Peroxisome Proliferator-activated Receptor Delta Gene Research Articles

Minor alleles of FTO rs9939609 and rs17817449 polymorphisms confer a higher risk of type 2 diabetes mellitus and dyslipidemia, but not coronary artery disease in a Chinese Han population.

Relationships of the polymorphisms in fat mass and obesity-associated gene (FTO) and peroxisome proliferator-activated receptor delta gene (PPARD) with metabolic-related diseases remain to be clarified. One thousand three hundred and eighty-one subjects were enrolled. Metabolic-related diseases including obesity, dyslipidemia, hyperhomocysteinemia, hyperuricemia, hypertension, type 2 diabetes mellitus (T2DM) and coronary artery disease (CAD) were defined based on diagnostic criteria. FTO rs9939609 and rs17817449, and PPARD rs2016520 and rs2267668 polymorphisms were genotyped by using polymerase chain reaction-restricted fragment length polymorphism method. Patients with T2DM or dyslipidemia had a higher frequency of AA, AT or AA + AT genotypes as well as A allele of FTO rs9939609 polymorphism than those free of T2DM or dyslipidemia (P ≤ 0.04 for all). Patients with T2DM or dyslipidemia had a higher frequency of GG, GT or GG + GT genotypes as well as G allele of FTO rs17817449 polymorphism than those free of T2DM or dyslipidemia (P ≤ 0.03 for all). Multivariate logistic regression analyses showed that FTO rs9939609 and rs17817449 polymorphisms were independently associated with T2DM as well as dyslipidemia after adjustment for age, sex, smoking and other metabolic diseases. FTO rs9939609 and rs17817449 polymorphisms were not associated with obesity, hyperhomocysteinemia, hyperuricemia, hypertension and CAD. Obese or T2DM carriers of the AA or AT genotype of the FTO rs9939609 polymorphism had a higher prevalence of dyslipidemia compared to non-obese or non-T2DM carriers of the AA or AT genotype (P = 0.03 for both). Among the carriers of GG or GT genotype of the FTO rs17817449 polymorphism, the prevalence of dyslipidemia in obese patients was higher than that in non-obese subjects (P < 0.01). PPARD rs2016520 and rs2267668 polymorphisms were not correlated with any of the metabolic-related diseases in the study population. Minor alleles of FTO rs9939609 and rs17817449 polymorphisms confer a higher risk of T2DM and dyslipidemia, and the risk is further increased among obese individuals. PPARD rs2016520 and rs2267668 polymorphisms are not associated with metabolic-related diseases.

Haplotype of ESR1 and PPARD Genes Is Associated with Higher Anthropometric Changes in Han Chinese Obesity by Adjusting Dietary Factors-An 18-Month Follow-Up.

The obesity genetic effect may play a major role in obesogenic environment. A combined case–control and an 18-month follow-up were carried out, including a total of 311 controls and 118 obese cases. All participants were aged in the range of 20–55 y/o. The body mass index (BMI) of obese cases and normal controls was in the range of 27.0–34.9 and 18.5–23.9 kg/m2, respectively. The rs712221 on Estrogen receptor1 (ESR1) and rs2016520 on Peroxisome proliferator–activated receptor delta (PPARD) showed significant associations with obesity. The TT (odds ratio (OR): 2.42; 95% confidence interval (CI): 1.46–4.01) and TT/TC (OR: 2.80; 95% CI: 1.14–6.85) genotypes on rs712221 and rs2016520 had significantly higher obesity risks, respectively. Moreover, the synergic effect of these two risk SNPs (2-RGH) exhibited an almost geometrical increase in obesity risk (OR: 7.00; 95% CI: 2.23–21.99). Obese individuals with 2-RGH had apparently higher changes in BMI increase, body weight gain and dietary fiber intake but a lower total energy intake within the 18-month follow-up.

