Parental overnutrition by carbohydrates in developmental origins of metabolic syndrome.

Metabolic syndrome is a prevalent disease resulting from an interplay of genomic component and the exposome. Parental diet has been shown to affect offspring metabolic health via multiple epigenetic mechanisms. Excess carbohydrate intake is one of the driving forces of the obesity and metabolic syndrome pandemics. This review summarizes the evidence for the effects of maternal carbohydrate (fructose, sucrose, glucose) overnutrition on the modulation of metabolic syndrome components in the offspring. Despite substantial discrepancies in experimental design, common effects of maternal carbohydrate overnutrition include increased body weight and hepatic lipid content of the "programmed" offspring. However, the administration of sucrose to several rat models leads to apparently favorable metabolic outcomes. Moreover, there is evidence for the role of genomic background in modulating the metabolic programming effect in the form of nutri-epigenomic interaction. Comprehensive, robust studies are needed to resolve the temporal, sex-specific, genetic, epigenetic and nutritional aspects of parental overnutrition in the intergenerational and transgenerational pathogenesis of metabolic syndrome.

Cell-free DNA in plasma as an essential immune system regulator.

The cell-free DNA (cfDNA) is always present in plasma, and it is biomarker of growing interest in prenatal diagnostics as well as in oncology and transplantology for therapy efficiency monitoring. But does this cfDNA have a physiological role? Here we show that cfDNA presence and clearance in plasma of healthy individuals plays an indispensable role in immune system regulation. We exposed THP1 cells to healthy individuals' plasma with (NP) and without (TP) cfDNA. In cells treated with NP, we found elevated expression of genes whose products maintain immune system homeostasis. Exposure of cells to TP triggered an innate immune response (IIR), documented particularly by elevated expression of pro-inflammatory interleukin 8. The results of mass spectrometry showed a higher abundance of proteins associated with IIR activation due to the regulation of complement cascade in cells cultivated with TP. These expression profiles provide evidence that the presence of cfDNA and its clearance in plasma of healthy individuals regulate fundamental mechanisms of the inflammation process and tissue homeostasis. The detailed understanding how neutrophil extracellular traps and their naturally occurring degradation products affect the performance of immune system is of crucial interest for future medical applications.

SHR-Zbtb16 minimal congenic strain reveals nutrigenetic interaction between Zbtb16 and high-sucrose diet.

Both prenatal and postnatal excessive consumption of dietary sucrose or fructose was shown to be detrimental to health and contributing to pathogenesis of metabolic syndrome. Our knowledge of genetic determinants of individual sensitivity to sucrose-driven metabolic effects is limited. In this study, we have tested the hypothesis that a variation of metabolic syndrome-related gene, Zbtb16 (Zinc Finger and BTB Domain Containing 16 will affect the reaction to high-sucrose diet (HSD) content in "matched" nutritional exposition settings, i.e. maternal HSD with re-exposition to HSD in adulthood vs. standard diet. We compared metabolic profiles of adult males of spontaneously hypertensive rats (SHR) and a single-gene, minimal congenic strain SHR-Zbtb16 fed either standard diet or exposed to HSD prenatally throughout gestation and nursing and again at the age of 6 months for the period of 14 days. HSD exposition led to increased adiposity in both strains and decrease of glucose tolerance and cholesterol (Ch) concentrations in majority of low-density lipoprotein (LDL) particle classes and in very large and large high-density lipoprotein (HDL) in SHR-Zbtb16 male offspring. There was a similar pattern of HSD-induced increase of triacylglycerols in chylomicrons and very low-density lipoprotein (VLDL) of both strains, though the increase of (triacylglycerol) TAG content was clearly more pronounced in SHR. We observed significant STRAIN*DIET interactions for the smallest LDL particles as their TAG content decreased in SHR-Zbtb16 and did not change in SHR in response to HSD. In summary, we provide evidence of nutrigenetic interaction between Zbtb16 and HSD in context of pathogenesis of metabolic syndrome.

Transcriptomic analysis of left ventricle myocardium in an SHR congenic line with ameliorated cardiac fibrosis.

