Peroxisome Proliferator-activated Receptor Alpha Gene Research Articles

Genetic Differences in Peroxisome Proliferator-Activated Receptor Alpha Gene in Endurance Athletes (Long Distance Runners) and Power/Endurance Athletes (Wrestlers, Football Players)

Introduction: Peroxisome proliferator-activated receptor alpha gene plays an important role in the expression of genes involved in fatty acid, glucose, and energy metabolism. PPARα intron 7 G/C polymorphism (rs4253778) is one of the genes associated with athletic performance. This study aimed to investigate the genotype distribution and allele frequencies of PPARα G/C of endurance-oriented athletes (long-distance runners) and power/endurance-oriented athletes (wrestlers and football players) (n=158) and non-athletic individuals (n=56). 
 Material and Methods: PPARα intron 7 G/C gene polymorphism was analyzed using the polymerase chain reaction and restriction fragment length polymorphism methods. 
 Results: Genotypes and allele frequencies of PPARα intron 7 G/C were compared between endurance-oriented athletes (long-distance runners) and power/endurance-oriented athletes (wrestlers, and football players) categorized according to their sport disciplines. In addition, athletes were compared to non-athletic individuals. The genotype and allele frequencies of PPARα intron 7 G/C were similar in the groups of athlete and non-athletic individuals (p˃0.05). There was no statistically significant association in genotype distribution and allele frequencies of the PPARα gene among endurance-oriented athletes, power/endurance-oriented athletes, and non-athletic individuals (p˃0.05). 
 Conclusion: The PPARα gene polymorphism may not be considered as a distinctive genetic marker in endurance and mixed sport disciplines.

A meta-analysis on the association of ACE and PPARA gene variants and endurance athletic status.

Genetics has an important role in determining the athletic ability and endurance performance potential. This study aimed to investigate the variable results obtained from endurance athletes and control participants in terms of angiotensin-converting enzyme (ACE) and peroxisome proliferator-activated receptor alpha (PPARA) polymorphism distributions. Multiple electronic databases were investigated independently by two researchers. A meta-analysis was conducted on the association of ACE insertion/deletion (I/D) polymorphism and PPARA G/C polymorphisms with endurance athletes. Odds ratios (OR) and 95% confidence intervals (CI) were estimated. Twenty-six studies were identified for the ACE I/D for 2979 endurance athletes and 10048 control participants while seven studies were identified for PPARA G/C for 901 endurance athletes and 2292 control participants. There was a significant difference in ACE genotype distribution between endurance athletes and control (II vs. ID+DD: OR=1.48; 95% CI=0.30-2.67; P=0.001). On the other hand, there was not a significant difference in PPARA G/C polymorphism genotype distribution between endurance athletes and control (GC+CC vs. GG: OR=0.93; 95% CI=-0.46-2.32; P=0.192; GC+GG vs CC: OR=0.62; 95% CI=-1.75-2.99; P=0.604). The results have shown that ACE I/D polymorphism may be associated with endurance performance in sports and that the predominance of the ACE II genotype in a person may play an advantageous role in being an endurance athlete. However, this effect has not been observed in PPARA G/C polymorphism.

Upregulation of peroxisome proliferator-activated receptor-α and the lipid metabolism pathway promotes carcinogenesis of ampullary cancer.

