Abstract
The objectives of the study were to determine the contribution, in mice, of members of the flavin-containing monooxygenase (FMO) family to the production of trimethylamine (TMA) N-oxide (TMAO), a potential proatherogenic molecule, and whether under normal dietary conditions differences in TMAO production were associated with changes in plasma cholesterol concentration or with an index of atherosclerosis (Als). Concentrations of urinary TMA and TMAO and plasma cholesterol were measured in 10-week-old male and female C57BL/6J and CD-1 mice and in mouse lines deficient in various Fmo genes (Fmo1−/−, 2−/−, 4−/−, and Fmo5−/−). In female mice most TMA N-oxygenation was catalyzed by FMO3, but in both genders 11%–12% of TMA was converted to TMAO by FMO1. Gender-, Fmo genotype-, and strain-related differences in TMAO production were accompanied by opposite effects on plasma cholesterol concentration. Plasma cholesterol was negatively, but weakly, correlated with TMAO production and urinary TMAO concentration. Fmo genotype had no effect on Als. There was no correlation between Als and either TMAO production or urinary TMAO concentration. Our results indicate that under normal dietary conditions TMAO does not increase plasma cholesterol or act as a proatherogenic molecule.
Highlights
A correlation between plasma trimethylamine (TMA) N-oxide (TMAO) concentrations and atherosclerotic plaque size has been reported in atherosclerosis-prone mice fed on diets supplemented with dietary precursors of TMA (Wang et al, 2011; Koeth et al, 2013)
In Fmo52/2 mice the proportion of total TMA excreted as trimethylamine N-oxide (TMAO) was the same as that in WT mice, in both males and females, indicating that FMO5 plays no role in the conversion of TMA to TMAO in vivo
This marked gender difference is consistent with previous findings (Li et al, 2013) and can be explained by the fact that at 5–6 weeks of age the expression of the gene encoding FMO3, the major enzyme involved in conversion of TMA to TMAO in both human and mouse (Dolphin et al, 1997; Lang et al, 1998; Zhang et al, 2007), is switched off in the liver of male, but not female, mice (Falls et al, 1995; Janmohamed et al, 2004)
Summary
A correlation between plasma trimethylamine (TMA) N-oxide (TMAO) concentrations and atherosclerotic plaque size has been reported in atherosclerosis-prone mice fed on diets supplemented with dietary precursors of TMA (Wang et al, 2011; Koeth et al, 2013). TMAO production is the result of a two-step process, requiring interplay between commensal gut bacteria and the host (Fennema et al, 2016). This process involves the liberation of TMA from dietary precursors, such as choline, carnitine, and TMAO itself (Mitchell et al, 2002; Fennema et al, 2016), and the subsequent host-dependent hepatic N-oxygenation of TMA to TMAO (Ayesh et al, 1993). Individuals homozygous or compound heterozygous for mutations that severely affect FMO3 activity have impaired N-oxygenation of TMA and suffer from the inherited metabolic disorder primary trimethylaminuria (Dolphin et al, 1997; Phillips and Shephard, 2015; Shephard et al, 2015)
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