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PubMed2005

PPAR alpha inhibits vascular smooth muscle cell proliferation underlying intimal hyperplasia by inducing the tumor suppressor p16INK4a.

Vascular SMC proliferation is a crucial event in occlusive cardiovascular diseases. PPARalpha is a nuclear receptor controlling lipid metabolism and inflammation, but its role in the regulation of SMC growth remains to be established. Here, we show that PPARalpha controls SMC cell-cycle progression at the G1/S transition by targeting the cyclin-dependent kinase inhibitor and tumor suppressor p16(INK4a) (p16), resulting in an inhibition of retinoblastoma protein phosphorylation. PPARalpha activates p16 gene transcription by both binding to a canonical PPAR-response element and interacting with the transcription factor Sp1 at specific proximal Sp1-binding sites of the p16 promoter. In a carotid arterial-injury mouse model, p16 deficiency results in an enhanced SMC proliferation underlying intimal hyperplasia. Moreover, PPARalpha activation inhibits SMC growth in vivo, and this effect requires p16 expression. These results identify an unexpected role for p16 in SMC cell-cycle control and demonstrate that PPARalpha inhibits SMC proliferation through p16. Thus, the PPARalpha/p16 pathway may be a potential pharmacological target for the prevention of cardiovascular occlusive complications of atherosclerosis.

Animals↗
PubMed2004

Enhancement of insulin signaling through inhibition of tissue lipid accumulation by activation of peroxisome proliferator-activated receptor (PPAR) alpha in obese mice.

BACKGROUND: The aim of the present study was to investigate the effect of PPARalpha activation on insulin signaling and lipid accumulation in the liver and skeletal muscle of insulin-resistant (ob/ob) mice. MATERIAL/METHODS: A known subtype-selective PPARalpha agonist, Wy-14,643, was administered to lean and ob/ob mice at 30 mg/kg/day for 4 weeks. Insulin (100 units/kg) or saline was injected into the portal vein of anesthetized mice. The liver and skeletal muscles were used for the detection of tyrosine phosphorylation of the insulin receptor (IR) and insulin receptor substrates (IRSs), as well as for the determination of both IRS-associated PI3-K activity and lipid content; in addition, the measurement of mRNA levels of PPAR-regulated genes was carried out. RESULTS: The PPARalpha agonist lowered plasma levels of glucose, insulin, triglycerides, and free fatty acids in ob/ob mice. Several PPARalpha-upregulated genes related to the transport and oxidation of fatty acids in the liver were increased by treatment with the agonist. The PPARalpha agonist significantly increased IR- and IRS-tyrosine phosphorylation and IRS-associated PI3-K activity in the liver and muscle of ob/ob mice, without exerting the same effects in lean mice. Moreover, these effects in ob/ob mice were accompanied by decreased triglyceride and fatty acyl-CoA contents in the liver and skeletal muscle. CONCLUSIONS: The present results suggest that inhibition of lipid accumulation by hepatic PPARalpha activation leads to an improvement in impaired insulin signaling in muscle tissue as well as in the liver of insulin-resistant mice.

Animals↗
PubMed2006

Fibrates upregulate TRB3 in lymphocytes independent of PPAR alpha by augmenting CCAAT/enhancer-binding protein beta (C/EBP beta) expression.

Fibrates, which function by binding and activating peroxisome proliferator-activated receptor alpha (PPARalpha), have been used successfully to treat hyperlipidemia and atherosclerosis. Increasing evidence suggests that in addition to their lipid lowering activities these medications also function as immunosuppressive agents. Tribbles is a Drosophila protein that slows cell cycle progression, and its mammalian homolog, TRB3 interferes with insulin-induced activation of AKT. In these studies we demonstrate that fibrates upregulate TRB3 expression in mitogen-activated lymphocytes. Interestingly, in lymphocytes fibrates augment TRB3 expression in both PPARalpha wildtype and knockout mice, suggesting that upregulation of this protein occurs in a PPARalpha-independent manner. Fibrates activate a proximal TRB3 promoter construct and mutation or partial deletion of a potential PPAR response element does not alter the ability of fibrates to drive TRB3 expression. Subsequent studies reveal that fibrates upregulate C/EBPbeta and CHOP in lymphocytes and mutation of potential C/EBPbeta and CHOP consensus sequences abrogates the ability of fibrates to upregulate TRB3 promoter activity. Accordingly, fibrates enhance the recruitment of C/EBPbeta and CHOP to the proximal TRB3 promoter. Finally, TRB3 expression in lymphocytes induces G2 cell cycle delay and cellular depletion. These studies outline a novel PPARalpha-independent mechanism of action of fibrates and document for the first time the expression of TRB3 in activated lymphocytes.