Ampullary cancer is a rare periampullary cancer currently with no targeted therapeutic agent. It is important to develop a deeper understanding of the carcinogenesis of ampullary cancer. We attempted to explore the characteristics of ampullary cancer in our dataset and a public database, followed by a search for potential drugs. We used a bioinformatics pipeline to analyze complementary (c)DNA microarray data of ampullary cancer and surrounding normal duodenal tissues from five patients. A public database from the National Center for Biotechnology Information Gene Expression Omnibus (NCBI GEO) was applied for external validation. Bioinformatics tools used included the Gene Set Enrichment Analysis (GSEA), Database for Annotation, Visualization and Integrated Discovery (DAVID), MetaCore, Kyoto Encyclopedia of Genes and Genomes (KEGG), Hallmark, BioCarta, Reactome, and Connectivity Map (CMap). In total, 9097 genes were upregulated in the five ampullary cancer samples compared to normal duodenal tissues. From the MetaCore analysis, genes of peroxisome proliferator-activated receptor alpha (PPARA) and retinoid X receptor (RXR)-regulated lipid metabolism were overexpressed in ampullary cancer tissues. Further a GSEA of the KEGG, Hallmark, Reactome, and Gene Ontology databases revealed that PPARA and lipid metabolism-related genes were enriched in our specimens of ampullary cancer and in the NCBI GSE39409 database. Expressions of PPARA messenger (m)RNA and the PPAR-α protein were higher in clinical samples and cell lines of ampullary cancer. US Food and Drug Administration (FDA)-approved drugs, including alvespimycin, trichostatin A (a histone deacetylase inhibitor), and cytochalasin B, may have novel therapeutic effects in ampullary cancer patients as predicted by the CMap analysis. Trichostatin A was the most potent agent for ampullary cancer with a half maximal inhibitory concentration of < 0.3 μM. According to our results, upregulation of PPARA and lipid metabolism-related genes are potential pathways in the carcinogenesis and development of ampullary cancer. Results from the CMap analysis suggested potential drugs for patients with ampullary cancer.

Differential gene expression in dairy cows under negative energy balance and ketosis: A systematic review and meta-analysis

Development of ketosis in high-producing dairy cows contributes to several animal health issues and highlights the need for a better understanding of the genetic basis of metabolic diseases. To evaluate the pattern of differential gene expression in the liver of cows under negative energy balance (NEB), and under subclinical and clinical ketosis, a meta-analysis of gene expression and genome-wide association studies results was performed. An initial systematic review identified 118 articles based on the key words "cow," "liver," "negative energy balance," "ketosis," "expression," "qPCR," "microarray," "proteomic," "RNA-Seq," and "GWAS." After further screening for only peer-reviewed and pertinent articles for gene expression during NEB and clinical and subclinical ketosis (considering plasma levels of β-hydroxybutyrate), 20 articles were included in the analysis. From the systematic review, 430 significant SNPs identified by genome-wide association studies (GWAS) were assigned to genes reported in gene expression studies by considering chromosome and base pair positions in the ARS-UCD 1.2 bovine assembly. Venn diagrams were created to integrate the data obtained in the systematic review, and Gene Ontology enrichment analysis was carried out using official gene names. A QTL enrichment analysis was also performed to identify potential positional candidate loci. Twenty-four significant SNPs were located within the coordinates of differentially expressed genes located on chromosomes 2, 3, 6, 9, 11, 14, 27, and 29. Three significant metabolic pathways were associated with NEB and subclinical and clinical ketosis. In addition, 2 important genes, PPARA (peroxisome proliferator activated receptor alpha) and ACACA (acetyl-coenzyme A carboxylase α), were identified, which were differentially expressed in the 3 metabolic conditions. The PPARA gene is involved in the regulation of lipid metabolism and fatty liver disease and the ACACA gene encodes an enzyme that catalyzes the carboxylation of acetyl-coenzyme A to malonyl-coenzyme A, which is a rate-limiting step in fatty acid synthesis. Gene network analysis revealed co-expression interactions among 34 genes associated with functions involving fatty acid transport and fatty acid metabolism. For the annotated QTL, 9 QTL were identified for ketosis. The genes FN1 (fibronectin 1) and PTK2 (protein tyrosine kinase 2), which are mainly involved in cell adhesion and formation of extracellular matrix constituents, were enriched for QTL previously associated with the trait "ketosis" on chromosome 2 and for the trait "milk iron content" on chromosome 14, respectively. This integration of gene expression and GWAS data provides an additional understanding of the genetic background of NEB and subclinical and clinical ketosis in dairy cattle. Thus, it is a useful approach to identify biological mechanisms underlying these metabolic conditions in dairy cattle.

