PPARs: Molecular Targets in the Pharmacogenomics Era

Abstract: The recent global increase in prevalence of diseases like obesity, type 2 diabetes and hypertension in westernized societies is unfortunately not paralleled by our full understanding of the causative mechanisms. It is now firmly established that the interacting genetic and environmental (diet, smoking) components together determine the development and severity of the particular condition, which makes detailed dissection of such complex traits even more complicated. In effect, there is an unmet urgent need for molecular targets so we can directly modulate the causative factors and devise effective preventive and therapeutic algorithms. Among the most promising molecular targets for treatment of metabolic syndrome-related conditions identified so far, the group of three lipidsensors, the peroxisome proliferator-activated receptors (PPARs) clearly stands out. The review focuses on pharmacogenetic aspects of recent developments in PPAR biology. Key words: PPAR -Systems biology -Pharmacogenetics -Thiazolidinediones -cd36 This work was supported by following grants: GAAV ČR B5105401 from the Grant Agency of the Academy of Sciences of the Czech Introduction Global epidemics of diseases like obesity, type 2 diabetes mellitus, hypertension or dyslipidemia represent a major health issue of today's world. These entities, often clustering under what becomes known as metabolic syndrome Among the most promising molecular targets for treatment of metabolic syndrome-related conditions, the group of three peroxisome proliferator-activated receptors (PPARs) clearly stands out. The first PPAR being identified in 1990, thousands of papers later we are uncovering, step-by-step, their integrative and orchestrating roles in lipid and carbohydrate metabolism, atherogenesis or cancer. PPARs are high on the lists of potential candidate genes for obesity As there are several excellent reviews available discussing the role of PPARs in obesit

Pharmacogenetic interaction between dexamethasone and Cd36-deficient segment of spontaneously hypertensive rat chromosome 4 affects triacylglycerol and cholesterol distribution into lipoprotein fractions

Dexamethasone (DEX) is known to induce diabetes and dyslipidemia. We have compared fasting triacylglycerol and cholesterol concentrations across 20 lipoprotein fractions and glucose tolerance in control (standard diet) and DEX-treated 7-month-old males of two rat strains, Brown Norway (BN) and congenic BN.SHR-(Il6-Cd36)/Cub (BN.SHR4). These two inbred strains differ in a defined segment of chromosome 4, originally transferred from the spontaneously hypertensive rat (SHR) including the mutant Cd36 gene, a known target of DEX. Compared to BN, the standard-diet-fed BN.SHR4 showed higher cholesterol and triacylglycerol concentrations across many lipoprotein fractions, particularly in small VLDL and LDL particles. Total cholesterol was decreased by DEX by more than 21% in BN.SHR4 contrasting with the tendency to increase in BN (strain*DEX interaction p = 0.0017). Similar pattern was observed for triacylglycerol concentrations in LDL. The LDL particle size was significantly reduced by DEX in both strains. Also, while control BN and BN.SHR4 displayed comparable glycaemic profiles during oral glucose tolerance test, we observed a markedly blunted DEX induction of glucose intolerance in BN.SHR4 compared to BN. In summary, we report a pharmacogenetic interaction between limited genomic segment with mutated Cd36 gene and dexamethasone-induced glucose intolerance and triacylglycerol and cholesterol redistribution into lipoprotein fractions

Grandmother’s Diet Matters: Early Life Programming with Sucrose Influences Metabolic and Lipid Parameters in Second Generation of Rats

Early life exposure to certain environmental stimuli is related to the development of alternative phenotypes in mammals. A number of these phenotypes are related to an increased risk of disease later in life, creating a massive healthcare burden. With recent focus on the determination of underlying causes of common metabolic disorders, parental nutrition is of great interest, mainly due to a global shift towards a Western-type diet. Recent studies focusing on the increase of food or macronutrient intake don’t always consider the source of these nutrients as an important factor. In our study, we concentrate on the effects of high-sucrose diet, which provides carbohydrates in form of sucrose as opposed to starch in standard diet, fed in pregnancy and lactation in two subsequent generations of spontaneously hypertensive rats (SHR) and congenic SHR-Zbtb16 rats. Maternal sucrose intake increased fasting glycaemia in SHR female offspring in adulthood and increased their chow consumption in gravidity. High-sucrose diet fed to the maternal grandmother increased brown fat weight and HDL cholesterol levels in adult male offspring of both strains, i.e., the grandsons. Fasting glycaemia was however decreased only in SHR offspring. In conclusion, we show the second-generation effects of maternal exposition to a high-sucrose diet, some modulated to a certain extent by variation in the Zbtb16 gene