Adjuvants, Immunologic↗
PubMed2004

Evidence for a new human CYP1A1 regulation pathway involving PPAR-alpha and 2 PPRE sites.

BACKGROUND AND AIMS: Cytochrome P450 1A1 catalyzes the degradation of endobiotics (estradiol, fatty acids, and so on) and the bioactivation of numerous environmental procarcinogens, such as arylamines and polycyclic aromatic hydrocarbons, that are found in food. Several peroxisome proliferators and arachidonic acid derivatives enhance cytochrome P450 1A1 activity, but the mechanisms involved remain unknown. The aim of this work was to study the role of peroxisome proliferator-activated receptors in cytochrome P450 1A1 gene induction. METHODS: The role of peroxisome proliferator-activated receptor transcription factors in cytochrome P450 1A1 induction was assessed by means of enzymatic activities, quantitative real-time polymerase chain reaction, gene reporter assays, mutagenesis, and electrophoretic mobility shift assay. RESULTS: We show that peroxisome proliferator-activated receptor-alpha agonists (WY-14643, bezafibrate, clofibrate, and phthalate) induce human cytochrome P450 1A1 gene expression, whereas 2,4-thiazolidinedione, a specific peroxisome proliferator-activated receptor-gamma agonist, represses it. The induction of cytochrome P450 1A1 transcripts by WY-14643 was associated with a marked increase of ethoxyresorufin O -deethylase activity (10-fold at 200 mumol/L). Transfection of peroxisome proliferator-activated receptor-alpha complementary DNA enhanced cytochrome P450 1A1 messenger RNA induction by WY-14643, although WY-14643 failed to activate xenobiotic responsive element sequences. Two peroxisome proliferator response element sites were located at positions -931/-919 and -531/-519 of the cytochrome P450 1A1 promoter. Their inactivation by directed mutagenesis suppressed the inductive effect of WY-14643 on cytochrome P450 1A1 promoter activation. Electrophoretic mobility shift assay and chromatin immunoprecipitation assay experiments showed that the 2 cytochrome P450 1A1 peroxisome proliferator response element sites bind the peroxisome proliferator-activated receptor-alpha/retinoid X receptor-alpha heterodimer. CONCLUSIONS: We describe here a new cytochrome P450 1A1 induction pathway involving peroxisome proliferator-activated receptor-alpha and 2 peroxisome proliferator response element sites, indicating that peroxisome proliferator-activated receptor-alpha ligands, which are common environmental compounds, may be involved in carcinogenesis.

Adenocarcinoma↗
PubMed1995

Novel sequence determinants in peroxisome proliferator signaling.

The gene encoding cytochrome P-450 4A6 (CYP4A6) is transcriptionally activated by peroxisome proliferators. This response is dependent on a strong enhancer element (Z) and weaker elements (X and -27). The peroxisome proliferator response is mediated by the binding of heterodimers containing the peroxisome proliferator-activated receptor alpha (PPAR alpha) and the retinoid X receptor alpha (RXR alpha) to these elements. These peroxisome proliferator response elements (PPREs) contain imperfect direct repeats of the nuclear receptor consensus recognition sequence with a spacing of one nucleotide (DR1) (AGGTCA N AGGTCA). This DR1 motif is seen in the binding sites for other nuclear receptor complexes, such as ARP-1, HNF-4, and RXR alpha homodimers. Mutational analysis of the Z element reveals that the DR1 motif is required for the transcriptional activation of the CYP4A6 gene by peroxisome proliferators; however, deletion of sequences immediately upstream of this motif also abolishes this response. Oligonucleotides corresponding to truncated and mutated Z elements were assayed by gel retardation for binding to RXR alpha, PPAR alpha, and ARP-1. Deletions or mutations within six nucleotides 5' of the DR1 motif dramatically diminish PPAR alpha.RXR alpha binding without reducing the binding of either RXR alpha or ARP-1 homodimers, whereas mutation or deletion of the core DR1 sequences abolishes the binding of PPAR alpha.RXR alpha heterodimers and of RXR alpha or ARP-1 homodimers. Thus, the DR1 motif in the Z element is not sufficient to constitute a PPRE. Moreover, the binding of PPAR alpha.RXR alpha to the Z element requires sequences immediately 5' of the DR1. These sequences are conserved in natural PPREs and promote binding of PPAR alpha.RXR alpha heterodimers in preference to potential competitors such as ARP-1 and RXR alpha.