Contribution of polymorphism in the non-coding region of PPARα to the development of axial spondyloarthritis

The study aimed to contribute to the overall understanding of axial spondyloarthritis by investigating the polymorphism in 5’ untranslated region of peroxisome proliferator-activated receptor alpha gene in patients. The study included 194 patients and 197 controls recruited. The DNA obtained from the samples was genotyped by multiplex Polymerase Chain Reaction and then Matrix-Assisted Laser Desorption Ionization- Time of Flight Mass Spectrometry. Data were analyzed by logistic regression. Five polymorphic regions analyzed in this study, three of the sites were associated with disease risk. An allele in the rs1800204 polymorphic region (p < 0.001), C allele in the rs4253657 polymorphic region (p = 0.040) and C allele in the rs13909022 polymorphic region (p = 0.005) were associated with disease risk. The association of disease risk could not be detected with G and A alleles in the rs881740 (p = 0.456) and rs115640476 (p = 0.674) polymorphic regions, respectively. PPARα 5' untranslated region polymorphism, which is shown to be associated with disease risk, is thought to contribute to the elucidation of the molecular mechanism of the disease. In axial spondyloarthritis, studying the effects of genetic changes in PPARα on other genes with which it interacts will contribute to the full understanding of the molecular mechanism of the disease.

Effects of dietary Antrodia cinnamomea fermented product supplementation on metabolism pathways of antioxidant, inflammatory, and lipid metabolism pathways-a potential crosstalk.

ObjectiveThis study was conducted to fathom the underlying mechanisms of nutrition intervention and redox sensitive transcription factors regulated by Antrodia cinnamomea fermented product (FAC) dietary supplementation in broiler chickens.MethodsFour hundreds d-old broilers (41±0.5 g/bird) assigned to 5 groups were examined after consuming control diet, or control diet replaced with 5% wheat bran (WB), 10% WB, 5% FAC, and 10% FAC. Liver mRNA expression of antioxidant, inflammatory and lipid metabolism pathways were analyzed. Prostaglandin E2 (PGE2) concentration in each group were tested in the chicken peripheral blood mononuclear cells (cPBMCs) of 35-d old broilers to represent the stress level of the chickens. Furthermore, these cells were stimulated with 2,2′-Azobis(2-amidinopropane) dihydrochloride (AAPH) and lipopolysaccharide (LPS) to evaluate the cell stress tolerance by measuring cell viability and oxidative species.ResultsHeme oxygenase-1, glutathione S-transferase, glutamate-cysteine ligase, catalytic subunit, and superoxide dismutase, and nuclear factor (erythroid-derived 2)-like 2 (Nrf2) that regulates the above antioxidant genes were all up-regulated significantly in FAC groups. Reactive oxygen species modulator protein 1 and NADPH oxygenase 1 were both rather down-regulated in 10% FAC group as comparison with two WB groups. Despite expressing higher level than control group, birds receiving diet containing FAC had significantly lower expression level in nuclear factor-kappa B (NF-κB) and other genes (inducible nitric oxide synthase, tumor necrosis factor-α, interleukin-1β, nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3, and cyclooxygenase 2) involving in inflammatory pathways. Additionally, except for 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase that showed relatively higher in both groups, the WB, lipoprotein lipase, Acetyl-CoA carboxylase, fatty acid synthase, fatty acid binding protein, fatty acid desaturase 2 and peroxisome proliferator-activated receptor alpha genes were expressed at higher levels in 10% FAC group. In support of above results, promoted Nrf2 and inhibited NF-κB nuclear translocation in chicken liver were found in FAC containing groups. H2O2 and NO levels induced by LPS and AAPH in cPBMCs were compromised in FAC containing diet. In 35-d-old birds, PGE2 production in cPBMCs was also suppressed by the FAC diet.ConclusionFAC may promote Nrf2 antioxidant pathway and positively regulate lipid metabolism, both are potential inhibitor of NF-κB inflammatory pathway.

Chinese yellow cattle PPARA gene: Analyses of expression, polymorphism and trait association

