microRNA-146a-5p association with the cardiometabolic disease risk factor TMAO
microRNA-146a-5p association with the cardiometabolic disease risk factor TMAO
复制标题
DOI：
10.1152/physiolgenomics.00079.2018
复制
发表时间：
2019-02-01
影响因子：
4.6
通讯作者：
Bennett, Brian J.
中科院分区：
文献类型：
--
作者：
Coffey, Alisha R.;Kanke, Matt;Bennett, Brian J.
三甲基胺-N-氧化物（TMAO）是一种微生物胆碱代谢副产物，在肝脏中加工并排泄到循环中，与动脉粥样硬化病变形成和心血管疾病风险增加相关。TMAO水平的遗传调节因子在很大程度上是未知的。在本研究中，我们使用了288只来自遗传异质性小鼠群体[Diversity Outbred（DO）]的小鼠，以确定在致动脉粥样硬化饮食的背景下肝脏microRNA与TMAO的相关性。我们还在另外两种动脉粥样硬化动物模型中验证了研究结果：肝脏特异性胰岛素受体敲除小鼠喂食普通饲料（LIRKO）和非洲绿色猴喂食高脂肪/高胆固醇饲料。在IX）小鼠、LIRKO小鼠和非洲绿色猴中进行的小RNA测序分析仅鉴定出一种肝脏microRNA（miR-146 a-5p），其在所有三种模型中异常表达。此外，在这些模型中的每一个中，miR-146 a-5 p水平与致动脉粥样硬化饮食后的循环TMAO相关。我们还进行了高分辨率的遗传作图，并确定了一个新的数量性状位点上的12号染色体的TMAO水平。这个区间包括两个基因。Numb和Dist与miR-146a和TMAO均呈负相关，是miR-146a的预测靶点。这两个基因都已被验证为miR-146a的直接靶点，尽管在其他细胞环境中。这是我们所知的miR-146和TMAO之间联系的第一份报告。我们的研究结果表明，miR-146 - 5 p以及12号染色体QTL上的一个或多个基因（可能是Numb或Dlst）与TMAO水平密切相关，并可能参与动脉粥样硬化的控制。
Trimethylamine-N-oxide (TMAO), a microbial choline metabolism byproduct that is processed in the liver and excreted into circulation, is associated with increased atherosclerotic lesion formation and cardiovascular disease risk. Genetic regulators of TMAO levels are largely unknown. In the present study, we used 288 mice from a genetically heterogeneous mouse population [Diversity Outbred (DO)] to determine hepatic microRNA associations with TMAO in the context of an atherogenic diet. We also validated findings in two additional animal models of atherosclerosis: liver-specific insulin receptor knockout mice fed a chow diet (LIRKO) and African green monkeys fed high-fat/high-cholesterol diet. Small RNA-sequencing analysis in IX) mice, LIRKO mice, and African green monkeys identified only one hepatic microRNA (miR-146a-5p) that is aberrantly expressed across all three models. Moreover, rniR-146a-5p levels are associated with circulating TMAO after atherogenic diet in each of these models. We also performed high-resolution genetic mapping and identified a novel quantitative trait locus on Chromosome 12 for TMAO levels. This interval includes two genes. Numb and Dist, which are inversely correlated with both miR-146a and TMAO and are predicted targets of miR-146a. Both of these genes have been validated as direct targets of miR-146a, though in other cellular contexts. This is the first report to our knowledge of a link between miR-146 and TMAO. Our findings suggest that miR-146-5p, as well as one or more genes at the Chromosome 12 QTL (possibly Numb or Dlst), is strongly linked to TMAO levels and likely involved in the control of atherosclerosis.