Genetic Deficiency of Flavin-Containing Monooxygenase 3 (Fmo3) Protects Against Thrombosis but Has Only a Minor Effect on Plasma Lipid Levels—Brief Report

May 10, 2019Arteriosclerosis, thrombosis, and vascular biology

Lack of the Fmo3 Gene May Protect Against Blood Clots but Has Little Impact on Blood Fat Levels

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Abstract

FMO3 knockout (FMO3KO) significantly reduces systemic TMAO levels and thrombosis potential in mice.

FMO3 converts trimethylamine to trimethylamine N-oxide (TMAO), which is linked to cardiovascular disease risk.
FMO3KO mice exhibited reduced TMAO levels when maintained on a 0.5% choline diet.
The effects on lipid metabolism in FMO3KO mice were less pronounced compared to those seen with an antisense oligonucleotide (ASO) knockdown strategy.
FMO3-ASO treatment produced similar lipid-lowering effects in both FMO3KO and wild-type mice, suggesting off-target effects.
No significant effect on atherosclerosis was observed in LDLRKO mice, regardless of FMO3 status.

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Objective- FMO (flavin-containing monooxygenase) 3 converts bacterial-derived trimethylamine to trimethylamine N-oxide (TMAO), an independent risk factor for cardiovascular disease. We generated FMO3 knockout (FMO3KO) mouse to study its effects on plasma TMAO, lipids, glucose/insulin metabolism, thrombosis, and atherosclerosis. Approach and Results- Previous studies with an antisense oligonucleotide (ASO) knockdown strategy targeting FMO3 in LDLRKO (low-density lipoprotein receptor knockout) mice resulted in major reductions in TMAO levels and atherosclerosis, but also showed effects on plasma lipids, insulin, and glucose. Although FMO3KO mice generated via CRISPR/Cas9 technology bred onto the LDLRKO background did exhibit similar effects on TMAO levels, the effects on lipid metabolism were not as pronounced as with the ASO knockdown model. These differences could result from either off-target effects of the ASO or from a developmental adaptation to the FMO3 deficiency. To distinguish these possibilities, we treated wild-type and FMO3KO mice with control or FMO3 ASOs. FMO3-ASO treatment led to the same extent of lipid-lowering effects in the FMO3KO mice as the wild-type mice, indicating off-target effects. The levels of TMAO in LDLRKO mice fed an atherogenic diet are very low in both wild-type and FMO3KO mice, and no significant effect was observed on atherosclerosis. When FMO3KO and wild-type mice were maintained on a 0.5% choline diet, FMO3KO showed a marked reduction in both TMAO and in vivo thrombosis potential. Conclusions- FMO3KO markedly reduces systemic TMAO levels and thrombosis potential. However, the previously observed large effects of an FMO3 ASO on plasma lipid levels appear to be due partly to off-target effects.

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Genetic Deficiency of Flavin-Containing Monooxygenase 3 (Fmo3) Protects Against Thrombosis but Has Only a Minor Effect on Plasma Lipid Levels—Brief Report

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