Metabolic syndrome and one of its manifestations, essential hypertension, is an important cause of worldwide morbidity and mortality. Morbidity and mortality associated with hypertension are caused by organ complications. Previously we revealed a decrease of blood pressure and an amelioration of cardiac fibrosis in a congenic line of spontaneously hypertensive rats (SHR), in which a short segment of chromosome 8 (encompassing only 7 genes) was exchanged for a segment of normotensive polydactylous (PD) origin. To unravel the genetic background of this phenotype we compared heart transcriptomes between SHR rat males and this chromosome 8 minimal congenic line (PD5). We found 18 differentially expressed genes, which were further analyzed using annotations from Database for Annotation, Visualization and Integrated Discovery (DAVID). Four of the differentially expressed genes (Per1, Nr4a1, Nr4a3, Kcna5) belong to circadian rhythm pathways, aldosterone synthesis and secretion, PI3K-Akt signaling pathway and potassium homeostasis. We were also able to confirm Nr4a1 2.8x-fold upregulation in PD5 on protein level using Western blotting, thus suggesting a possible role of Nr4a1 in pathogenesis of the metabolic syndrome.

Expression profiling of Nme7 interactome in experimental models of metabolic syndrome.

Nucleoside diphosphate kinase 7, non-metastatic cells 7 (NME7) is an acknowledged member of ciliome and is involved in the biogenesis or function of cilia. As obesity and diabetes are common in several ciliopathies, we aimed to analyze changes of gene expression within Nme7 interactome in genetically designed rat models of metabolic syndrome. We assessed the liver transcriptome by Affymetrix microarrays in adult males of 14 PXO recombinant inbred rat strains and their two progenitor strains, SHR-Lx and BXH2. In the strains with the lowest expression of Nme7, we have identified significant enrichment of transcripts belonging to Nme7 interactome. In the subsequent network analysis, we have identified three major upstream regulators - Hnf4a, Ppara and Nr1h4 and liver steatosis (p=0.0001) and liver necrosis/cell death (apoptosis of liver cells, p=0.0003) among the most enriched Tox categories. The mechanistic network reaching the top score showed substantial overlap with Assembly of non-motile cilium and Glucose metabolism disorder gene lists. In summary, we show in a genetic model of metabolic syndrome that rat strains with the lowest expression of Nme7 present gene expression shifts of Nme7 interactome that are perturbing networks relevant for carbohydrate and lipid metabolism as well as ciliogenesis.

ZBTB16 and metabolic syndrome: a network perspective.

Metabolic syndrome is a prevalent, complex condition. The search for genetic determinants of the syndrome is currently undergoing a paradigm enhancement by adding systems genetics approaches to association studies. We summarize the current evidence on relations between an emergent new candidate, zinc finger and BTB domain containing 16 (ZBTB16) transcription factor and the major components constituting the metabolic syndrome. Information stemming from studies on experimental models with altered Zbtb16 expression clearly shows its effect on adipogenesis, cardiac hypertrophy and fibrosis, lipid levels and insulin sensitivity. Based on current evidence, we provide a network view of relations between ZBTB16 and hallmarks of metabolic syndrome in order to elucidate the potential functional links involving the ZBTB16 node. Many of the identified genes interconnecting ZBTB16 with all or most metabolic syndrome components are linked to immune function, inflammation or oxidative stress. In summary, ZBTB16 represents a promising pleiotropic candidate node for metabolic syndrome.

ZBTB16 gene variability influences obesity-related parameters and serum lipid levels in Czech adults.

The data derived from rat models and the preliminary results of human studies provide strong indices of involvement of common ZBTB16 variants in a range of cardiovascular and metabolic traits. This cross-sectional study in the Caucasian cohort of 1517 Czech adults aimed to verify the hypothesis that ZBTB16 gene variation directly affects obesity and serum lipid levels. Genotyping of nine polymorphisms of the ZBTB16 gene (rs11214863, rs593731, rs763857, rs2846027, rs681200, rs686989, rs661223, rs675044, rs567057) was performed. A multivariate bidirectional regression with the reduction of dimensionality (O2PLS model) revealed relationships between basal lipid levels and anthropometric parameters and some minor ZBTB16 alleles. In men, the predictors - age and presence of minor ZBTB16 alleles of rs686989, rs661223, rs675044, rs567057 - were associated with significantly higher body mass index, waist to hip ratio, body adiposity index, waist and abdominal circumferences, higher total cholesterol and LDL cholesterol and explained 20 % of variability of these variables. In women, the predictors - age and presence of the rs686989 minor T allele - were also associated with increased anthropometric parameters and total cholesterol and LDL cholesterol but the obtained O2PLS model explained only 7.8 % of the variability of the explained variables. Our study confirmed that the selected gene variants of the transcription factor ZBTB16 influence the obesity-related parameters and lipid levels. This effect was more pronounced in men.