Peroxisome proliferator-activated receptor alpha (PPARA) is a member of the nuclear receptor superfamily that regulates key proteins involved in fatty acid oxidation and extracellular lipid metabolism. Given the importance of PPARA in modulating energy metabolism, PPARA may be a suitable candidate gene for assessing economic traits in cattle. In the present study, the genetic diversity of the PPARA gene in Chinese cattle breeds and its effects on growth traits in the Nanyang and Jiaxian breeds were investigated. First, the transcript profiles for PPARA were determined in eight adult cattle tissue types. Next, polymorphisms were identified in the coding and predicted promoter regions of the bovine PPARA gene in 424 animals. Finally, an association study was carried out to evaluate the relationship between PPARA and the development of cattle. Based on quantitative real-time polymerase chain reaction, PPARA was mainly expressed in the kidney and liver. Nine single nucleotide polymorphisms (SNPs) were identified in Chinese domestic cattle, including one novel SNP. Haplotype frequencies and linkage disequilibrium were also investigated. Four SNPs (g.17148558A&amp;gt;T, g.117195348A&amp;gt;G, g.117228160T&amp;gt;C, and g.117233248A&amp;gt;G) showed significant associations with growth traits in NY and JX cattle, including body weight, average daily gain, and hipbone width. These results confirmed the importance of PPARA as a candidate gene for marker-assisted selection for growth traits in cattle.

The Contribution of Genetic Variants of the Peroxisome Proliferator-Activated Receptor-Alpha Gene to High-Altitude Hypoxia Adaptation in Sherpa Highlanders.

Kinota, Fumiya, Yunden Droma, Nobumitsu Kobayashi, Toshimichi Horiuchi, Yoshiaki Kitaguchi, Masanori Yasuo, Masao Ota, and Masayuki Hanaoka. The contribution of genetic variants of the gene encoding peroxisome proliferator-activated receptor-alpha gene (PPARA) to high-altitude hypoxia adaptation in Sherpa highlanders. High Alt Med Biol. 24:186-192, 2023.-Sherpa highlanders, who play invaluable roles in the exploration of Mount Everest, have exceptional tolerance to hypobaric hypoxia. Sherpa people are well known to possess the traits determined by genetic background for high-altitude adaptation. The metabolic adaptation mechanism is one of the biological ways for Sherpa highlanders in protecting them from hypoxia stress at high altitude. Studies have suggested that the gene encoding PPARA is associated with metabolic adaptation in the Himalayan population of Tibetans. This study attempts to investigate the genetic variants of the PPARA in Sherpa highlanders and the association with high-altitude hypoxia adaptation. Seven single-nucleotide polymorphisms (SNPs; rs135547, rs5769178, rs881740, rs4253712, rs5766741, and rs5767700 in introns and rs1800234 in exon 6) in the PPARA were genotyped in 105 Sherpa highlanders who lived in the Khumbu region (3440 m above sea level) and 111 non-Sherpa lowlanders who resided in Kathmandu (1300 m) in Nepal. By means of analyses of genetic distances, genotype distributions, allele frequencies, linkage disequilibrium, and haplotype constructions of the seven SNPs in the Sherpa highlanders versus the non-Sherpa lowlanders, it was revealed that the frequencies of minor alleles of rs4253712, rs5766741, rs5767700, and rs1800234 SNPs, as well as the frequency of haplotype constructed by the minor alleles of rs5766741-rs5767700-rs1800234, were significantly overrepresented in the Sherpa highlanders in comparison with the non-Sherpa lowlanders. The results strongly suggest that the genetic variants of the PPARA are likely to contribute to the high-altitude adaptation in Sherpa highlanders.

Impact of single nucleotide polymorphisms on P450 oxidoreductase and peroxisome proliferator-activated receptor alpha on tacrolimus pharmacokinetics in renal transplant recipients.

The P450 oxidoreductase (POR) and peroxisome proliferator-activated receptor alpha (PPARA) genes are associated with the activity of cytochrome P450 enzymes in vivo. We aimed to investigate the impact of single nucleotide polymorphisms (SNPs) in the POR and PPARA genes on the pharmacokinetics of tacrolimus (TAC) in renal transplant recipients. A total of 220 recipients were assessed and 105 recipients were included for final quantitative analysis. Blood samples were collected and DNA was extracted. Targeting sequencing based on next-generation sequencing was applied to detect the SNPs in the POR and PPARA genes. In addition, a systematic review and meta-analysis was performed to comprehensively evaluate the influence of POR and PPARA mutations on the TAC concentrations. A total of 81 SNPs were obtained. Three SNPs (POR*28, Chr7:75619677 and Chr7:75614288) were found to be significantly associated with the TAC pharmacokinetics at 3 months, 6 months, and more than 12 months. No significant association was observed in the combined effect analysis of CYP3A4*1G and CYP3A5*3 with three significant SNPs in the POR gene. Age, post-transplant duration, and the use of sirolimus were identified as the most important factors that influenced the TAC concentrations. A meta-analysis of four studies results and our cohort indicated that compared with recipients carrying the CT or TT genotypes, recipients carrying the CC genotypes of POR*28 showed significantly higher TAC concentrations. Our study suggested the positive influence of mutations in the POR gene on TAC exposure at 3 months after kidney transplantation.

