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

Overview

Journal Cell Metab

Publisher Cell Press

Specialties Cell Biology
Endocrinology

Date 2013 Jan 15

PMID 23312283

Citations 494

Authors

Brian J Bennett

Thomas Q de Aguiar Vallim

Zeneng Wang

Diana M Shih

Yonghong Meng

Jill Gregory

Hooman Allayee

Richard Lee

Mark Graham

Rosanne Crooke

Peter A Edwards

Stanley L Hazen

Aldons J Lusis

Affiliations

Soon will be listed here.

Abstract

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.

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