Spontaneously Hypertensive Rat Chromosome 2 with Mutant Connexin 50 Triggers Divergent Effects on Metabolic Syndrome Components.

Metabolic syndrome is a frequent condition with multifactorial aetiology. Previous studies indicated the presence of genetic determinants of metabolic syndrome components on rat chromosome 2 (RNO2) and syntenic regions of the human genome. Our aim was to further explore these findings using novel rat models. We derived the BN-Dca and BN-Lx.Dca congenic strains by introgression of a limited RNO2 region from a spontaneously hypertensive rat strain carrying a mutation in the Gja8 gene (SHR-Dca, dominant cataract) into the genomic background of Brown Norway strain and congenic strain BN-Lx, respectively. We compared morphometric, metabolic and cytokine profiles of adult male BN-Lx, BN-Dca and BN-Lx.Dca rats. We performed in silico comparison of the DNA sequences throughout RNO2 differential segments captured in the new congenic strains. Both BN-Dca and BN-Lx.Dca showed lower total triacylglycerols and cholesterol concentrations compared to BN-Lx. Fasting insulin in BN-Dca was higher than in BN-Lx.Dca and BN-Lx. Concentrations of several proinflammatory cytokines were elevated in the BN-Dca strain, including IL-1α, IL-1ß, IFN-γ and MCP-1. In silico analyses revealed over 740 DNA variants between BN-Lx and SHR genomes within the differential segment of the congenic strains. We derived new congenic models that prove that a limited genomic region of SHR-Dca RNO2 significantly affects lipid levels and insulin sensitivity in a divergent fashion.

Connexin 50 mutation lowers blood pressure in spontaneously hypertensive rat.

We assessed the effect of the previously uncovered gap junction protein alpha 8 (Gja8) mutation present in spontaneously hypertensive rat - dominant cataract (SHR-Dca) strain on blood pressure, metabolic profile, and heart and renal transcriptomes. Adult, standard chow-fed male rats of SHR and SHR-Dca strains were used. We found a significant, consistent 10-15 mmHg decrease in both systolic and diastolic blood pressures in SHR-Dca compared with SHR (P<0.01 and P<0.05, respectively; repeated measures analysis of variance (ANOVA)). With immunohistochemistry, we were able to localize Gja8 in heart, kidney, aorta, liver, and lungs, mostly in endothelium; with no differences in expression between strains. SHR-Dca rats showed decreased body weight, high-density lipoprotein cholesterol concentrations and basal insulin sensitivity in muscle. There were 21 transcripts common to the sets of 303 transcripts in kidney and 487 in heart showing >1.2-fold difference in expression between SHR and SHR-Dca. Tumor necrosis factor was the most significant upstream regulator and glial cell-derived neurotrophic factor family ligand-receptor interactions was the common enriched and downregulated canonical pathway both in heart and kidney of SHR-Dca. The connexin 50 mutation L7Q lowers blood pressure in the SHR-Dca strain, decreases high-density lipoprotein cholesterol, and leads to substantial transcriptome changes in heart and kidney.

Genome-wide methylation analysis of tubulocystic and papillary renal cell carcinomas.

Tubulocystic renal cell carcinoma (TRCC) represents a rare tumor with incidence lower than 1 % of all renal carcinomas. This study was undertaken to contribute to characterization of molecular signatures associated with TRCC and to compare them with the features of papillary renal cell carcinoma (PRCC) at the level of genome wide methylation analysis.We performed methylated DNA immunoprecipitation (MeDIP) coupled with microarray analysis (Roche NimbleGen). Using the CHARM package, we compared the levels of gene methylation between paired samples of tumors and control renal tissues of each examined individual. We found significant global demethylation in all tumor samples in comparison with adjacent kidney tissues of normal histological appearance but no significant differences in gene methylation between the both compared tumor entities. Therefore we focused on characterization of differentially methylated regions between both tumors and control tissues. We found 42 differentially methylated genes.Hypermethylated genes for protocadherins (PCDHG) and genes coding for products associated with functions of plasma membrane were evaluated as significantly overrepresented among hypermethylated genes detected in both types of renal cell carcinomas.In our pilot study, we provide the first evidence that identical features in the process of carcinogenesis leading to TRCC and/or to PRCC may be found at the gene methylation level.

A Novel Mutation in the FECH Gene in a Czech Family with Erythropoietic Protoporphyria and a Population Study of IVS3-48C Variant Contributing to the Disease.