Animals↗
PubMed2006

The dominant negative thyroid hormone receptor beta-mutant {Delta}337T alters PPAR{alpha} signaling in heart.

PPARalpha and TR independently regulate cardiac metabolism. Although ligands for both these receptors are currently under evaluation for treatment of congestive heart failure, their interactions or signaling cooperation have not been investigated in heart. We tested the hypothesis that cardiac TRs interact with PPARalpha regulation of target genes and used mice exhibiting a cardioselective Delta337T TRbeta1 mutation (MUT) to reveal cross-talk between these nuclear receptors. This dominant negative transgene potently inhibits DNA binding for both wild-type (WT) TRalpha and TRbeta. We used UCP3 and MTE-1 as principal reporters and analyzed gene expression from hearts of transgenic (MUT) and nontransgenic (WT) littermates 6 h after receiving either specific PPARalpha ligand (WY-14643) or vehicle. Interactions were determined through qRT-PCR analyses, and the extent of these interactions across multiple genes was determined using expression arrays. In the basal state, we detected no differences between groups for protein content for UCP3, PPARalpha, TRalpha2, RXRbeta, or PGC-1alpha. However, protein content for TRalpha1 and the PPARalpha heterodimeric partner RXRalpha was diminished in MUT, whereas PPARbeta increased. We demonstrated cross-talk between PPAR and TR for multiple genes, including the reporters UCP3 and MTE1. WY-14643 induced a twofold increase in UCP3 gene expression that was totally abrogated in MUT. We demonstrated variable cross-talk patterns, indicating that multiple mechanisms operate according to individual target genes. The non-ligand-binding TRbeta1 mutation alters expression for multiple nuclear receptors, providing a novel mechanism for interaction that has not been previously demonstrated. These results indicate that therapeutic response to PPARalpha ligands may be determined by thyroid hormone state and TR function.

Animals↗
PubMed2006

PPAR{alpha} mediates the hypolipidemic action of fibrates by antagonizing FoxO1.

High-fructose consumption is associated with insulin resistance and diabetic dyslipidemia, but the underlying mechanism is unclear. We show in hamsters that high-fructose feeding stimulated forkhead box O1 (FoxO1) production and promoted its nuclear redistribution in liver, correlating with augmented apolipoprotein C-III (apoC-III) production and impaired triglyceride metabolism. High-fructose feeding upregulated peroxisome proliferator-activated receptor-gamma coactivator-1beta and sterol regulatory element binding protein-1c expression, accounting for increased fat infiltration in liver. High-fructose-fed hamsters developed hypertriglyceridemia, accompanied by hyperinsulinemia and glucose intolerance. These metabolic aberrations were reversible by fenofibrate, a commonly used anti-hypertriglyceridemia agent that is known to bind and activate peroxisome proliferator-activated receptor-alpha (PPARalpha). PPARalpha physically interacted with, but functionally antagonized, FoxO1 in hepatic apoC-III expression. These data underscore the importance of FoxO1 deregulation in the pathogenesis of hypertriglyceridemia in high-fructose-fed hamsters. Counterregulation of hepatic FoxO1 activity by PPARalpha constitutes an important mechanism by which fibrates act to curb apoC-III overproduction and ameliorate hypertriglyceridemia.

Animals↗
PubMed2003

Down-regulation of STAT5b transcriptional activity by ligand-activated peroxisome proliferator-activated receptor (PPAR) alpha and PPARgamma.