Липидный профиль плазмы молодых женщин в зависимости от физической активности и наследственной предрасположенности

We studied the association of the polymorphic rs320 variant of the lipoprotein lipase (LPL) gene, rs2016520 variant of the peroxisome proliferator-activated receptor delta (PPARD) gene and rs670 variant of the apolipoprotein A1 (APOA1) gene with blood lipids in female athletes and women not involved in sports. Key indicators of the lipid spectrum – total cholesterol (TC), triglycerides (TG), highdensity lipoproteins (HDL) and low-density lipoproteins (LDL) in the blood serum – were determined by the enzymatic method using Cormay reagents (Germany) and Fluorat-02-ABLF-T analyser (Russia). Genotyping of the samples was carried out by means of the PCR-RFLP analysis. A direct correlation was found between the *H+ allele of the rs320 polymorphic variant of the LPL gene and the blood levels of TC (r = 0.17; p = 0.01), TG (r = 0.33; p = 0.000005), LDL (r = 0.16; p = 0.02), and atherogenic index (AI) (r = 0.28; p = 0.0002), as well as an inverse correlation between this allele and HDL (r = –0.19; p = 0.009) in women not involved in sports. The *A allele of the polymorphic variant rs670 of the APOA1 gene in this group showed a negative correlation with TC (r = –0.22; p = 0.004) and TG (r = –0.31; p = 0.00004), while the polymorphic variant rs2016520 of the PPARD gene revealed a linear correlation of the *C allele with LDL (r = 0.15; p = 0.02) and AI (r = 0.16; p = 0.01). Three alleles – *H of the LPL gene, *G of the APOA1 gene and *T of the PPARD gene – demonstrated an additive effect on the decrease in TG, LDL and AI and on the increase in HDL in women regardless of their level of motor activity. There were no statistically significant differences in the level of blood lipids in female athletes with different genotypes of the LPL, PPARD, and APOA1 genes. Further research is needed involving larger samples of athletes.

PPARD rs7770619 polymorphism in a Korean population: Association with plasma malondialdehyde and impaired fasting glucose or newly diagnosed type 2 diabetes.

Both the peroxisome proliferator-activated receptor delta gene ( PPARD) and malondialdehyde plasma concentrations may play a role in impaired glucose metabolism. The aim of this work was to determine whether PPARD is a candidate gene for impaired fasting glucose or type 2 diabetes and whether a particular genetic variant shows association with plasma malondialdehyde levels. Among the 10 single-nucleotide polymorphisms that were most strongly associated with malondialdehyde, the rs7770619 polymorphism in PPARD was analysed in 1798 subjects with normal fasting glucose, impaired fasting glucose and newly diagnosed type 2 diabetes. Our data demonstrate that the CT genotype of the rs7770619 is associated with a lower risk of impaired fasting glucose or type 2 diabetes together with lower plasma levels of malondialdehyde in both groups ( p < 0.05). Glucose levels and the rs7770619 are significantly associated in individuals with normal fasting glucose, and a trend towards an association between glucose levels and rs7770619 is also observed in individuals with impaired fasting glucose or type 2 diabetes. In conclusion, PPARD rs7770619 is a novel candidate variant for impaired fasting glucose and type 2 diabetes and shows association with malondialdehyde levels. Future work is required to understand the mechanisms for these associations and the clinical implications of our findings.

