Šeda O, Křenová D, Šedová L, Kazdová L, Krupková M, Chylíková B, Liška F, Křen V
Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
Centre for Experimental Medicine, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
Folia Biol (Praha). 2017;63(2):67-77. doi: 10.14712/fb2017063020067.
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-1β, 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.
代谢综合征是一种病因多因素的常见病症。先前的研究表明，大鼠2号染色体（RNO2）以及人类基因组的同线区域存在代谢综合征各组分的遗传决定因素。我们的目的是使用新型大鼠模型进一步探究这些发现。我们通过将携带Gja8基因突变的自发性高血压大鼠品系（SHR-Dca，显性白内障）的有限RNO2区域分别导入到棕色挪威品系和同基因品系BN-Lx的基因组背景中，培育出了BN-Dca和BN-Lx.Dca同基因品系。我们比较了成年雄性BN-Lx、BN-Dca和BN-Lx.Dca大鼠的形态学、代谢和细胞因子谱。我们对新同基因品系中捕获的整个RNO2差异片段的DNA序列进行了电子计算机比较。与BN-Lx相比，BN-Dca和BN-Lx.Dca的总三酰甘油和胆固醇浓度均较低。BN-Dca中的空腹胰岛素水平高于BN-Lx.Dca和BN-Lx。BN-Dca品系中几种促炎细胞因子的浓度升高，包括IL-1α、IL-1β、IFN-γ和MCP-1。电子计算机分析显示，在同基因品系的差异片段内，BN-Lx和SHR基因组之间存在740多个DNA变异。我们培育出了新的同基因模型，证明SHR-Dca RNO2的有限基因组区域以不同方式显著影响脂质水平和胰岛素敏感性。
