Several corresponding regions of human and mammalian genomes have been shown to affect sensitivity to the manifestation of metabolic syndrome via nutrigenetic interactions. In this study, we assessed the effect of sucrose administration in a newly established congenic strain BN.SHR20, in which a limited segment of rat chromosome 20 from a metabolic syndrome model, spontaneously hypertensive rat (SHR), was introgressed into Brown Norway (BN) genomic background. We mapped the extent of the differential segment and compared the genomic sequences of BN vs. SHR within the segment in silico. The differential segment of SHR origin in BN.SHR20 spans about 9 Mb of the telomeric portion of the short arm of chromosome 20. We identified non-synonymous mutations e.g., in ApoM, Notch4, Slc39a7, Smim29 genes and other variations in or near genes associated with metabolic syndrome in human genome-wide association studies. Male rats of BN and BN.SHR20 strains were fed a standard diet for 18 weeks (control groups) or 16 weeks of standard diet followed by 14 days of high-sucrose diet (HSD). We assessed the morphometric and metabolic profiles of all groups. Adiposity significantly increased only in BN.SHR20 after HSD. Fasting glycemia and the glucose levels during the oral glucose tolerance test were higher in BN.SHR20 than in BN groups, while insulin levels were comparable. The fasting levels of triacylglycerols were the highest in sucrose-fed BN.SHR20, both compared to the sucrose-fed BN and the control BN.SHR20. The non-esterified fatty acids and total cholesterol concentrations were higher in BN.SHR20 compared to their respective BN groups, and the HSD elicited an increase in non-esterified fatty acids only in BN.SHR20. In a new genetically defined model, we have isolated a limited genomic region involved in nutrigenetic sensitization to sucrose-induced metabolic disturbances.

• Klíčová slova
• animal model, congenic rat, metabolic syndrome, nutrigenetics,
• MeSH
• apolipoproteiny M genetika   MeSH
• celogenomová asociační studie MeSH
• hypertenze * metabolismus   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• lidské chromozomy, pár 20 metabolismus   MeSH
• mastné kyseliny MeSH
• metabolický syndrom * genetika   metabolismus   MeSH
• nutrigenomika MeSH
• omezení příjmu potravy MeSH
• potkani inbrední BN MeSH
• potkani inbrední SHR MeSH
• proteiny přenášející kationty * genetika   MeSH
• sacharosa škodlivé účinky   MeSH
• savci genetika   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• apolipoproteiny M MeSH
• Apom protein, rat MeSH Prohlížeč
• mastné kyseliny MeSH
• proteiny přenášející kationty * MeSH
• sacharosa MeSH
• SLC39A7 protein, human MeSH Prohlížeč

Metabolic syndrome is a highly prevalent human disease with substantial genomic and environmental components. Previous studies indicate the presence of significant genetic determinants of several features of metabolic syndrome on rat chromosome 16 (RNO16) and the syntenic regions of human genome. We derived the SHR.BN16 congenic strain by introgression of a limited RNO16 region from the Brown Norway congenic strain (BN-Lx) into the genomic background of the spontaneously hypertensive rat (SHR) strain. We compared the morphometric, metabolic, and hemodynamic profiles of adult male SHR and SHR.BN16 rats. We also compared in silico the DNA sequences for the differential segment in the BN-Lx and SHR parental strains. SHR.BN16 congenic rats had significantly lower weight, decreased concentrations of total triglycerides and cholesterol, and improved glucose tolerance compared with SHR rats. The concentrations of insulin, free fatty acids, and adiponectin were comparable between the two strains. SHR.BN16 rats had significantly lower systolic (18-28 mmHg difference) and diastolic (10-15 mmHg difference) blood pressure throughout the experiment (repeated-measures ANOVA, P < 0.001). The differential segment spans approximately 22 Mb of the telomeric part of the short arm of RNO16. The in silico analyses revealed over 1200 DNA variants between the BN-Lx and SHR genomes in the SHR.BN16 differential segment, 44 of which lead to missense mutations, and only eight of which (in Asb14, Il17rd, Itih1, Syt15, Ercc6, RGD1564958, Tmem161a, and Gatad2a genes) are predicted to be damaging to the protein product. Furthermore, a number of genes within the RNO16 differential segment associated with metabolic syndrome components in human studies showed polymorphisms between SHR and BN-Lx (including Lpl, Nrg3, Pbx4, Cilp2, and Stab1). Our novel congenic rat model demonstrates that a limited genomic region on RNO16 in the SHR significantly affects many of the features of metabolic syndrome.

• MeSH
• genom MeSH
• glukózový toleranční test MeSH
• hemodynamika MeSH
• lidé MeSH
• lidské chromozomy, pár 16 genetika   MeSH
• metabolický syndrom genetika   metabolismus   patofyziologie   MeSH
• metabolom MeSH
• potkani inbrední BN genetika   metabolismus   fyziologie   MeSH
• potkani inbrední SHR genetika   metabolismus   fyziologie   MeSH
• zvířata kongenní genetika   metabolismus   fyziologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The plasma profile of major lipoprotein classes and its subdivision into particular fractions plays a crucial role in the pathogenesis of atherosclerosis and is a major predictor of coronary artery disease. Our aim was to identify genomic determinants of triglyceride and cholesterol distribution into lipoprotein fractions and lipoprotein particle sizes in the recombinant inbred rat set PXO, in which alleles of two rat models of the metabolic syndrome (SHR and PD inbred strains) segregate together with those from Brown Norway rat strain. Adult male rats of 15 PXO strains (n = 8-13/strain) and two progenitor strains SHR-Lx (n = 13) and BXH2/Cub (n = 18) were subjected to one-week of high-sucrose diet feeding. We performed association analyses of triglyceride (TG) and cholesterol (C) concentrations in 20 lipoprotein fractions and the size of major classes of lipoprotein particles utilizing 704 polymorphic microsatellite markers, the genome-wide significance was validated by 2,000 permutations per trait. Subsequent in silico focusing of the identified quantitative trait loci was completed using a map of over 20,000 single nucleotide polymorphisms. In most of the phenotypes we identified substantial gradient among the strains (e.g. VLDL-TG from 5.6 to 66.7 mg/dl). We have identified 14 loci (encompassing 1 to 65 genes) on rat chromosomes 3, 4, 7, 8, 11 and 12 showing suggestive or significant association to one or more of the studied traits. PXO strains carrying the SHR allele displayed significantly higher values of the linked traits except for LDL-TG and adiposity index. Cholesterol concentrations in large, medium and very small LDL particles were significantly associated to a haplotype block spanning part of a single gene, low density lipoprotein receptor-related protein 1B (Lrp1b). Using genome-wide association we have identified new genetic determinants of triglyceride and cholesterol distribution into lipoprotein fractions in the recombinant inbred panel of rat model strains.

• MeSH
• celogenomová asociační studie MeSH
• cholesterol chemie   MeSH
• druhová specificita MeSH
• genomika * MeSH
• jednonukleotidový polymorfismus MeSH
• krysa rodu Rattus MeSH
• lipoproteiny chemie   MeSH
• triglyceridy chemie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cholesterol MeSH
• lipoproteiny MeSH
• triglyceridy MeSH