The nuclear receptor peroxisome proliferator-activated receptor (PPAR) is activated by a diverse group of acidic ligands, including many peroxisome proliferator chemicals present in the environment. Janus tyrosine kinase-signal transducer and activator of transcription (JAK-STAT) signaling is activated by multiple cytokines and hormones and leads to the translocation of dimerized STAT proteins to the nucleus where they activate transcription of target genes. Previous studies have shown that growth hormone (GH)-activated STAT5b can inhibit PPAR-regulated transcription. Here, we show that this inhibitory cross-talk is mutual, and that GH-induced, STAT5b-dependent beta-casein promoter-luciferase reporter gene transcription can be inhibited up to approximately 80% by ligand-activated PPARalpha or PPARgamma. Dose-response experiments showed a direct relationship between the extent of PPAR activation and the degree of inhibition of STAT5-regulated transcription. PPAR did not block STAT5b tyrosine phosphorylation or inhibit DNA-binding activity. Both PPARs inhibited the transcriptional activity of a constitutively active STAT5b mutant, indicating that inhibition occurs downstream of the GH-stimulated STAT5 activation step. Transcriptionally inactive, dominant-negative PPAR mutants did not block STAT5b inhibition by wild-type PPAR, indicating that PPAR target gene transcription is not required. PPARalpha retained its STAT5b inhibitory activity in the presence of the histone deacetylase inhibitor trichostatin, indicating that enhanced histone deacetylase recruitment does not contribute to STAT5b inhibition. PPARalpha lacking the ligand-independent AF-1 trans-activation domain failed to inhibit STAT5b, highlighting the importance of the AF-1 region in STAT5-PPAR inhibitory cross-talk. These findings demonstrate the bidirectionality of cross-talk between the PPAR and STAT pathways and provide a mechanism whereby exposure to environmental chemical activators of PPAR can suppress expression of GH target genes.

Animals↗
PubMed2006

Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis.

PPARalpha is a nuclear receptor that regulates liver and skeletal muscle lipid metabolism as well as glucose homeostasis. Acting as a molecular sensor of endogenous fatty acids (FAs) and their derivatives, this ligand-activated transcription factor regulates the expression of genes encoding enzymes and transport proteins controlling lipid homeostasis, thereby stimulating FA oxidation and improving lipoprotein metabolism. PPARalpha also exerts pleiotropic antiinflammatory and antiproliferative effects and prevents the proatherogenic effects of cholesterol accumulation in macrophages by stimulating cholesterol efflux. Cellular and animal models of PPARalpha help explain the clinical actions of fibrates, synthetic PPARalpha agonists used to treat dyslipidemia and reduce cardiovascular disease and its complications in patients with the metabolic syndrome. Although these preclinical studies cannot predict all of the effects of PPARalpha in humans, recent findings have revealed potential adverse effects of PPARalpha action, underlining the need for further study. This Review will focus on the mechanisms of action of PPARalpha in metabolic diseases and their associated vascular pathologies.

Animals↗
PubMed2004

Differential regulation of cytosolic and peroxisomal bile acid amidation by PPAR alpha activation favors the formation of unconjugated bile acids.

In human liver, unconjugated bile acids can be formed by the action of bile acid-CoA thioesterases (BACTEs), whereas bile acid conjugation with taurine or glycine (amidation) is catalyzed by bile acid-CoA:amino acid N-acyltransferases (BACATs). Both pathways exist in peroxisomes and cytosol. Bile acid amidation facilitates biliary excretion, whereas the accumulation of unconjugated bile acids may become hepatotoxic. We hypothesized that the formation of unconjugated and conjugated bile acids from their common substrate bile acid-CoA thioesters by BACTE and BACAT is regulated via the peroxisome proliferator-activated receptor alpha (PPARalpha). Livers from wild-type and PPARalpha-null mice either untreated or treated with the PPARalpha activator WY-14,643 were analyzed for BACTE and BACAT expression. The total liver capacity of taurochenodeoxycholate and taurocholate formation was decreased in WY-14,643-treated wild-type mice by 60% and 40%, respectively, but not in PPARalpha-null mice. Suppression of the peroxisomal BACAT activity was responsible for the decrease in liver capacity, whereas cytosolic BACAT activity was essentially unchanged by the treatment. In both cytosol and peroxisomes, the BACTE activities and protein levels were upregulated 5- to 10-fold by the treatment. These effects caused by WY-14,643 treatment were abolished in PPARalpha-null mice. The results from this study suggest that an increased formation of unconjugated bile acids occurs during PPARalpha activation.

