title: Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation.
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.
authors: Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. brian_bennett@med.unc.edu
authors: Brian J
authors: BJ
authors: Bennett
authors: Thomas Q
authors: TQ
authors: de Aguiar Vallim
authors: Zeneng
authors: Z
authors: Wang
authors: Diana M
authors: DM
authors: Shih
authors: Yonghong
authors: Y
authors: Meng
authors: Jill
authors: J
authors: Gregory
authors: Hooman
authors: H
authors: Allayee
authors: Richard
authors: R
authors: Lee
authors: Mark
authors: M
authors: Graham
authors: Rosanne
authors: R
authors: Crooke
authors: Peter A
authors: PA
authors: Edwards
authors: Stanley L
authors: SL
authors: Hazen
authors: Aldons J
authors: AJ
authors: Lusis
mesh_terms: D000728:Androgens / Q000494:pharmacology; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001483:Base Sequence; D001647:Bile Acids and Salts; D002794:Choline / Q000378:metabolism; D004032:Diet; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D020868:Gene Silencing; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008744:Methylamines / Q000097:blood* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010105:Oxygenases / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D012737:Sex Factors; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000728:Androgens; D001647:Bile Acids and Salts; D002794:Choline; D008744:Methylamines; D010105:Oxygenases; D018160:Receptors, Cytoplasmic and Nuclear; D000099150:Receptor, Farnesoid X-Activated; C020066:dimethylaniline monooxygenase (N-oxide forming); C005855:trimethyloxamine; C023336:trimethylamine