Assembly and Analysis of Changes in Transcriptomes of Dairy Cattle Rumen Epithelia during Lactation and Dry Periods

Lactation in dairy cattle is coupled with increased nutrient requirements for milk synthesis. Therefore, dairy cattle metabolism has to adapt to meet lactation-associated challenges and requires major functional adjustments of the rumen and whole digestive system. This report describes the use of next-generation sequencing technology for assembly and profiling of the transcriptome of cattle rumen epithelial tissues from cattle in both dry and lactation periods. Transcriptomics profiling and comparison revealed extensive changes in gene expression related to metabolism in rumen epithelial tissue due to the adaptation to lactation. Ruminal epithelial adaptation to the challenges of metabolism and high nutrient requirements during lactation is presumably the primary triggers for these alterations in gene expression. Principal component analysis (PCA) indicated that the gene expression profiles of the rumen epithelia from dry and lactating cattle fall into two very distinct clusters. Gene Ontology (GO) enrichment analysis revealed that the most GO terms were related to various metabolic processes in lactating cattle. The most significantly (false discovery rate (FDR) p-value < 0.05) enriched GO term in biological processes was “carbohydrate derivative metabolic process”, followed by “nucleoside metabolic process”. Up-stream regulators, such as PPARA (Peroxisome proliferator-activated receptor alpha) gene, and up-regulated genes of molecular transporters are the focal points of this report.

L162v Polymorphism of Peroxisome Proliferator-activated Receptor-alpha Gene and Markers of Immune Inflammation in Patients with Coronary Artery Disease

New risk factors for coronary artery disease (CAD) have been identified recently – mediators of immune inflammation. Peroxisome proliferator-activated receptors alpha (PPAR-α) belong to nuclear receptors superfamily and regulate the activity of different genes coding the factors of immune inflammation. The goal of this study is to determine the association of L162V polymorphism of PPAR-α gene with factors of immune inflammation and the risk of coronary artery disease development in Russian population. The current study included 424 patients with coronary artery disease (359 men and 65 women) aged 33 to 80 years (mean age- 61,6 ± 0,48 years). The control group consisted of 220 people without CAD of comparable age (mean age- 60,09 ± 0,72 years, p = 0.081). Polymerase chain reaction and restriction analysis were performed. IL-6, interferon-gamma (IF-γ) and tumor necrosis factor-alpha (TNF-α) levels of blood plasma were tested by Elisa. The frequency of L162V genotype of PPAR-α gene in coronary artery disease patients was higher than in control group (14,0% and 6,4% respectively, p=0.004). No significant differences in L162L and L162V genotype distribution in CAD patients with or without arterial hypertension, abdominal obesity, diabetes type2, smoking factor, family history were revealed. In CAD patients with the debut of the disease at the age of 45 and younger the frequency of L162V genotype was higher than in the subgroup of patients with the disease progress at age 46-59 years and (OR=4,68; CI:2,3÷9,52). The level of interleukin 6 was significantly higher in patients with CAD - L162V genotype carriers compared to L162L genotype carriers (37,5 ± 8,3 pg/ml and 9,2 ± 3,5 pg/ml respectively, p = 0.0006). The levels of TNF—α and IF-γ were significantly higher in patients with CAD - L162V genotype carriers compared with L162L genotype carriers. The study has demonstrated that 162V PPARα allelic variant influence the predisposition for CAD in human subjects, probably mediated by modulation of the proinflammatory cytokines profile. L162V genotype and V162 allele of PPAR-α gene was associated with the risk of coronary artery disease debut at the age 45 years and younger.

Sports genetics: the PPARA gene and athletes' high ability in endurance sports. A systematic review and meta-analysis.

