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.

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.

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.

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.

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.

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.

The L162V Polymorphism of the Peroxisome Proliferator Activated Receptor Alpha Gene (PPARA) is not Associated with Type 2 Diabetes, BMI or Body Fat Composition

The L162V single nucleotide polymorphism in PPARA is suggested to play an important role in the pathogenesis of type 2 diabetes, obesity, and body fat composition. However, clinical evidence is controversial. Our aim was to investigate the relationships of the L162V SNP with type 2 diabetes, pre-diabetes phenotypes, adiposity, and plasma lipid levels. In addition, we studied the associations of the L162V SNP with body fat composition, intramyocellular lipids, and liver fat content. Furthermore, we examined if the L162V SNP was associated with changes in BMI, insulin secretion, insulin resistance, body fat composition, intramyocellular lipids, and liver fat content in response to lifestyle intervention. Data from two large cross sectional studies, the combined TULIP/TUEF cohorts, and the LURIC study were analysed. Prospective data were obtained from TULIP participants who underwent a lifestyle intervention. A total of 4,779 subjects were studied. BMI was measured in all subjects. Type 2 diabetes was diagnosed in a subgroup of the LURIC study. In the TULIP study total body fat, non-visceral adipose tissue, and visceral adipose tissue were measured with magnetic resonance tomography. Liver fat and intramyocellular lipid content were quantified with (1)H magnetic resonance spectroscopy. Insulin sensitivity and insulin secretion were estimated from oral glucose tolerance testing. The L162V SNP was neither associated with type 2 diabetes or BMI nor with body fat composition, intramyocellular lipids or liver fat content. According to our study, the L162V SNP does not have a strong impact on the pathogenesis of type 2 diabetes or obesity.

Peroxisome proliferator-activated receptor α polymorphisms and postprandial lipemia in healthy men

Peroxisome proliferator-activated receptor alpha (PPARalpha) is a ligand-dependent transcription factor that plays a key role in lipid and glucose homeostasis. This study evaluated whether variants of PPARalpha are associated with postprandial lipemia. Subjects were given a single fat load composed of 60% calories as fat, 15% as protein, and 25% as carbohydrate. Blood was drawn every hour from baseline to 6 h, then every 2.5 h to 11 h to determine triglyceride (TG) levels. The minor allele of the nonsynonymous p.Leu162Val variant was associated with higher fasting total cholesterol, LDL-cholesterol, and apolipoprotein B. There were no significant associations with all of the postprandial parameters examined. Conversely, the noncoding variant c.140+5435T>C was not associated with fasting lipid concentrations but was significantly associated with decreased postprandial TG and cholesterol in the small TG-rich lipoprotein particle. Although the minor allele carriers displayed lower mean concentrations of TG and cholesterol throughout the postprandial period, the differences were most pronounced in the latter period. These data suggest that PPARalpha variants may modulate the risk of cardiovascular disease by influencing both fasting and postprandial lipid concentrations.

Interleukin-6 inhibits human peroxisome proliferator activated receptor alpha gene expression via CCAAT/enhancer-binding proteins in hepatocytes

Peroxisome proliferator activated receptor alpha has been implicated as a regulator of acute phase response genes in hepatocytes. Interleukin-6 is widely known as a major cytokine responsible in the regulation of acute phase proteins and, therefore, acute phase response. Unfortunately, to date, very little is understood about the molecular mechanisms by which interleukin-6 regulates the gene expression of peroxisome proliferator activated receptor alpha. Here, we report the molecular mechanisms by which peroxisome proliferator activated receptor alpha was regulated by interleukin-6 in human HepG2 cells. Interleukin-6 was shown to down-regulate the peroxisome proliferator activated receptor alpha gene expression at the level of gene transcription. Functional dissection of human peroxisome proliferator activated receptor alpha promoter B revealed the role of predicted CCAAT/enhancer-binding protein binding site (−164/+34) in mediating the interleukin-6 inhibitory effects on peroxisome proliferator activated receptor alpha mRNA expression and electrophoretic mobility shift assay showed the binding of CCAAT/enhancer-binding protein isoforms to this cis-acting elements was increased in interleukin-6-treated HepG2 cells. Co-transfection experiments, then, demonstrated that CCAAT/enhancer-binding protein beta either in homodimer or heterodimer with CCAAT/enhancer-binding protein alpha and CCAAT/enhancer-binding protein delta plays a predominant role in inhibiting the transcriptional activity of peroxisome proliferator activated receptor alpha promoter B, thus, reducing the peroxisome proliferator activated receptor alpha mRNA expression. These studies, therefore, suggest a novel mechanism for interleukin-6-mediated inhibition of peroxisome proliferator activated receptor alpha gene expression that involves the activation of CCAAT/enhancer-binding protein isoforms with CCAAT/enhancer-binding protein beta may play a major role.

