PDF(Pubmed)
Abstract：
The 9p21.3 genomic locus is a hot spot for disease-associated single-nucleotide polymorphisms (SNPs), and its strongest associations are with coronary artery disease (CAD). The disease-associated SNPs are located within the sequence of a long noncoding RNA ANRIL, which potentially contributes to atherogenesis by regulating vascular cell stress and proliferation, but also affects pancreatic β-cell proliferation. Altered expression of a neighboring gene, CDKN2B, has been also recognized to correlate with obesity and hepatic steatosis in people carrying the risk SNPs. In the present study, we investigated the impact of 9p21.3 on obesity accompanied by hyperlipidemia in mice carrying a deletion of the murine ortholog for the 9p21.3 (Chr4Δ70/Δ70) risk locus in hyperlipidemic Ldlr-/-ApoB100/100 background. The Chr4Δ70/Δ70 mice showed decreased mRNA expression of insulin receptors in white adipose tissue already at a young age, which developed into insulin resistance and obesity by aging. In addition, the Sirt1-Ppargc1a-Ucp2 pathway was downregulated together with the expression of Cdkn2b, specifically in the white adipose tissue in Chr4Δ70/Δ70 mice. These results suggest that the 9p21.3 locus, ANRIL lncRNA, and their murine orthologues may regulate the key energy metabolism pathways in a white adipose tissue-specific manner in the presence of hypercholesterolemia, thus contributing to the pathogenesis of metabolic syndrome.
摘要：
9p21.3基因组位点是疾病相关单核苷酸多态性（SNP）的热点，其与冠状动脉疾病(CAD)的相关性最强。疾病相关的SNP位于长链非编码RNAANRIL的序列内,它可能通过调节血管细胞的应激和增殖来促进动脉粥样硬化，但也会影响胰腺β细胞的增殖。改变了邻近基因的表达，CDKN2B,在携带风险SNP的人群中,也已经认识到与肥胖和肝脂肪变性相关。在本研究中,我们研究了在高脂血症Ldlr-/-ApoB100/100背景中9p21.3（Chr4Δ70/Δ70）风险基因座缺失的小鼠中，9p21.3对伴有高脂血症的肥胖的影响。Chr4Δ70/Δ70小鼠在年轻时已经显示出白色脂肪组织中胰岛素受体的mRNA表达降低，随着年龄的增长发展为胰岛素抵抗和肥胖。此外,Sirt1-Ppargc1a-Ucp2通路与Cdkn2b的表达一起下调，特别是在Chr4Δ70/Δ70小鼠的白色脂肪组织中。这些结果表明，9p21.3基因座，ANRILlncRNA，在高胆固醇血症的存在下，它们的鼠直系同源物可能以白色脂肪组织特异性方式调节关键的能量代谢途径，从而促进代谢综合征的发病机制。