Acyltransferases↗
PubMed2004

Population prevalence of APOE, APOC3 and PPAR-alpha mutations associated to hypertriglyceridemia in French Canadians.

Hypertriglyceridemia (HTG) is known as a common metabolic disorder associated with increased production, decrease catabolism and/or decreased hepatic uptake of triglyceride (TG)-rich particles. We assessed, in the Quebec City population, the allele frequency and haplotype distributions of mutations in genes related to HTG, such as the apolipoprotein E (APOE) (C112R and C158R), the apolipoprotein CIII (APOC3) (C-482T and C3238G) and the peroxisome proliferator-activated receptor alpha (PPARalpha) (L162V) genes. A total of 938 anonymous unlinked newborns from the metropolitan Quebec City area have been genotyped. Allele frequencies observed in the Quebec City population differed from known frequencies determined in other Caucasian populations. The co-transmitted allele distribution between the two-marker genotypes APOE/APOC3(C3238G) and APOC3(C-482T)/PPARalpha(L162V) presented a weak deviation from the assumption of genetic independence. Also, we observed a non-independent distribution of the T-482/G3238 allele combinations within the APOC3 gene, suggesting strong linkage disequilibrium between the C-482T and C3238G polymorphisms. Moreover, comparisons of allele frequencies observed in the population of Québec City to those obtained in other Caucasian populations suggested that the population of Québec City may be at a lower risk of developing HTG due to APOE, APOC3 and PPARalpha genetic variants. However, the strong linkage disequilibrium and the two-marker genotype distributions observed in the APOC3 gene suggest that these two variants may functionally interact in the Québec City population.

Amino Acid Substitution↗
PubMed2003

Inhibition of cholesterol absorption associated with a PPAR alpha-dependent increase in ABC binding cassette transporter A1 in mice.

Dietary supplementation with the peroxisome proliferator-activated receptor alpha (PPAR alpha) ligand WY 14,643 gave rise to a 4- to 5-fold increase in the expression of mRNA for the ATP binding cassette transporter A1 (ABCA1) in the intestine of normal mice. There was no effect in the intestine of PPAR alpha-null mice. Consumption of a high-cholesterol diet also increased intestinal ABCA1 expression. The effects of WY 14,643 and the high-cholesterol diet were not additive. WY 14,643 feeding reduced intestinal absorption of cholesterol in the normal mice, irrespective of the dietary cholesterol concentration, and this resulted in lower diet-derived cholesterol and cholesteryl ester concentrations in plasma and liver. At each concentration of dietary cholesterol, there was a similar significant inverse correlation between intestinal ABCA1 mRNA content and the amount of cholesterol absorbed. The fibrate-induced changes in the intestines of the normal mice were accompanied by an increased concentration of the mRNA encoding the sterol-regulatory element binding protein-1c gene (SREBP-1c), a known target gene for the oxysterol receptor liver X receptor alpha (LXR alpha). There was a correlation between intestinal ABCA1 mRNA and SREBP-1c mRNA contents, but not between SREBP-1c mRNA content and cholesterol absorption. These results suggest that PPAR alpha influences cholesterol absorption through modulating ABCA1 activity in the intestine by a mechanism involving LXR alpha.

ATP-Binding Cassette Transporters↗
PubMed2005

Gene expression profiling of the PPAR-alpha agonist ciprofibrate in the cynomolgus monkey liver.