A genetic mutation in the peroxisome proliferator-activated receptor alpha gene in patients with non-alcoholic steatohepatitis: Raphael B Merriman, Bradley E Aouizerat, Mary J Molloy, John P Kane, University of California, San Francisco, San Francisco, CA; Bruce Bacon, St Louis University, St. Louis, MO; Nathan M Bass, University of California, San Francisco, San Francisco, CA

A genetic mutation in the peroxisome proliferator-activated receptor alpha gene in patients with non-alcoholic steatohepatitis: Raphael B Merriman, Bradley E Aouizerat, Mary J Molloy, John P Kane, University of California, San Francisco, San Francisco, CA; Bruce Bacon, St Louis University, St. Louis, MO; Nathan M Bass, University of California, San Francisco, San Francisco, CA

Calcineurin and Calcium/Calmodulin-dependent Protein Kinase Activate Distinct Metabolic Gene Regulatory Programs in Cardiac Muscle

To learn more about the targets of Cn (Cn) and calcium/calmodulin-dependent protein kinase in cardiac muscle, we investigated their actions in cultured cardiac myocytes and the hearts of mice in vivo. Adenoviral-mediated expression of constitutively active forms of either pathway induced expression of peroxisome proliferator-activated receptor gamma coactivator 1alpha, a transcriptional coactivator involved in the control of multiple cellular energy metabolic pathways in cardiac myocytes. Transcriptional profiling studies demonstrated that Cn and calcium/calmodulin-dependent protein kinase activate distinct but overlapping metabolic gene regulatory programs. Expression of the nuclear receptor, peroxisome proliferator-activated receptor alpha, was markedly increased by Cn, but not calcium/calmodulin-dependent protein kinase, providing one mechanism whereby cellular fatty acid utilization genes are selectively activated by Cn. Transfection experiments demonstrated that Cn directly activates the mouse peroxisome proliferator-activated receptor alpha gene promoter. Co-transfection "add-back" experiments demonstrated that the transcription factors, myocyte enhancer factors 2C or 2D, were sufficient to confer Cn-mediated activation of the peroxisome proliferator-activated receptor alpha gene. Cn was also shown to directly activate a known peroxisome proliferator-activated receptor alpha target, muscle-type carnitine palmitoyltransferase I, providing a second mechanism by which Cn activates genes of cellular fatty acid utilization. Lastly, the gene expression of peroxisome proliferator-activated receptor gamma coactivator 1alpha and peroxisome proliferator-activated receptor alpha was reduced in the hearts of mice with cardiac-specific ablation of the Cn regulatory subunit. These data support a role for calcium-triggered signaling pathways in the regulation of cardiac energetics and identify pathway-specific control of metabolic targets.

Mutation analysis of the retinoid X receptor beta, nuclear-related receptor 1, and peroxisome proliferator-activated receptor alpha genes in schizophrenia and alcohol dependence: possible haplotype association of nuclear-related receptor 1 gene to alcohol dependence.

Because retinoid cascades are involved in the regulation and development of the central nervous system, including dopaminergic neurons, retinoic acid signaling defects may contribute to schizophrenia and substances dependence. Retinoid X receptors (RXRs) form heterodimer complexes with nuclear-related receptor 1 (NURR1) or with peroxisome proliferator-activated receptors (PPARs). We examined 48 Japanese patients with schizophrenia and 32 patients with alcohol dependence to detect mutations in the retinoid X receptor beta gene (RXRB) on chromosome 6p21.3, the NURR1 gene (NR4A2) on chromosome 2q22-q23, and the PPAR alpha gene (PPARA) on chromosome 22q12.2-13.1. A Val95Ala polymorphism of the RXRB gene, a Val227Ala polymorphism in the PPARA gene, and two synonymous single-nucleotide and CA repeat polymorphisms in the 5' region and 3' untranslated region of the NR4A2 gene were identified. Extended case control samples did not suggest an association between the diseases and the RXRB or PPARA polymorphisms. However, they revealed a significant association between the NR4A2 gene haplotype and alcohol dependence, indicating that 2q22-q23 including the NR4A2 gene locus is a possible genomic region contributing to genetic susceptibility to alcohol dependence.

Identification of three missense mutations in the peroxisome proliferator-activated receptor alpha gene in Japanese subjects with maturity-onset diabetes of the young.