A meta-analysis was performed with the aim of re-evaluating the role of the peroxisome proliferator activated receptor alpha (PPARA) gene intron 7 G/C polymorphism (rs4253778) in athletes’ high ability in endurance sports. Design: A meta-analysis of case control studies assessing the association between the G/C polymorphisms of the PPARA gene and endurance sports was conducted. The Cochrane Review Manager software was used to compare the genotype and allele frequencies between endurance athletes and controls to determine whether a genetic variant is more common in athletes than in the general population. Five studies, encompassing 760 endurance athletes and 1792 controls, fulfilled our inclusion criteria. The pooled odds ratio (and confidence intervals, CIs) for the G allele compared to the C allele was 1.65 (95% CI 1.39-1.96). The pooled OR for the GG genotype compared to the GC genotype was 1.79 (95% CI 1.44-2.22), and for the GG genotype compared to the CC genotype 2.37 (95% CI 1.40-3.99). There was no evidence of heterogeneity (I2 =0%) or of publication bias. Athletes with high ability in endurance sports had a higher frequency of the GG genotype and G allele.

PPARA intron polymorphism associated with power performance in 30-s anaerobic Wingate Test.

To date, polymorphisms in several genes have been associated with a strength/power performance including alpha 3 actinin, ciliary neurotrophic factor, vitamin D receptor, or angiotensin I converting enzyme, underlining the importance of genetic component of the multifactorial strength/power-related phenotypes. The single nucleotide variation in peroxisome proliferator-activated receptor alpha gene (PPARA) intron 7 G/C (rs4253778; g.46630634G>C) has been repeatedly found to play a significant role in response to different types of physical activity. We investigated the effect of PPARA intron 7 G/C polymorphism specifically on anaerobic power output in a group of 77 elite male Czech ice hockey players (18–36 y). We determined the relative peak power per body weight (Pmax.kg−1) and relative peak power per fat free mass (W.kg−1 FFM) during the 30-second Wingate Test (WT30) on bicycle ergometer (Monark 894E Peak bike, MONARK, Sweden). All WT30s were performed during the hockey season. Overall genotype frequencies were 50.6% GG homozygotes, 40.3% CG heterozygotes, and 9.1% CC homozygotes. We found statistically significant differences in Pmax.kg−1 and marginally significant differences in Pmax.kg−1 FFM values in WT30 between carriers and non-carriers for C allele (14.6±0.2 vs. 13.9±0.3 W.kg−1 and 15.8±0.2 vs. 15.2±0.3 W.kg−1 FFM, P = 0.036 and 0.12, respectively). Furthermore, Pmax.kg−1 FFM strongly positively correlated with the body weight only in individuals with GG genotypes (R = 0.55; p<0.001). Our results indicate that PPARA 7C carriers exhibited higher speed strength measures in WT30. We hypothesize that C allele carriers within the cohort of trained individuals may possess a metabolic advantage towards anaerobic metabolism.

L162V polymorphism of peroxisome proliferator-activated receptor-alpha gene and markers of endothelial dysfunction in coronary heart disease patients in Russia

L162V polymorphism of peroxisome proliferator-activated receptor-alpha gene and markers of endothelial dysfunction in coronary heart disease patients in Russia

Relationship of glucose and oleate metabolism to cardiac function in lipin-1 deficient (fld) mice

Lipin-1 is the major phosphatidate phosphatase (PAP) in the heart and a transcriptional coactivator that regulates fatty acid (FA) oxidation in the liver. As the control of FA metabolism is essential for maintaining cardiac function, we investigated whether lipin-1 deficiency affects cardiac metabolism and performance. Cardiac PAP activity in lipin-1 deficient [fatty liver dystrophy (fld)] mice was decreased by >80% compared with controls. Surprisingly, oleate oxidation and incorporation in triacylglycerol (TG), as well as glucose oxidation, were not significantly different in perfused working fld hearts. Despite this, [³H]oleate accumulation in phosphatidate and phosphatidylinositol was increased in fld hearts, reflecting the decreased PAP activity. Phosphatidate accumulation was linked to increased cardiac mammalian target of rapamycin complex 1 (mTORC1) signaling and endoplasmic reticulum (ER) stress. Transthoracic echocardiography showed decreased cardiac function in fld mice; however, cardiac dysfunction was not observed in ex vivo perfused working fld hearts. This showed that changes in systemic factors due to the global absence of lipin-1 could contribute to the decreased cardiac function in vivo. Collectively, this study shows that fld hearts exhibit unchanged oleate esterification, as well as oleate and glucose oxidation, despite the absence of lipin-1. However, lipin-1 deficiency increases the accumulation of newly synthesized phosphatidate and induces aberrant cell signaling.

