenan-induced leukocyte infiltration in vivo.

Fenofibrate induces effective apoptosis in mantle cell lymphoma by inhibiting the TNFα/NF-κB signaling axis

Mantle cell lymphoma (MCL) is a type of aggressive B-cell non-Hodgkin's lymphoma characterized by frequent resistance to conventional chemotherapy. In this study we provided evidence that fenofibrate, which is widely known as an agonist for peroxisome proliferator-activated receptor-alpha (PPARalpha), can induce effective apoptosis in treating MCL cells. Addition of fenofibrate to MCL cell lines significantly decreased the number of viable cells by 50% at approximately 20 microM at 72 h. This decrease in cell growth was due to apoptosis, as evidenced by the cleavage of caspase 3 and poly(ADP-ribose) polymerase. The fenofibrate-mediated effects were not significantly affected by GW6471, a specific PPARalpha antagonist. Using an apoptosis pathway-specific oligonucleotide array, we found that fenofibrate significantly downregulated several pro-survival genes, including tumor necrosis factor-alpha (TNFalpha). Importantly, addition of recombinant TNF-alpha conferred partial protection against fenofibrate-induced apoptosis. Fenofibrate also decreased the nuclear translocation of nuclear factor (NF)-kappaB-p65 and significantly inhibited the DNA binding of NF-kappaB in a dose-dependent manner. To conclude, fenofibrate shows efficacy against MCL, and the mechanism can be attributed to its inhibitory effects on the TNF-alpha/NF-kappaB signaling axis. In view of the documented safety of fenofibrate in humans, it may provide a valuable therapeutic option for MCL patients.

Differing short-term neuroprotective effects of the fibrates fenofibrate and bezafibrate in MPTP and 6-OHDA experimental models of Parkinson's disease

Earlier study from our group indicated that the peroxisome proliferator-activated receptor-alpha agonist fenofibrate prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic cell loss in C57Bl/6 mice. Our objective was to determine whether or not fibratescan improve motor activity in two experimental models of Parkinson's disease: the MPTP C57Bl/6 mouse and the 6-hydroxydopamine (6-OHDA) Wistar rat. Six groups of mice were set up: sham, sham-fenofibrate, sham-bezafibrate, MPTP, MPTP-fenofibrate and MPTP-bezafibrate. Mice were fed a diet containing 0.2% fenofibrate, 0.2% bezafibrate or no hypolipidaemic agent for 2 weeks. Four groups of rats were set up: sham, sham-fenofibrate, 6-OHDA and 6-OHDA-fenofibrate. Rats were fed a diet containing 0.2% fenofibrate or no hypolipidaemic agent for 4 weeks. In mice, motor activity was quantified using actimetry. Nine parameters were recorded. The results were analyzed with a mixed linear model. In rats, behavioural sensitization was studied with repetitive injections of apomorphine. All the actimetry parameters indicated a decrease of locomotion the day after MPTP injections and eight parameters improved in MPTP mice treated with fenofibrate or bezafibrate. The apomorphine-induced rotation behaviour mildly decreased in 6-OHDA rats treated with fenofibrate, but behavioural sensitization was unchanged. The 6-OHDA and MPTP compounds have different toxicity mechanisms, which could explain why we did not observe the same effect in 6-OHDA rats as in MPTP mice. These data suggest that the protective effect of fibrates can be carried through inhibition of inflammation rather than oxidative stress.

Retinyl retinoate induces hyaluronan production and less irritation than other retinoids

Hyaluronan, a non-sulfated glycosaminoglycan, retains water, maintains the extracellular spaces and facilitates the transport of ion solutes and nutrients. Hyaluronan is closely involved in keratinocyte proliferation, migration and differentiation. The synthesis of hyaluronan in vitro can be stimulated by several growth factors, including retinoids, dibutyryl cyclic adenosine monophosphate and peroxisome proliferator-activated receptor-alpha agonist. In this study, we examined retinyl retinoate (a novel retinol derivative) on hyaluronan expression in primary human keratinocytes and in hairless mouse epidermal skin. Histochemistry using hyaluronan-binding protein revealed that topical retinyl retinoate increased the intensity of hyaluronan staining in murine skin. Moreover, topical retinyl retinoate increased CD44 (hyaluronan receptor) expression. Using reverse transcription polymerase chain reaction, we assessed the expression level of the hyaluronan synthase 2 (HAS2) gene in primary human keratinocytes and in hairless mouse epidermal skin. We found that retinyl retinoate upregulated mouse HAS2 and human HAS2 mRNA. Application of retinyl retinoate induced increasing transepidermal water loss less than retinol, retinoic acid and retinaldehyde. Taken together, we suggest that retinyl retinoate is more effective on hyaluronan production and less of an irritant than other retinoids.

Phytanic acid—an overlooked bioactive fatty acid in dairy fat?

