Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Cell Metab. 2013 Jan 8;17(1):49-60. doi: 10.1016/j.cmet.2012.12.011.
Circulating trimethylamine-N-oxide (TMAO) levels are strongly associated with atherosclerosis. We now examine genetic, dietary, and hormonal factors regulating TMAO levels. We demonstrate that two flavin mono-oxygenase family members, FMO1 and FMO3, oxidize trimethylamine (TMA), derived from gut flora metabolism of choline, to TMAO. Further, we show that FMO3 exhibits 10-fold higher specific activity than FMO1. FMO3 overexpression in mice significantly increases plasma TMAO levels while silencing FMO3 decreases TMAO levels. In both humans and mice, hepatic FMO3 expression is reduced in males compared to females. In mice, this reduction in FMO3 expression is due primarily to downregulation by androgens. FMO3 expression is induced by dietary bile acids by a mechanism that involves the farnesoid X receptor (FXR), a bile acid-activated nuclear receptor. Analysis of natural genetic variation among inbred strains of mice indicates that FMO3 and TMAO are significantly correlated, and TMAO levels explain 11% of the variation in atherosclerosis.
循环三甲基胺 N-氧化物 (TMAO) 水平与动脉粥样硬化密切相关。我们现在研究调节 TMAO 水平的遗传、饮食和激素因素。我们证明，两种黄素单加氧酶家族成员，FMO1 和 FMO3，氧化来自肠道菌群代谢胆碱的三甲基胺 (TMA) 为 TMAO。此外，我们表明 FMO3 的比活性比 FMO1 高 10 倍。在小鼠中过表达 FMO3 可显著增加血浆 TMAO 水平，而沉默 FMO3 则降低 TMAO 水平。在人类和小鼠中，与女性相比，雄性肝脏中的 FMO3 表达减少。在小鼠中，这种 FMO3 表达的减少主要是由于雄激素的下调。FMO3 的表达被膳食胆酸诱导，这一机制涉及法尼醇 X 受体 (FXR)，一种胆酸激活的核受体。对近交系小鼠的天然遗传变异分析表明，FMO3 和 TMAO 显著相关，TMAO 水平解释了动脉粥样硬化变异的 11%。