Fibrates, such as ciprofibrate, fenofibrate, and clofibrate, are peroxisome proliferator-activated receptor-alpha (PPARalpha) agonists that have been in clinical use for many decades for treatment of dyslipidemia. When mice and rats are given PPARalpha agonists, these drugs cause hepatic peroxisome proliferation, hypertrophy, hyperplasia, and eventually hepatocarcinogenesis. Importantly, primates are relatively refractory to these effects; however, the mechanisms for the species differences are not clearly understood. Cynomolgus monkeys were exposed to ciprofibrate at various dose levels for either 4 or 15 days, and the liver transcriptional profiles were examined using Affymetrix human GeneChips. Strong upregulation of many genes relating to fatty acid metabolism and mitochondrial oxidative phosphorylation was observed; this reflects the known pharmacology and activity of the fibrates. In addition, (1) many genes related to ribosome and proteasome biosynthesis were upregulated, (2) a large number of genes downregulated were in the complement and coagulation cascades, (3) a number of key regulatory genes, including members of the JUN, MYC, and NFkappaB families were downregulated, which appears to be in contrast to the rodent, where JUN and MYC are reported to upregulated after PPARalpha agonist treatment, (4) no transcriptional signal for DNA damage or oxidative stress was observed, and (5) transcriptional signals consistent with an anti-proliferative and a pro-apoptotic effect were seen. We also compared the primate data to literature reports of hepatic transcriptional profiling in PPARalpha-treated rodents, which showed that the magnitude of induction in beta-oxidation pathways was substantially greater in the rodent than the primate.

Animals↗
PubMed2005

Evaluation of polycyclic aromatic hydrocarbons in the activation of early growth response-1 and peroxisome proliferator activated receptors.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental and food contaminants with known or suspected carcinogenic properties. In this study, we have evaluated whether PAHs activate the early growth response (EGR-1) gene and bind to peroxisome proliferator-activated receptor alpha (PPAR alpha) and delta (PPAR beta/delta) in cell culture systems. Luciferase reporter systems were employed and several PAHs were evaluated for their ability to activate EGR-1 and PPARs. Some PAHs enhanced EGR-1 expression and activated PPAR alpha and PPAR beta. Among them, benz(a)anthracene was found to act as a relatively potent activator of PPAR alpha and PPAR beta/delta, and to significantly enhance EGR-1 transcription. These in vitro assays were confirmed by Western blot analysis, using cell lysates of tissue samples from mouse trapped at a highly contaminated Superfund site in the Chattanooga Creek floodplain in Chattanooga, Tennessee. We have found that a PPAR target gene, glycogen synthase kinase-3beta (GSK-3beta), was down-regulated and EGR-1 was up-regulated in the mouse samples of Chattanooga Creek. In addition, select PAHs repressed GSK-3beta and induced CYP4A in FaO rat hepatoma cells. In conclusion, PAHs activate PPAR alpha and PPAR beta/delta, and up-regulate EGR-1 expression in vitro as well as in vivo. These data may provide a diversity of PAH activity in several biological pathways.

Animals↗
PubMed2004

Expression of peroxisome proliferator-activated receptors in the liver of gray mullet (Mugil cephalus).

During the last decade, peroxisome proliferation has emerged as a novel biomarker of exposure to certain organic chemical pollutants in aquatic organisms. Peroxisome proliferation is mediated by nuclear receptors, peroxisome proliferator-activated receptors (PPARs). Three PPAR subtypes have been described in mammals: PPAR alpha, PPAR beta and PPAR gamma. PPARs have also been discovered in several fish species. The aim of the present study was to investigate the expression of PPAR subtypes and their cellular distribution patterns in the liver of gray mullet Mugil cephalus, a fish species widely distributed in estuaries and coastal areas in Europe and used as sentinel of environmental pollution. For this purpose, antibodies were generated against the three subtypes of mouse PPARs and different protocols of antigen retrieval were used. In western blots, main bands were detected of approximately 44 kDa for PPAR alpha, two bands of 44 and 58 kDa for PPAR beta and a single band of 56 kDa for PPAR gamma. Similar results were obtained in mouse liver and may indicate antibody recognition of two forms of the protein in certain cases. PPAR alpha was the subtype most markedly expressed in gray mullet liver, being expressed mainly in melanomacrophages, nuclei of hepatocytes and sinusoidal cells and connective tissue surrounding bile ducts. PPAR beta was expressed in the same cell types but immunolabeling was generally weaker than for PPAR alpha. PPAR gamma showed very weak expression; positivity was mainly found in melanomacrophages and connective tissue surrounding bile ducts. Our results demonstrate that all the three PPAR subtypes are expressed in gray mullet liver but in different intensities. The cellular distribution patterns of PPAR subtypes in gray mullet liver resembled partly those found in mouse liver with PPAR alpha as the main subtype expressed in hepatocytes. The fact that melanomacrophages, cells of the immune system in fish, show strong expression of both PPAR alpha and PPAR beta whereas PPAR gamma expression is almost restricted to this cell type suggest a significant role of PPAR-mediated regulation of cell function in melanomacrophages.