Abstract 3819: PPAR-delta promotes Wnt/B-catenin-driven colorectal tumorigenesis

Abstract Introduction Aberrant Wnt/B-catenin signaling activation due to mutations in the adenomatous poliposis coli gene, APC, is a critical event in colorectal cancer (CRC). However, to drive CRC tumorigenesis, aberrant Wnt/B-catenin activation requires additional enhancing regulatory mechanisms. The peroxisome proliferator-activated receptor delta gene (PPARD), which is upregulated in CRC, is a downstream target of aberrant Wnt/B-catenin activation in human colon cancer cells. However, PPARD has also been reported to inhibit intestinal tumorigenesis in mice with germline APCmin mutations. Thus, the mechanistic interaction between PPARD and Wnt/β-catenin remains poorly understood. PPARD is a druggable protein for which agonists and antagonists are being developed. Determining PPARD effects on Wnt/B-catenin activation would define the direction of its therapeutic targeting in cancer and other diseases. Methods We developed a novel mouse model that simulates PPARD overexpression in CRC by inducing PPARD overexpression in intestinal epithelial cells via a villin promoter (villin-PPARD mice). We bred villin-PPARD mice with mice that have Apc580 mutation in intestinal epithelial cells induced by CDX2-Cre recombinase expression (Apc580mu mice) to generate Apc580mu-PPARD-Gut mice. Apc580mu-PPARD-Gut mice and Apc580mu control mice were monitored for CRC tumorigenesis. We also assessed the effects of PPARD expression modulation on Wnt/B-catenin activation in human colon cancer cell lines. Results PPARD overexpression in colonic epithelial cells increased CRC tumorigenesis in mice with Apc580 mutation. At 10 weeks of age, 100% of Apc580mu-PPARD-Gut mice but only 60% of Apc580mu mice had tumors of any size, and the mean number of tumors per Apc580mu-PPARD-Gut mouse (1.6 ± 2.5) was significantly higher than that per Apc580mu mouse (0.6 ± 0.25; P = 0.02). Tumors &amp;gt;3.5 mm were present in all Apc580mu-PPARD-Gut mice but only 20% of Apc580mu mice, and the mean number of tumors &amp;gt;3.5 mm per Apc580mu-PPARD-Gut mouse (1.4 ± 2.5) was significantly higher than that per Apc580mu mouse (0.2 ± 0.2; p = 0.005). In mice, colonic epithelial PPARD overexpression increased activated B-catenin protein levels and Wnt/B-catenin target gene mRNA levels. In human colon cancer cells, PPARD increased the levels of activated β-catenin, its nuclear localization and transcriptional activity. Conclusion Our findings indicate that PPARD augments Wnt/B-catenin signaling to promote CRC tumorigenesis and thus support the targeted inhibition of PPARD to suppress CRC tumorigenesis. Citation Format: Xiangsheng Zuo, Rui Tian, Shen Gao, Micheline J. Moussalli, Weidong Chen Chen, Ling Wu, Imad Shureiqi. PPAR-delta promotes Wnt/B-catenin-driven colorectal tumorigenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3819.

The Functional SNPs in the 5' Regulatory Region of the Porcine PPARD Gene Have Significant Association with Fat Deposition Traits.

Peroxisome proliferator-activated receptor delta (PPARD) is a key regulator of lipid metabolism, insulin sensitivity, cell proliferation and differentiation. In this study, we identified two Single Nucleotide Polymorphisms (SNPs, g.1015 A>G and g.1018 T>C) constituting four haplotypes (GT, GC, AC and AT) in the 5’ regulatory region of porcine PPARD gene. Functional analysis of the four haplotypes showed that the transcriptional activity of the PPARD promoter fragment carrying haplotype AC was significantly lower than that of the other haplotypes in 3T3-L1, C2C12 and PK-15 cells, and haplotype AC had the lowest binding capacities to the nuclear extracts. Transcription factor 7-like 2 (TCF7L2) enhanced the transcription activities of promoter fragments of PPARD gene carrying haplotypes GT, GC and AT in C2C12 and 3T3-L1 cells, and increased the protein expression of PPARD gene in C2C12 myoblasts. TCF7L2 differentially bound to the four haplotypes, and the binding capacity of TCF7L2 to haplotype AC was the lowest. There were significant associations between -655A/G and fat deposition traits in three pig populations including the Large White × Meishan F2 pigs, France and American Large White pigs. Pigs with genotype GG had significantly higher expression of PPARD at both mRNA and protein level than those with genotype AG. These results strongly suggested that the SNPs in 5’ regulatory region of PPARD genes had significant impact on pig fat deposition traits.

Variants of the PPARD Gene and Their Clinicopathological Significance in Colorectal Cancer

BackgroundPeroxisome proliferator-activated receptor delta (PPARD) is nuclear hormone receptor involved in colorectal cancer (CRC) differentiation and progression. The purpose of this study was to determine prevalence and spectrum of variants in the PPARD gene in CRC, and their contribution to clinicopathological endpoints.Methods and FindingsDirect sequencing of the PPARD gene was performed in 303 primary tumors, in blood samples from 50 patients with ≥3 affected first-degree relatives, 50 patients with 2 affected first-degree relatives, 50 sporadic patients, 360 healthy controls, and in 6 colon cancer cell lines. Mutation analysis revealed 22 different transversions, 7 of them were novel. Three of all variants were somatic (c.548A>G, p.Y183C, c.425-9C>T, and c.628-16G>A). Two missense mutations (p.Y183C and p.R258Q) were pathogenic using in silico predictive program. Five recurrent variants were detected in/adjacent to the exons 4 (c.1-87T>C, c.1-67G>A, c.130+3G>A, and c.1-101-8C>T) and exon 7 (c.489T>C). Variant c.489C/C detected in tumors was correlated to worse differentiation (P = 0.0397).ConclusionsWe found 7 novel variants among 22 inherited or acquired PPARD variants. Somatic and/or missense variants detected in CRC patients are rare but indicate the clinical importance of the PPARD gene.