Phytanic acid is a multibranched fatty acid with reported retinoid X receptor (RXR) and peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonist activity, which have been suggested to have preventive effects on metabolic dysfunctions. Serum level in man is strongly correlated to the intake of red meat and dairy products and the concentration in these products is strongly correlated to the chlorophyll content in the feed of the cattle. Available data suggest that phytanic acid is a natural agonist for RXR at physiological concentrations, while it is more likely that it is the metabolite pristanic acid, rather than phytanic acid itself, that acts as PPAR-alpha agonist. Animal studies show increased expression of genes involved in fatty acid oxidation, after intake of phytol, the metabolic precursor of phytanic acid, but it is at present not possible to deduce whether phytanic acid is useful in the prevention of ectopic lipid deposition. Phytanic acid is an efficient inducer of the expression of uncoupler protein 1 (UCP1). UCP1 is expressed in human skeletal muscles, were it might be important for the total energy balance. Therefore, phytanic acid may be able to stimulate energy dissipation in skeletal muscles. Phytanic acid levels in serum are associated with an increased risk of developing prostate cancer, but the available data do not support a general causal link between circulating phytanic acid and prostate cancer risk. However, certain individuals, with specific single-nucleotide polymorphisms in the gene for the enzyme alpha-methylacyl-CoA racemase, might be susceptible to raised phytanic acid levels.

Evaluation of in vivo liver genotoxic potential of Wy-14,643 and piperonyl butoxide in rats subjected to two-week repeated oral administration

Wy-14,643 (WY), a peroxisome proliferator-activated receptor-alpha agonist, and piperonyl butoxide (PBO), a pesticide synergist, induce oxidative stress and promote hepatocarcinogenesis in the liver of rodents. These chemicals belong to a class of non-genotoxic carcinogens, but DNA damage secondary to the oxidative stress resulting from reactive oxygen species generation is suspected in rodents given these chemicals. To examine whether WY or PBO have DNA-damaging potential in livers of rats subjected to repeated oral administration for 14 days, the in vivo liver comet assay was performed in partially hepatectomized rats, and the expression of some DNA-repair genes was examined. Then, to examine whether they have genotoxic potential, the in vivo liver initiation assay was performed in rats. In the comet assay, positive results were obtained at 3 h after the last treatment of WY, and some DNA-repair genes such as Apex1, Mlh1, Xrcc5, and Gadd45 were up-regulated in the liver. In the liver initiation assay, negative results were obtained for both WY and PBO. The results of the present study suggest that WY, but not PBO, causes some DNA damage in livers of rats, but such DNA damage was repaired by the increased activity of some DNA repair genes and may not lead to a DNA mutation.

Adipophilin protein expression in muscle – a possible protective role against insulin resistance

Adipophilin is a 50 kDa protein that belongs to the PAT family (perilipin, adipophilin, TIP47, S3-12 and OXPAT), which comprises proteins involved in the coating of lipid droplets. Little is known about the functional role of adipophilin in muscle. Using the C2C12 cell line as a model, we demonstrate that palmitic acid-treated cells highly express the adipophilin protein in a dose-dependent way. Next, we show that oleic acid is a more potent inducer of adipophilin protein levels than palmitic acid. Cells treated with oleic acid have a higher adipophilin protein expression and higher triglyceride levels but less impairment of insulin signaling than cells treated with palmitic acid. Additionally, we show that peroxisome proliferator-activated receptor (PPAR)alpha, PPARbeta/delta and PPARgamma agonists all increase the expression of the adipophilin protein in C2C12 cells. This effect was most pronounced for the PPARalpha agonist GW7647. Furthermore, the expression of adipophilin as a 37 kDa N-terminally truncated protein is higher in the gastrocnemius than in the quadriceps of C57BL/6J mice, especially after an 8-week high-fat diet. The expression of adipophilin was higher in the muscle of mice fed a 4-week high-fat diet based on olive oil or safflower oil than in mice fed a 4-week high-fat diet based on palm oil. After 2 weeks of intervention, plasma glucose, plasma insulin and the homeostasis model assessment of insulin resistance index were lower in mice fed a 4-week high-fat diet based on olive oil or safflower oil than in mice fed a 4-week high-fat diet based on palm oil. Taken together, the results obtained in the present study indicate that adipophilin protein expression in muscle is involved in maintaining insulin sensitivity.

