Department of Radiology and Medical Imaging, University of Virginia, Charlottesville, USA.
Physiol Genomics. 2012 Mar 19;44(6):345-51. doi: 10.1152/physiolgenomics.00087.2011. Epub 2012 Jan 24.
Bglu3 is a quantitative trait locus for fasting glucose on distal chromosome 1 identified in an intercross between C57BL/6 (B6) and C3H/HeJ (C3H) apolipoprotein E-deficient (apoE(-/-)) mice. This locus was subsequently replicated in two separate mouse intercrosses. The objective of this study was to characterize Bglu3 through construction and analysis of a congenic strain and identify underlying candidate genes. Congenic mice were constructed by introgressing a genomic region harboring Bglu3 from C3H.apoE(-/-) into B6.apoE(-/-) mice. Mice were started with a Western diet at 6 wk of age and maintained on the diet for 12 wk. Gene expression in the liver was analyzed by microarrays. Congenic mice had significantly higher fasting glucose levels and developed more significant glucose intolerance compared with B6.apoE(-/-) mice on the Western diet. Microarray analysis revealed 336 genes to be differentially expressed in the liver of congenic mice. Further pathway analysis suggested a role for acute phase response signaling in regulating glucose intolerance. Apcs, encoding an acute phase response protein serum amyloid P (SAP), is located underneath the linkage peak of Bglu3. Multiple single nucleotide polymorphisms between B6 and C3H mice were detected within and surrounding Apcs. Apcs expression in the liver was significantly higher in congenic and C3H mice compared with B6 mice. The Western diet consumption led to a gradual rise in plasma SAP levels, which was accompanied by rising fasting glucose in both B6 and C3H apoE(-/-) mice. Expression of C3H Apcs in B6.apoE(-/-) mice aggravated glucose intolerance. Bglu3 is confirmed to be a locus affecting diabetes susceptibility, and Apcs is a probable candidate gene.
Bglu3 是在载脂蛋白 E 缺陷（apoE(-/-)）的 C57BL/6（B6）和 C3H/HeJ（C3H）小鼠的杂交后代中鉴定的用于空腹血糖的数量性状位点。该位点随后在两个独立的小鼠杂交实验中得到了复制。本研究的目的是通过构建和分析一个同源性基因来对 Bglu3 进行特征分析，并鉴定潜在的候选基因。通过将源自 C3H.apoE(-/-)的含有 Bglu3 的基因组区域导入 B6.apoE(-/-)，构建了同源性基因小鼠。在 6 周龄时，小鼠开始使用西方饮食，并在该饮食下维持 12 周。通过微阵列分析肝脏中的基因表达。与 B6.apoE(-/-)相比，同源性基因小鼠在西方饮食下空腹血糖水平显著升高，且葡萄糖耐量明显更差。微阵列分析显示 336 个基因在同源性基因小鼠肝脏中差异表达。进一步的途径分析表明，急性相反应信号在调节葡萄糖耐量方面发挥作用。编码急性相反应蛋白血清淀粉样蛋白 P（SAP）的 Apcs 位于 Bglu3 的连锁峰下方。在 B6 和 C3H 小鼠之间检测到多个位于 Apcs 内及其周围的单核苷酸多态性。与 B6 相比，同源性基因和 C3H 小鼠肝脏中的 Apcs 表达显著升高。西方饮食的摄入导致血浆 SAP 水平逐渐升高，这伴随着 B6 和 C3H apoE(-/-)小鼠空腹血糖的升高。B6.apoE(-/-) 小鼠中 C3H Apcs 的表达加重了葡萄糖耐量的恶化。Bglu3 被证实是一个影响糖尿病易感性的基因座，Apcs 是一个可能的候选基因。