Haplotypes of the porcine peroxisome proliferator-activated receptor delta gene are associated with backfat thickness.

BackgroundPeroxisome proliferator-activated receptor delta belongs to the nuclear receptor superfamily of ligand-inducible transcription factors. It is a key regulator of lipid metabolism. The peroxisome proliferator-activated receptor delta gene (PPARD) has been assigned to a region on porcine chromosome 7, which harbours a quantitative trait locus for backfat. Thus, PPARD is considered a functional and positional candidate gene for backfat thickness. The purpose of this study was to test this candidate gene hypothesis in a cross of breeds that were highly divergent in lipid deposition characteristics.ResultsScreening for genetic variation in porcine PPARD revealed only silent mutations. Nevertheless, significant associations between PPARD haplotypes and backfat thickness were observed in the F2 generation of the Mangalitsa × Piétrain cross as well as a commercial German Landrace population. Haplotype 5 is associated with increased backfat in F2 Mangalitsa × Piétrain pigs, whereas haplotype 4 is associated with lower backfat thickness in the German Landrace population. Haplotype 4 and 5 carry the same alleles at all but one SNP. Interestingly, the opposite effects of PPARD haplotypes 4 and 5 on backfat thickness are reflected by opposite effects of these two haplotypes on PPAR-δ mRNA levels. Haplotype 4 significantly increases PPAR-δ mRNA levels, whereas haplotype 5 decreases mRNA levels of PPAR-δ.ConclusionThis study provides evidence for an association between PPARD and backfat thickness. The association is substantiated by mRNA quantification. Further studies are required to clarify, whether the observed associations are caused by PPARD or are the result of linkage disequilibrium with a causal variant in a neighbouring gene.

PGC-1α: important for exercise performance?

since the identification of the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α as a factor interacting with PPARγ in brown adipose tissue (BAT) ([12][1]), it has become clear that PGC-1α plays important roles in regulating several cellular processes

Germ cell nuclear factor directly represses the transcription of peroxisome proliferator-activated receptor delta gene

Germ cell nuclear factor (GCNF) is a transcription factor that can repress gene transcription and plays an important role during spermatogenesis. Peroxisome proliferator-activated receptor delta (PPARdelta) is a nuclear hormone receptor belonging to the steroid receptor superfamily. It can activate the expression of many genes, including those involved in lipid metabolism. In this report, we showed that GCNF specifically interacts with PPARdelta promoter. Overexpression of GCNF in African green monkey SV40-transformed kidney fibroblast COS7 cells and mouse embryo fibroblast NIH 3T3 cells represses the activity of PPARdelta promoter. The mutation of GCNF response element in PPARdelta promoter relieves the repression in NIH 3T3 cells and mouse testis. Moreover, we showed that GCNF in nuclear extracts of mouse testis is able to bind to PPARdelta promoter directly. We also found that GCNF and PPARdelta mRNA were expressed with different patterns in mouse testis by in situ hybridization. These results suggested that GCNF might be a negative regulator of PPARdelta gene expression through its direct interaction with PPARdelta promoter in mouse testis.