Mice lacking the peroxisome proliferator-activated receptor alpha gene present reduced number of dopamine neurons in the substantia nigra without altering motor behavior or dopamine neuron decline over life

Peroxisome proliferator-activated receptor alpha (PPAR-α), which is expressed by neurons of the nigrostriatal circuit, plays a prominent role in oxidative stress and neuroinflammation. The objectives were: (i) to discern if levels of antioxidant molecules and pro-inflammatory cytokines, along with PPAR-γ expression are modified in the nigrostriatal region of null PPAR-α mice, (ii) to discern whether dopaminergic neuronal features of the substantia nigra pars compacta (SNpc) and dorsal striatum are affected in null mice, and (iii) to establish if aging-induced decline of nigral neurons is different in null PPAR-α mice relative to wild-type littermates. A substantial decrease in antioxidant molecules was found in SNpc of null mice, by using ELISA. The pro-inflammatory factors TNF-α and IL-3 were found to be reduced in the substantia nigra, suggesting dual and opposite effects of PPAR-α deficiency on oxidative and pro-inflammatory molecules. Immunohistological and stereological studies revealed that young null mice present a smaller SNpc (-19.8%; TH downregulation was discarded). Normal locomotion in an open-field was not affected in null mice. Dopamine cell death could be caused by reduced protection against oxidative stress. Old null mice showed a percentage reduction of nigral dopamine neurons similar to that of young null animals, with a rate of decline over life of around 44%, the same value than that of wild-type littermates. These findings suggest that nuclear PPAR-α is necessary for the normal development of the substantia nigra along with normal levels of antioxidant molecules. Lack of PPAR-α does not modify the normal motor behavior of mice or decline of nigral dopamine neurons throughout life.

Genetic Variation of the Peroxisome Proliferator-Activated Receptor α Gene (PPARA) in Chickens Bred for Different Purposes

Peroxisome proliferator-activated receptor alpha (PPARA) is involved in fatty acid oxidation by upregulating the expression of acyl-coenzyme A oxidase and carnitine palmitoyltransferase. In this study, PPARA gene variations in four chicken breeds (Guyuan, Wenchang, Tibetan, and Hisex) were detected by PCR-SSCP and DNA sequencing. The results indicated six genotypes (AA-EF). When compared with the PPARA reference sequence (GenBank accession no. AF163809), the nucleotide sequences of genotypes AA, BB, AB, and CC revealed silent mutations in the three Chinese breeds. The nucleotide sequences of genotypes DD and EF in Hisex showed several frame-shift mutations, implying variations involving five alleles of the PPARA gene in chicken breeds. In addition, the distribution of genotype frequency within the PPARA gene was significantly different in the four breeds studied, implying that this locus would probably be an effective marker in marker-assisted selection for layer, meat-and-egg, and broiler breeds.

The absence of a functional peroxisome proliferator-activated receptor-alpha gene in mice enhances motor sensitizing effects of morphine, but not cocaine

Neuroinflammation of the CNS seems to participate in sensitizing effects of drugs of abuse such as psychostimulants and morphine. The nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR-α) plays a prominent role in several physiological processes including the inflammatory response, and its activation mediates a reduced production of pro-inflammatory factors. The objectives were to examine the involvement of nuclear PPAR-α in motor sensitization to morphine and cocaine, by using null mice (PPAR-α −/−mice), or the injection of a selective PPAR-α agonist, [[4-chloro-6-[(2,3-dimethylphenyl)amino]-2-pyrimidinyl] thio]acetic acid (WY14643), in morphine-treated mice. The findings indicate that PPAR-α plays an inhibitory role in the expression (not induction) of motor sensitization to morphine, but it is devoid of effects on sensitization to cocaine, suggesting that this nuclear receptor participates in motor activating effects of opiates but not psychostimulants. Furthermore, brain PPAR-α expression is upregulated after the highest dose of repeated morphine, but not chronic cocaine, suggesting that this receptor could play a homeostatic role. In accordance, systemic WY14643 was able to block sensitization to morphine, confirming that PPAR-α plays a homeostatic role opposing morphine-induced motor sensitization, likely through a reduction of inflammation-associated changes.