Erythropoietic protoporphyria (EPP), a chronic erythropoietic porphyria, is characterized by excess accumulation of protoporphyrin, particularly in erythroid cells. EPP inheritance is complex, almost always associated with two molecular defects. In most EPP patients, clinical expression requires coinheritance of a private ferrochelatase (FECH) mutation trans- to a hypomorphic FECH*IVS3-48C allele. This leads to a decrease of FECH activity below the critical threshold. This is characterized by cutaneous photosensitivity in early childhood such as itching, burning, swelling and redness in sun-exposed areas. Hepatic failure occurs in some patients (about 1-10 % of EPP patients), which may necessitate liver transplantation. We investigated a Czech family with two patients with manifested EPP in four generations. We found a novel mutation, c.84G >A, in the FECH gene in four individuals including proband and his mother (G84A transition in exon 2; p.W28*). Both clinically manifested probands inherited the hypomorphic IVS3-48C allele as well, while two clinically latent individuals with FECH mutation did not. To address the question whether the relatively low incidence of EPP in the Czech Republic might be due to lower frequency of the IVS3-48C allele, we screened for the frequency of the low expression allele in a control Czech (West Slaves) Caucasian population. Such study has not been performed in any Slavic population. Among 312 control individuals, there were no IVS3-48C/C (c.68-23C-T) homozygotes; 35 IVS3-48C/T heterozygous individuals were detected. The frequency of IVS3-48C allele was thus found to be 5.5 % in the Czech population, comparable to most West Caucasian populations.

Dynamic genetic linkage of intermediate blood pressure phenotypes during postural adaptations in a founder population.

Blood pressure (BP) is a dynamic phenotype that varies rapidly to adjust to changing environmental conditions. Standing upright is a recent evolutionary trait, and genetic factors that influence postural adaptations may contribute to BP variability. We studied the effect of posture on the genetics of BP and intermediate BP phenotypes. We included 384 sib-pairs in 64 sib-ships from families ascertained by early-onset hypertension and dyslipidemia. Blood pressure, three hemodynamic and seven neuroendocrine intermediate BP phenotypes were measured with subjects lying supine and standing upright. The effect of posture on estimates of heritability and genetic covariance was investigated in full pedigrees. Linkage was conducted on 196 candidate genes by sib-pair analyses, and empirical estimates of significance were obtained. A permutation algorithm was implemented to study the postural effect on linkage. ADRA1A, APO, CAST, CORIN, CRHR1, EDNRB, FGF2, GC, GJA1, KCNB2, MMP3, NPY, NR3C2, PLN, TGFBR2, TNFRSF6, and TRHR showed evidence of linkage with any phenotype in the supine position and not upon standing, whereas AKR1B1, CD36, EDNRA, F5, MMP9, PKD2, PON1, PPARG, PPARGC1A, PRKCA, and RET were specifically linked to standing phenotypes. Genetic profiling was undertaken to show genetic interactions among intermediate BP phenotypes and genes specific to each posture. When investigators perform genetic studies exclusively on a single posture, important genetic components of BP are missed. Supine and standing BPs have distinct genetic signatures. Standardized maneuvers influence the results of genetic investigations into BP, thus reflecting its dynamic regulation.

CD36-deficient congenic strains show improved glucose tolerance and distinct shifts in metabolic and transcriptomic profiles.

Deficiency of fatty acid translocase Cd36 has been shown to have a major role in the pathogenesis of metabolic syndrome in the spontaneously hypertensive rat (SHR). We have tested the hypothesis that the effects of Cd36 mutation on the features of metabolic syndrome are contextually dependent on genomic background. We have derived two new congenic strains by introgression of limited chromosome 4 regions of SHR origin, both including the defective Cd36 gene, into the genetic background of a highly inbred model of insulin resistance and dyslipidemia, polydactylous (PD) rat strain. We subjected standard diet-fed adult males of PD and the congenic PD.SHR4 strains to metabolic, morphometric and transcriptomic profiling. We observed significantly improved glucose tolerance and lower fasting insulin levels in PD.SHR4 congenics than in PD. One of the PD.SHR4 strains showed lower triglyceride concentrations across major lipoprotein fractions combined with higher levels of low-density lipoprotein cholesterol compared with the PD progenitor. The hepatic transcriptome assessment revealed a network of genes differentially expressed between PD and PD.SHR4 with significant enrichment by members of the circadian rhythmicity pathway (Arntl (Bmal1), Clock, Nfil3, Per2 and Per3). In summary, the introduction of the chromosome 4 region of SHR origin including defective Cd36 into the PD genetic background resulted in disconnected shifts of metabolic profile along with distinct changes in hepatic transcriptome. The synthesis of the current results with those obtained in other Cd36-deficient strains indicates that the eventual metabolic effect of a deleterious mutation such as that of SHR-derived Cd36 is not absolute, but rather a function of complex interactions between environmental and genomic background, upon which it operates.