Variations inPPARDDetermine the Change in Body Composition during Lifestyle Intervention: A Whole-Body Magnetic Resonance Study

We recently demonstrated that single-nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptor-delta gene (PPARD), i.e. rs1053049, rs6902123, and rs2267668, affect the improvement of mitochondrial function, aerobic physical fitness, and insulin sensitivity by lifestyle intervention (LI). The objective of the study was to determine whether the aforementioned PPARD SNPs influence the change in body composition and ectopic fat storage during LI. A total of 156 subjects at an increased risk for type 2 diabetes were genotyped for rs1053049, rs6902123, and rs2267668 and participated in a LI program. Body fat depots, ectopic liver fat, and muscle volume of the leg were quantified using magnetic resonance spectroscopy and imaging. With regard to body composition, carriers of the minor SNP alleles displayed reduced responses to LI, i.e. LI-induced reduction in adipose tissue mass (nonvisceral adipose tissue: rs1053049, P = 0.02; rs2267668, P = 0.04; visceral adipose tissue: rs1053049, P = 0.01) and hepatic lipids (rs1053049, P = 0.04; rs6902123, P = 0.001; independent of changes in adiposity) as well as LI-induced increase in relative muscle volume of the leg (rs1053049, P = 0.003; rs2267668, P = 0.009) were less pronounced in homo- and heterozygous carriers of the minor alleles as compared with homozygous carriers of the major alleles. SNPs rs1053049, rs6902123, and rs2267668 in PPARD affect LI-induced changes in overall adiposity, hepatic fat storage, and relative muscle mass. Our findings provide a mechanistic explanation for the involvement of these genetic variations in the development of insulin resistance and type 2 diabetes.

Interaction between Calpain-5, Peroxisome proliferator-activated receptor-gamma and Peroxisome proliferator-activated receptor-delta genes: a polygenic approach to obesity.

ContextObesity is a multifactorial disorder, that is, a disease determined by the combined effect of genes and environment. In this context, polygenic approaches are needed.ObjectiveTo investigate the possibility of the existence of a crosstalk between the CALPAIN 10 homologue CALPAIN 5 and nuclear receptors of the peroxisome proliferator-activated receptors family.DesignCross-sectional, genetic association study and gene-gene interaction analysis.SubjectsThe study sample comprise 1953 individuals, 725 obese (defined as body mass index ≥ 30) and 1228 non obese subjects.ResultsIn the monogenic analysis, only the peroxisome proliferator-activated receptor delta (PPARD) gene was associated with obesity (OR = 1.43 [1.04–1.97], p = 0.027). In addition, we have found a significant interaction between CAPN5 and PPARD genes (p = 0.038) that reduces the risk for obesity in a 55%.ConclusionOur results suggest that CAPN5 and PPARD gene products may also interact in vivo.

Peroxisome proliferator‐activated receptor (PPAR) delta genetic polymorphism and its association with insulin resistance index and fasting plasma glucose concentrations in Chinese subjects

Previous studies have shown that the peroxisome proliferator-activated receptor delta (PPARD) genetic polymorphism affects cholesterol metabolism in Whites. This association was not observed in a Korean population in a separate study, but this study showed a link between the PPARD polymorphism and body weight and fasting plasma glucose. The purpose of this study was to determine whether polymorphisms of PPARD influence glucose and cholesterol metabolism in Chinese subjects. We investigated the association between the polymorphism (-87T/C) of the human PPARD gene and phenotypes related to body weight, insulin sensitivity, glucose and lipid metabolism in Chinese subjects. Unrelated Chinese subjects (n = 663) in Shanghai were studied; 287 had newly diagnosed Type 2 diabetes mellitus and 376 were non-diabetic control subjects over 40 years old. Clinical parameters were collected and genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism. In normal glucose tolerant (NGT) subjects, the C allele carriers had higher fasting plasma glucose concentrations (P = 0.0078) and a lower insulin sensitivity index (ISI) (P = 0.0365). The C allele carriers also showed higher concentrations of low-density lipoprotein cholesterol (P = 0.0261) and percentage of body fat (P = 0.0357). There was a trend towards higher visceral adiposity in C allele carriers, but the difference was not significant (P = 0.0830). In diabetes patients, similar results were detected for plasma glucose concentrations (fasting plasma glucose P < 0.0001, 2-h plasma glucose P = 0.0052) and insulin sensitivity (homeostasis model assessment of insulin resistance P = 0.0094; ISI P = 0.0058). The PPARD-87T/C polymorphism is associated with higher fasting plasma glucose concentrations in both NGT and diabetic subjects, largely due to impaired insulin sensitivity.