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

By Brian J. Bennett, T. Q. de Aguiar Vallim, Zeneng Wang, D. Shih, Yonghong Meng, J. Gregory, H. Allayee, Richard G. Lee, M. Graham, R. Crooke and 3 more. Cell Metabolism, 2013

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SUMMARY 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 monooxygenase 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 down-regulation 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 explains 11% of the variation in atherosclerosis.

Subfields: Molecular Biology, Pharmacology

View Paper: https://www.semanticscholar.org/paper/91ad590c04e9ffa54ab8d90d8d82ab764daf1ba1

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Citations in the corpus

Non-lethal inhibition of gut microbial trimethylamine production for the treatment of atherosclerosis (2015, methodology): “…importance of both TMAO and host hepatic FMO3, the primary FMO responsible for TMAO production, as important regulators in host lipid and sterol metabolism, as well as atherosclerosis development (Bennett et al., 2013; Koeth et al., 2013; Shih et al., 2015; Wang et al., 2011; Warrier et al., 2015).”
Gut Microbiota-Dependent Trimethylamine N-oxide (TMAO) Pathway Contributes to Both Development of Renal Insufficiency and Mortality Risk in Chronic Kidney Disease (2014, background): “Furthermore, animal model studies have revealed that TMAO is mechanistically linked to atherosclerosis development through multiple distinct pathways.(8,14) Animal model and human clinical studies demonstrate an obligatory role for gut microbiota in TMAO formation from TMA-containing nutrients, incl”
Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide (2015, background): “2B), but rather higher FMO activity in females, consistent with previous studies in conventionally raised mice which demonstrated that FMO3 is expressed at higher levels in females than in males (8, 27).”
Dietary lipids, gut microbiota and lipid metabolism (2019, background): “FMO3 expression is regulated by bile acids by a mechanism that involves FXR [121].”
Gut Microbiota in Cardiovascular Health and Disease (2017, background): “flavin monooxygenase enzymes in the liver and then released into the circulation.(58) TMAO is mainly cleared from circula-”
Resveratrol Attenuates Trimethylamine-N-Oxide (TMAO)-Induced Atherosclerosis by Regulating TMAO Synthesis and Bile Acid Metabolism via Remodeling of the Gut Microbiota (2016, background): “Dietary choline is metabolized by the intestinal microbiota to TMA, which is further metabolized by FMO enzymes, in particular, FMO3, to produce TMAO in the liver (23).”
Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk (2016, positive): “Recent studies involving genetic manipulation of FMO3, the major FMO responsible for converting TMA into TMAO (Bennett et al., 2013), further confirm the involvement of this metaorganismal pathway in both atherosclerosis development and regulation of whole body cholesterol and sterol metabolism…”
Pleiotropic Roles of Bile Acids in Metabolism (2013, background): “…in a mechanism that requires FXR. FMO3 is an enzyme previously thought to be part of the detoxification pathway but was shown to be required for the synthesis of trimethylamine-N-oxide (TMAO), a metabolite that is strongly associated with atherosclerosis in mice and humans (Bennett et al., 2013).”
Trimethylamine N‐Oxide Promotes Vascular Inflammation Through Signaling of Mitogen‐Activated Protein Kinase and Nuclear Factor‐κB (2016, background): “LDLR / mice were injected intraperitoneally with vehicle or a sterile solution of TMAO.”