Region of rat chromosome 8 determines complex nutrigenetic interactions under conditions of sucrose and cholesterol diets.

We have previously established a congenic strain SHR-Lx that carries a differential segment of rat chromosome 8 introgressed from a model of metabolic syndrome--the polydactylous rat strain--on the genomic background of spontaneously hypertensive rat (SHR). We compared the glucose tolerance and lipid profile of adult SHR and SHR-Lx males under conditions of standard diet and diets enriched in sucrose and cholesterol, respectively. While there was no evident difference between the SHR and SHR-Lx on standard diet, the one-week sucrose administration revealed the congenic strain sensitivity to carbohydrate-induced dyslipidemia conferred by the differential segment with only mild derangement of glucose tolerance. On the other hand, the high-cholesterol diet administration for three-weeks resulted in a contrasting pattern as the congenic strain displayed significantly lower concentrations of free fatty acids and improved glucose tolerance compared to SHR. After one-month washout period, the SHR-Lx showed higher insulin, triglyceride and cholesterol concentrations together with diminished insulin sensitivity of visceral adipose tissue. In summary, we have identified a genomic region syntenic to human chromosome 11q23, which determines complex nutrigenetic interactions under conditions of sucrose- and cholesterol-enriched diets.

A 14-gene region of rat chromosome 8 in SHR-derived polydactylous congenic substrain affects muscle-specific insulin resistance, dyslipidaemia and visceral adiposity.

The SHR and the PD/Cub are two established rodent models of human metabolic syndrome. Introgression of a ca 30 cM region of rat chromosome 8 from PD/Cub onto the genetic background of SHR was previously shown to influence several of the metabolic syndrome-related traits along with causing the PLS in the SHR-Lx congenic strain. In the process of identification of the causative alleles, we have produced several congenic sublines. The differential segment of SHR-Lx PD5 congenic substrain [SHR.PD(D8Rat42-D8Arb23)/Cub] spans approximately 1.4 Mb encompassing only 14 genes. When comparing the metabolic, morphometric and gene expression profiles of the SHR-Lx PD5 vs. SHR, the polydactyly and several distinct metabolic features observed in the original SHR-Lx congenic were still manifested, suggesting that the responsible genes were "trapped" within the relatively short differential segment of PD/Cub origin in SHR-Lx PD5. Particularly, the SHR-Lx PD5 displayed substantial reduction of insulin sensitivity confined to skeletal muscle. Among the candidate genes, the promyelocytic leukaemia zinc-finger Plzf (Zbtb16) transcription repressor is most likely responsible for the Lx mutation resulting in PLS and could also be involved in the alteration of metabolic pathways. The sequence analysis of the Plzf gene revealed a SNP leading to a threonine to serine substitution in SHR at aminoacid position 208 (T208S). In summary, we have isolated a 1.4 Mb genomic region syntenic to human chromosome 11q23, which, apart from causing polydactyly-luxate syndrome (PLS), affects total body weight, adiposity, lipid profile, insulin sensitivity of skeletal muscle and related gene expression as shown in the SHR-Lx PD5 congenic substrain.

Quantitative founder-effect analysis of French Canadian families identifies specific loci contributing to metabolic phenotypes of hypertension.

The Saguenay-Lac St-Jean population of Quebec is relatively isolated and has genealogical records dating to the 17th-century French founders. In 120 extended families with at least one sib pair affected with early-onset hypertension and/or dyslipidemia, we analyzed the genetic determinants of hypertension and related cardiovascular and metabolic conditions. Variance-components linkage analysis revealed 46 loci after 100,000 permutations. The most prominent clusters of overlapping quantitative-trait loci were on chromosomes 1 and 3, a finding supported by principal-components and bivariate analyses. These genetic determinants were further tested by classifying families by use of LOD score density analysis for each measured phenotype at every 5 cM. Our study showed the founder effect over several generations and classes of living individuals. This quantitative genealogical approach supports the notion of the ancestral causality of traits uniquely present and inherited in distinct family classes. With the founder effect, traits determined within population subsets are measurably and quantitatively transmitted through generational lineage, with a precise component contributing to phenotypic variance. These methods should accelerate the uncovering of causal haplotypes in complex diseases such as hypertension and metabolic syndrome.