Cannabinoid activation of PPARα; a novel neuroprotective mechanism

Although CB(1) receptor activation evokes neuroprotection in response to cannabinoids, some cannabinoids have been reported to be peroxisome proliferator activated receptor (PPAR) ligands, offering an alternative protective mechanism. We have, therefore, investigated the ability of a range of cannabinoids to activate PPAR alpha and for N-oleoylethanolamine (OEA), an endogenous cannabinoid-like compound (ECL), to evoke neuroprotection. Assays of PPAR alpha occupancy and gene transactivation potential were conducted in cell-free and transfected HeLa cell preparations, respectively. In vivo estimates of PPAR alpha activation through fat mobilization and gene transcription were conducted in mice. Neuroprotection in vivo was investigated in wild-type and PPAR alpha gene-disrupted mice. The ECLs OEA, anandamide, noladin ether and virodhamine were found to bind to the purified PPAR alpha ligand binding domain and to increase PPAR alpha-driven transcriptional activity. The high affinity synthetic CB(1/2) cannabinoid agonist WIN 55212-2 bound to PPAR alpha equipotently with the PPARalpha agonist fenofibrate, and stimulated PPARalpha-mediated gene transcription. The phytocannabinoid delta 9 tetrahydrocannabinol was without effect. OEA and WIN 55212-2 induced lipolysis in vivo, while OEA pre-treatment reduced infarct volume from middle cerebral artery occlusion in wild-type, but not in PPAR alpha-null mice. OEA treatment also led to increased expression of the NFkappa B-inhibitory protein, Ikappa B, in mouse cerebral cortex, while expression of the NFkappa B-regulated protein COX-2 was inhibited. These data demonstrate the potential for a range of cannabinoid compounds, of diverse structures, to activate PPAR alpha and suggest that at least some of the neuroprotective properties of these agents could be mediated by nuclear receptor activation.

The PPARα-Humanized Mouse: A Model to Investigate Species Differences in Liver Toxicity Mediated by PPARα

To determine the impact of the species difference between rodents and humans in response to peroxisome proliferators (PPs) mediated by peroxisome proliferator-activated receptor (PPAR)alpha, PPAR alpha-humanized transgenic mice were generated using a P1 phage artificial chromosome (PAC) genomic clone bred onto a ppar alpha-null mouse background, designated hPPAR alpha PAC. In hPPAR alpha PAC mice, the human PPAR alpha gene is expressed in tissues with high fatty acid catabolism and induced upon fasting, similar to mouse PPAR alpha in wild-type (Wt) mice. Upon treatment with the PP fenofibrate, hPPAR alpha PAC mice exhibited responses similar to Wt mice, including peroxisome proliferation, lowering of serum triglycerides, and induction of PPAR alpha target genes encoding enzymes involved in fatty acid metabolism in liver, kidney, and heart, suggesting that human PPAR alpha (hPPAR alpha) functions in the same manner as mouse PPAR alpha in regulating fatty acid metabolism and lowering serum triglycerides. However, in contrast to Wt mice, treatment of hPPAR alpha PAC mice with fenofibrate did not cause significant hepatomegaly and hepatocyte proliferation, thus indicating that the mechanisms by which PPAR alpha affects lipid metabolism are distinct from the hepatocyte proliferation response, the latter of which is only induced by mouse PPAR alpha. In addition, a differential regulation of several genes, including the oncogenic let-7C miRNA by PPs, was observed between Wt and hPPAR alpha PAC mice that may contribute to the inherent difference between mouse and human PPAR alpha in activation of hepatocellular proliferation. The hPPAR alpha PAC mouse model provides an in vivo platform to investigate the species difference mediated by PPAR alpha and an ideal model for human risk assessment PPs exposure.