A common polymorphism in the bile acid receptor farnesoid X receptor is associated with decreased hepatic target gene expression
A common polymorphism in the bile acid receptor farnesoid X receptor is associated with decreased hepatic target gene expression
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DOI：
10.1210/me.2007-0025
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发表时间：
2007-08-01
影响因子：
--
通讯作者：
Kim, Richard B.
中科院分区：
文献类型：
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作者：
Marzolini, Catia;Tirona, Rommel G.;Kim, Richard B.
法尼醇X受体(FXR或NR1H4)是胆汁酸激活的重要转录调节因子，参与胆汁酸、脂肪和葡萄糖的稳态。因此，FXR表达和功能的个体间差异可能表现为对胆固醇结石疾病、动脉粥样硬化和糖尿病等疾病的可变易感性。我们对欧洲、非洲、中国和西班牙裔美国人进行了FXR多态发现分析，发现了两个罕见的功能获得变异和一个常见的单核苷酸多态，导致翻译起始点(FXR*1B)附近的核苷酸发生G-1T替换，群体等位基因频率从2.5%到12%不等。在基于细胞的反式激活实验中，FXR*1B(-1T)活性比FXR*1A(-1G)活性降低。FXR*1B活性的降低既不是因为翻译效率降低，也不是因为可能形成截短的翻译变体。为了进一步确定这种多态的相关性，在人类肝库中进行的基因表达检测显示，在含有FXR*1B等位基因的肝脏中，FXR靶基因小异二聚体伙伴和有机阴离子转运多肽1B3的水平显著降低。这些发现首次确定了FXR中存在一种常见的基因变异，其功能后果可能有助于疾病风险或治疗结果。
The farnesoid X receptor (FXR or NR1H4) is an important bile-acid-activated, transcriptional regulator of genes involved in bile acid, lipid, and glucose homeostasis. Accordingly, interindividual variations in FXR expression and function could manifest as variable susceptibility to conditions such as cholesterol gallstone disease, atherosclerosis, and diabetes. We performed an FXR polymorphism discovery analysis of European-, African, Chinese-, and Hispanic-Americans and identified two rare gain-of-function variants and a common single nucleotide polymorphism resulting in a G-1T substitution in the nucleotide adjacent to the translation initiation site (FXR*1B) with population allelic frequencies ranging from 2.5 to 12%. In cell-based transactivation assays, FXR*1B (-1T) activity was reduced compared with FXR*1A (-1G). This reduced activity for FXR*1B resulted from neither decreased translational efficiency nor the potential formation of a truncated translational variant. To further define the relevance of this polymorphism, gene expression was examined in a human liver bank to reveal that levels of the FXR target genes small heterodimer partner and organic anion transporting polypeptide 1B3 were significantly reduced in livers harboring an FXR*1B allele. These findings are the first to identify the presence of a common genetic variant in FXR with functional consequences that could contribute to disease risk or therapeutic outcomes.