Trimethylamine-N-Oxide, a Metabolite Associated with Atherosclerosis, Exhibits Complex Genetic and Dietary Regulation

被引：841

作者：

Bennett, Brian J. ^{[1
,2
]}

Vallim, Thomas Q. de Aguiar ^{[1
,3
]}

Wang, Zeneng ^{[5
,6
]}

Shih, Diana M. ^{[1
]}

Meng, Yonghong ^{[1
]}

Gregory, Jill ^{[5
,6
]}

Allayee, Hooman ^{[7
,8
]}

Lee, Richard ^{[9
]}

Graham, Mark ^{[9
]}

Crooke, Rosanne ^{[9
]}

Edwards, Peter A. ^{[1
,3
]}

Hazen, Stanley L. ^{[5
,6
]}

Lusis, Aldons J. ^{[1
,2
,4
]}

机构：

[1] Univ Calif Los Angeles, Dept Med, Los Angeles, CA 90095 USA

[2] Univ Calif Los Angeles, Dept Human Genet, Los Angeles, CA 90095 USA

[3] Univ Calif Los Angeles, Dept Biol Chem, Los Angeles, CA 90095 USA

[4] Univ Calif Los Angeles, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90095 USA

[5] Cleveland Clin, Dept Cellular & Mol Med, Ctr Cardiovasc Diagnost & Prevent, Cleveland, OH 44195 USA

[6] Cleveland Clin, Dept Cardiovasc Med, Cleveland, OH 44195 USA

[7] Univ So Calif, Keck Sch Med, Dept Prevent Med, Los Angeles, CA 90089 USA

[8] Univ So Calif, Keck Sch Med, Inst Med Genet, Los Angeles, CA 90089 USA

[9] ISIS Pharmaceut, Carlsbad, CA 92010 USA

来源：

CELL METABOLISM | 2013年 / 17卷 / 01期

关键词：

CONTAINING MONOOXYGENASE ACTIVITY; GUT MICROBIOTA; POLYMORPHISMS; ACTIVATION; REVEALS; LIVER; FXR;

D O I：

10.1016/j.cmet.2012.12.011

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：49 / 60

页数：12

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