Ellagic Acid Affects Metabolic and Transcriptomic Profiles and Attenuates Features of Metabolic Syndrome in Adult Male Rats

Ellagic acid, a natural substance found in various fruits and nuts, was previously shown to exhibit beneficial effects towards metabolic syndrome. In this study, using a genetic rat model of metabolic syndrome, we aimed to further specify metabolic and transcriptomic responses to ellagic acid treatment. Adult male rats of the SHR-Zbtb16Lx/k.o. strain were fed a high-fat diet accompanied by daily intragastric gavage of ellagic acid (50 mg/kg body weight; high-fat diet–ellagic acid (HFD-EA) rats) or vehicle only (high-fat diet–control (HFD-CTL) rats). Morphometric and metabolic parameters, along with transcriptomic profile of liver and brown and epididymal adipose tissues, were assessed. HFD-EA rats showed higher relative weight of brown adipose tissue (BAT) and decreased weight of epididymal adipose tissue, although no change in total body weight was observed. Glucose area under the curve, serum insulin, and cholesterol levels, as well as the level of oxidative stress, were significantly lower in HFD-EA rats. The most differentially expressed transcripts reflecting the shift induced by ellagic acid were detected in BAT, showing downregulation of BAT activation markers Dio2 and Nr4a1 and upregulation of insulin-sensitizing gene Pla2g2a. Ellagic acid may provide a useful nutritional supplement to ameliorate features of metabolic syndrome, possibly by suppressing oxidative stress and its effects on brown adipose tissue

Ellagic Acid Affects Metabolic and Transcriptomic Profiles and Attenuates Features of Metabolic Syndrome in Adult Male Rats

Ellagic acid, a natural substance found in various fruits and nuts, was previously shown to exhibit beneficial effects towards metabolic syndrome. In this study, using a genetic rat model of metabolic syndrome, we aimed to further specify metabolic and transcriptomic responses to ellagic acid treatment. Adult male rats of the SHR-Zbtb16Lx/k.o. strain were fed a high-fat diet accompanied by daily intragastric gavage of ellagic acid (50 mg/kg body weight; high-fat diet–ellagic acid (HFD-EA) rats) or vehicle only (high-fat diet–control (HFD-CTL) rats). Morphometric and metabolic parameters, along with transcriptomic profile of liver and brown and epididymal adipose tissues, were assessed. HFD-EA rats showed higher relative weight of brown adipose tissue (BAT) and decreased weight of epididymal adipose tissue, although no change in total body weight was observed. Glucose area under the curve, serum insulin, and cholesterol levels, as well as the level of oxidative stress, were significantly lower in HFD-EA rats. The most differentially expressed transcripts reflecting the shift induced by ellagic acid were detected in BAT, showing downregulation of BAT activation markers Dio2 and Nr4a1 and upregulation of insulin-sensitizing gene Pla2g2a. Ellagic acid may provide a useful nutritional supplement to ameliorate features of metabolic syndrome, possibly by suppressing oxidative stress and its effects on brown adipose tissue

PPARA Intron Polymorphism Associated with Power Performance in 30-s Anaerobic Wingate Test

<div><p>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 (<i>PPARA</i>) 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 <i>PPARA</i> 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 (P_max.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 P_max.kg⁻¹ and marginally significant differences in P_max.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, P_max.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 <i>PPARA</i> 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.</p></div

PPARA 7 G/C genotype and allelic frequencies in 77 elite hockey players.

<p>PPARA 7 G/C genotype and allelic frequencies in 77 elite hockey players.</p