Animals↗
PubMedDate not supplied

Influences of the PPAR alpha-L162V polymorphism on plasma HDL(2)-cholesterol response of abdominally obese men treated with gemfibrozil.

PURPOSE: The effect of gemfibrozil is mediated by the activation of peroxisome proliferator-activated receptor alpha (PPAR alpha). The objective of this study was to determine whether the lipid response to gemfibrozil therapy is influenced by the PPAR alpha-L162V polymorphism. METHODS: Sixty-three abdominally obese men were randomly assigned to a 6-month-intervention program with either receiving a placebo (N = 31) or gemfibrozil (N = 32). RESULTS: In response to gemfibrozil therapy, L162-homozygotes exhibited a 5.5% increase in high-density lipoprotein 2 cholesterol (HDL(2)-C) levels compared with a 50.0% increase among carriers of the V162 allele (P = 0.03). CONCLUSION: These results suggest that the HDL(2)-C response to gemfibrozil is modulated by the PPAR alpha-L162V polymorphism.

Abdomen↗
PubMed2002

WY14,643, a PPAR alpha ligand, has profound effects on immune responses in vivo.

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors with diverse actions. PPARalpha and PPARgamma are expressed in different lymphocyte subpopulations. Recently, we have observed that PPARalpha ligands elicit augmented IL-4 expression in cultures of mitogen-activated splenocytes. The following studies were undertaken to characterize the in vivo effects of WY14,643, a PPARalpha ligand. Our studies demonstrate that oral administration of WY14,643 markedly reduces splenocyte number in immunized and nonimmunized C57BL/6 mice. Mice fed WY14,643 display impaired IgG responses to myelin oligodendrocyte glycoprotein peptide 35-55 (pMOG(35-55)), following immunization with pMOG(35-55)/CFA. Following in vitro restimulation with pMOG(35-55), splenocytes harvested from WY14,643-fed mice demonstrate impaired production of IFN-gamma, IL-6, and TNF-alpha despite similar proliferative responses. We also demonstrate higher expression of PPARalpha in B than T cells. Finally, to obtain an understanding of the cause of splenocyte depletion with fibrate therapy, we studied the effect of WY14,643 on apoptosis of activated splenocytes. WY14,643 in vitro induces apoptosis in lymphocytes and this effect appears to occur in a PPARalpha-independent manner. Thus WY14,643, a fibrate, is a profound immunosuppressive agent.

Administration, Oral↗
PubMed2001

Impaired skin wound healing in peroxisome proliferator-activated receptor (PPAR)alpha and PPARbeta mutant mice.

We show here that the alpha, beta, and gamma isotypes of peroxisome proliferator-activated receptor (PPAR) are expressed in the mouse epidermis during fetal development and that they disappear progressively from the interfollicular epithelium after birth. Interestingly, PPARalpha and beta expression is reactivated in the adult epidermis after various stimuli, resulting in keratinocyte proliferation and differentiation such as tetradecanoylphorbol acetate topical application, hair plucking, or skin wound healing. Using PPARalpha, beta, and gamma mutant mice, we demonstrate that PPARalpha and beta are important for the rapid epithelialization of a skin wound and that each of them plays a specific role in this process. PPARalpha is mainly involved in the early inflammation phase of the healing, whereas PPARbeta is implicated in the control of keratinocyte proliferation. In addition and very interestingly, PPARbeta mutant primary keratinocytes show impaired adhesion and migration properties. Thus, the findings presented here reveal unpredicted roles for PPARalpha and beta in adult mouse epidermal repair.

Animals↗