Fenofibrate Reduces Systemic Inflammation Markers Independent of Its Effects on Lipid and Glucose Metabolism in Patients with the Metabolic Syndrome

Fenofibrate is a peroxisome proliferator-activated receptor alpha agonist widely used in clinical practice, but its mechanism of action is incompletely understood. The aim of the study was to assess whether improvement in subclinical inflammation or glucose metabolism contributes to its antiatherogenic effects in insulin-resistant subjects with the metabolic syndrome (MetS). We conducted a randomized, double-blind, placebo-controlled study in the research unit at an academic center. We studied 25 nondiabetic insulin-resistant MetS subjects. We administered fenofibrate (200 mg/d) and placebo for 12 wk. Before and after treatment, we measured plasma lipids/apolipoproteins, inflammatory markers (high-sensitivity C-reactive protein, IL-6, intercellular adhesion molecule/vascular cell adhesion molecule), adipocytokines (adiponectin, TNFalpha, leptin), and insulin secretion (oral glucose tolerance test). We also assessed adipose tissue, hepatic and peripheral (muscle) insulin resistance fasting and during a euglycemic insulin clamp with (3)H glucose and (14)C palmitate infusion combined with indirect calorimetry. Subjects displayed severe insulin resistance and systemic inflammation. Fenofibrate significantly reduced plasma triglyceride, apolipoprotein (apo) CII, apo CIII, and apo E (all P < 0.01), with a modest increase in high-density lipoprotein-cholesterol (+12%; P = 0.06). Fenofibrate markedly decreased plasma high-sensitivity C-reactive protein by 49.5 +/- 8% (P = 0.005) and IL-6 by 29.8 +/- 7% (P = 0.03) vs. placebo. However, neither insulin secretion nor adipose tissue, hepatic or muscle insulin sensitivity or glucose/lipid oxidation improved with treatment. Adiponectin and TNF-alpha levels were also unchanged. Improvement in plasma markers of vascular/systemic inflammation was dissociated from changes in triglyceride/high-density lipoprotein-cholesterol, apo CII/CIII, or free fatty acid concentrations or insulin secretion/insulin sensitivity. In subjects with the MetS, fenofibrate reduces systemic inflammation independent of improvements in lipoprotein metabolism and without changing insulin sensitivity. This suggests a direct peroxisome proliferator-activated receptor alpha-mediated effect of fenofibrate on inflammatory pathways, which may be important for the prevention of CVD in high-risk patients.

Peroxisome Proliferator-activated Receptor Alpha (PPARα) Agonists Induce Constitutive Androstane Receptor (CAR) and Cytochrome P450 2B in Rat Primary Hepatocytes

The constitutive androstane receptor (CAR; NR1I3) is a key transcriptional factor that regulates genes encoding drug-metabolizing enzymes and drug transporters. However, studies on regulation of CAR target genes via up- or down-regulation of CAR are limited. In this study, we examined the effects of PPARalpha agonists (ciprofibrate, bezafibrate, fenofibrate and WY14643) on the expression of CAR and its target gene CYP2B1/2 in rat primary hepatocytes. Results from real-time PCR analysis showed that CAR and CYP2B1/2 mRNAs exhibit increases in response to all PPARalpha agonists studied (5 to 10-folds of control). Pretreatment of cells with cycloheximide, an inhibitor of protein synthesis, completely suppressed increase in CYP2B1/2 mRNA in response to ciprofibrate, suggesting that protein synthesis is required in this process. In addition, the induction of CAR by ciprofibrate on the protein level was observed with nuclear extracts as well as total cell lysates. These results indicate that CYP2B1/2 mRNAs are induced by PPARalpha agonists and that this effect is accompanied by increase in the expression of CAR gene at both mRNA and nuclear protein levels. Activated PPARalpha may increase functional CAR protein, which can induce the expression of CAR target genes such as CYP2B.

Effects of the endogenous PPAR‐α agonist, oleoylethanolamide on MDMA‐induced cognitive deficits in mice

MDMA (3,4-Methylenedioxymethamphetamine) is an amphetamine derivative widely used for recreational purposes. We have recently shown that repeated treatment with high doses of MDMA-induced impairments in the acquisition and recall of an active avoidance task in mice. In this study, we examined whether the endogenous peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonist, oleoylethanolamide (OEA) protects against these MDMA-induced deficits. Mice were pretreated twice a day with OEA (0, 5, and 25 mg/kg) 30 min before an injection of MDMA (30 mg/kg) or saline during four consecutive days. Twenty-four hours after the last treatment, animals were trained in an active avoidance task for two consecutive weeks. After a 5-day resting period, a recall session was performed. Mice treated with MDMA showed reduced learning and recall of the task when compared with saline-treated controls. OEA at 5 mg/kg ameliorated and at 25 mg/kg worsened this deficit. Dopamine transporter (DAT)-binding sites significantly decreased 4 days after the last MDMA administration and pretreatment with both doses of OEA prevented this effect. In immunohistochemical studies, coexpression of tyrosine-hydroxylase and PPAR-alpha receptors was observed in the striatum and substantia nigra pars compacta of mice. These results suggest that OEA administration can modulate the cognitive deficits induced by MDMA in a DAT-independent manner.