[Nutrition genomics]. / Nutricní genomika.

The importance of nutrition for human health and its influence on the onset and course of many diseases are nowadays considered as proven. Only the recent development of molecular biology and biochemical methods allows the elucidation of the molecular mechanisms of diet constituent actions and their subsequent effect on homeostatic mechanisms in health and disease states. The availability of the draft human genome sequence as well as the genome sequences of model organisms, combined with the functional and integrative genomics approaches of systems biology, bring about the possibility to identify alleles and haplotypes responsible for specific reaction to the dietary challenge in susceptible individuals. Such complex interactions are studied within the newly conceived field, the nutrition genomics (nutrigenomics). Using the tools of highly parallel analyses of transcriptome, proteome and metabolome, the nutrition genomics pursues its ultimate goal, i.e. the individualized diet, respecting not only quantitative and qualitative nutritional needs and the actual health status, but also the genetic predispositions of an individual. This approach should lead to prevention of the onset of such diseases as obesity, hypertension or type 2 diabetes, or enhance the efficiency of their therapy.

Comparative gene map of hypertriglyceridaemia.

Elevated triglyceride levels in the circulation are currently recognized as an independent risk factor for coronary artery disease. Hypertriglyceridaemia represents one of the attributes of metabolic syndrome and is present in the most common genetic dyslipidaemia, the familial combined hyperlipidaemia. The factual concentration of triglycerides is determined by a complex interaction of environmental and genetic components. Deeper understanding of the causative gene variants and the mode of their participation in the pathogenesis of hypertriglyceridaemia is required for devising efficient therapy of hypertriglyceridaemia. This is the first systematic review of linkage and candidate gene studies dealing with the dissection of genetic determinants of (hyper)triglyceridaemia in human and two major mammalian model species, mouse and rat. Based on the merged sets of data, a synthetic view of the genetic component of triglyceridaemia, the "hypertriglyceridaemia gene map", is presented.

Isotretinoin and fenofibrate induce adiposity with distinct effect on metabolic profile in a rat model of the insulin resistance syndrome.

OBJECTIVE: To investigate the effect of transcription-modulating drugs, fenofibrate and isotretinoin, on metabolic profile, insulin sensitivity of adipose and muscle tissues and gene expression in a genetic model of insulin resistance syndrome, polydactylous rat strain (PD/Cub). DESIGN: Administration of fenofibrate (100 mg/kg/day), isotretinoin (30 mg/kg/day) or vehicle to adult male PD/Cub rats fed standard laboratory chow for 15 days. MEASUREMENTS: Parameters of lipid and carbohydrate metabolism-oral glucose tolerance test, serum concentrations of insulin, triglycerides (TG), free fatty acids (FFA), glycerol, total cholesterol (CH); morphometric variables, in vitro insulin sensitivity of adipose and muscle tissues, catecholamine-stimulated lipolysis and the expression of ApoC-III and Hnf-4 genes in liver. RESULTS: Both experimental groups displayed an increase in adiposity with contrasting effects on TG (lowered by fenofibrate and increased by isotretinoin) and gene expression (no change in fibrate-treated rats and increased expression of ApoC-III and Hnf-4 in isotretinoin-treated group). Fenofibrate-treated rats also showed decreased concentrations of FFA and CH with concomitant decrease of catecholamine-induced lipolysis in adipocytes, but also hyperinsulinemia and the highest insulin/glucose ratio. Isotretinoin increased glycerol concentrations and decreased the insulin sensitivity of peripheral tissues. CONCLUSION: The PD/Cub rat showed a distinct pharmacogenetic reaction to fenofibrate and isotretinoin administration. Several lines of evidence now implicate specific variant(s) of ApoC-III and/or ApoA-V alleles as responsible for the dyslipidemia observed in this genetic model. The PD/Cub strain may also serve as a pharmacogenetic model for dissection of the retinoid-induced hypertriglyceridemia.

PPARs: molecular targets in the pharmacogenomics era.

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 lipid-sensors, the peroxisome proliferator-activated receptors (PPARs) clearly stands out. The review focuses on pharmacogenetic aspects of recent developments in PPAR biology.