We screened the protein-coding region of the peroxisome proliferator-activated receptor alpha gene (PPARA) and the flanking intron sequences for mutations in 57 unrelated Japanese subjects with maturity-onset diabetes of the young (MODY). We found three missense mutations, designated P22R, D140Y, and V227A. The D140Y and V227A mutations were found at similar frequencies in MODY and in nondiabetic Japanese subjects, suggesting that they were unlikely to be pathogenic. The P22R mutation was found in a single female subject with MODY. Two of her four siblings, all of whom were diagnosed with diabetes before age 35 years, also inherited the P22R mutation. However, two other diabetic siblings had not inherited the mutant allele, implying that the P22R mutation was not the cause of MODY in this family. Variation in the coding region of PPARA is unlikely to be a major cause of MODY in Japanese people.

Genome-wide scan of obesity in the Old Order Amish.

To identify the genetic determinants of typical obesity, we performed a genome-wide scan of obesity-related traits using data from the Amish. Multipoint linkage analysis was performed using a variance components procedure on body mass index (BMI), waist circumference, percentage of body fat, and serum leptin concentrations. All 672 individuals were genotyped for 357 markers in 22 autosomes. We observed modest evidence for linkage, with the maximum log odds (lod) scores for linkage for these traits occurring on chromosomes 3p (percentage of body fat: lod = 1.61, near the peroxisome proliferator-activated receptor-alpha gene), 14q (waist: lod = 1.80), and 16p (leptin: lod = 1.72; BMI: lod = 1.68). We also tested for linkage to BMI-adjusted leptin concentrations and observed suggestive evidence for linkage on chromosome 10p (lod = 2.73), approximately 10-20 cM telomeric from obesity loci previously reported in French and German Caucasians. Two additional linkage signals for this trait were observed on chromosomes 7q (lod = 1.77, approximately 20 cM from the leptin gene) and 14q (lod = 2.47). Follow-up studies may be warranted to pursue some of these linkage signals, especially those detected near known obesity candidate genes, and those in regions coinciding with linkage signals reported previously.

Down-Regulation of Cytochrome P450 2C Family Members and Positive Acute-Phase Response Gene Expression by Peroxisome Proliferator Chemicals

In this study, we show that peroxisome proliferator chemical (PPC) exposure leads to alterations in the expression of genes in rat liver regulated by the sex-specific growth hormone secretory pattern and induced during inflammation. Expression of the male-specific cytochrome P450 (P450) 2C11 and alpha2 urinary globulin (alpha2u) genes and the female-specific P450 2C12 gene was down-regulated by some PPC. Expression of P450 2C13, also under control by the sex-specific growth hormone secretory pattern, was not altered by PPC treatment, indicating that regulation of CYP2C family members does not involve perturbation of the growth hormone secretory pattern. In contrast to the increases in expression observed when inflammation was induced in male rats, two positive acute-phase response genes, alpha1-acid glycoprotein and beta-fibrinogen, were decreased by PPC exposure. The down-regulation of the P450 2C11 by WY-14,643 could be reproduced in cultured rat hepatocytes, indicating the down-regulation is a direct effect. Experiments in wild-type mice and mice that lacked a functional peroxisome proliferator-activated receptor-alpha gene showed that down-regulation by WY of alpha1-acid glycoprotein, beta-fibrinogen, and a mouse homologue of alpha2u was dependent on peroxisome proliferator-activated receptor-alpha expression. Our results demonstrate that PPC exposure leads to down-regulation of diverse liver-specific genes, including CYP2C family members important in hormonal homeostasis and acute-phase response genes important in inflammatory responses.

Regulation of the peroxisome proliferator-activated receptor alpha gene by glucocorticoids.

This study demonstrates that the expression of the peroxisome proliferator-activated receptor alpha (PPAR alpha) is regulated by glucocorticoid hormones in hepatocytes. Hydrocortisone, dexamethasone, and triamcinolone stimulated PPAR alpha mRNA synthesis in a dose-dependent manner in primary rat hepatocyte cultures. This glucocorticoid stimulation was inhibited by RU 486, a specific glucocorticoid antagonist. Moreover, in contrast to glucocorticoid hormones, the mineralocorticoid aldosterone had only a weak effect, suggesting that the hormonal stimulation of PPAR alpha was mediated by the glucocorticoid receptor. The induction was not prevented by cycloheximide treatment of the hepatocytes, indicating that it was mediated by preexisting glucocorticoid receptor. Finally, the RNA synthesis inhibitor actinomycin D abolished the stimulatory effect of dexamethasone, and nuclear run-on analysis showed an increase of PPAR alpha transcripts after hormonal induction. Thus, the PPAR alpha gene is an early response gene of glucocorticoids that control its expression at the transcriptional level.