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Genetic Deficiency of Flavin-Containing Monooxygenase 3 ( Fmo3) Protects Against Thrombosis but Has Only a Minor

Diana M Shih1, Weifei Zhu2, Rebecca C Schugar2

  • 1From the Department of Medicine/Division of Cardiology (D.M.S., Y.M., A.M., A.J.L.), University of California, Los Angeles.

Arteriosclerosis, Thrombosis, and Vascular Biology
|May 10, 2019
PubMed

Insights

Flavin-containing monooxygenase 3 knockout mice significantly lower trimethylamine N-oxide (TMAO) and reduce thrombosis. Antisense oligonucleotide knockdown of FMO3 showed off-target lipid-lowering effects, not seen in knockout models.

Area of Science:

  • Biochemistry and Metabolism
  • Cardiovascular Disease Research
  • Genetics and Molecular Biology

Background:

  • Flavin-containing monooxygenase 3 (FMO3) metabolizes trimethylamine (TMA) to trimethylamine N-oxide (TMAO).
  • Elevated TMAO is an independent risk factor for cardiovascular disease.
  • Previous studies using antisense oligonucleotide (ASO) knockdown of FMO3 in LDLRKO mice showed reduced TMAO and atherosclerosis, but also affected lipid and glucose metabolism.

Purpose of the Study:

  • To investigate the effects of FMO3 knockout (FMO3KO) on TMAO, lipids, glucose/insulin metabolism, thrombosis, and atherosclerosis.
  • To differentiate between developmental adaptation to FMO3 deficiency and off-target effects of FMO3 ASO.

Main Methods:

  • Generation of FMO3 knockout (FMO3KO) mice on an LDLRKO background using CRISPR/Cas9 technology.
  • Treatment of wild-type and FMO3KO mice with control or FMO3 ASOs.
  • Analysis of plasma TMAO, lipid levels, glucose/insulin metabolism, thrombosis potential, and atherosclerosis in mice under different dietary conditions (atherogenic diet, choline diet).

Main Results:

  • FMO3KO mice exhibited reduced plasma TMAO levels and in vivo thrombosis potential, particularly on a choline-supplemented diet.
  • FMO3 ASO treatment caused significant lipid-lowering effects in both wild-type and FMO3KO mice, indicating off-target effects.
  • FMO3KO mice on an atherogenic diet showed no significant changes in TMAO levels or atherosclerosis compared to wild-type controls.

Conclusions:

  • FMO3 deficiency, achieved through genetic knockout, effectively reduces systemic TMAO levels and thrombosis potential.
  • Observed lipid-lowering effects in previous FMO3 ASO studies were partly attributed to off-target effects of the ASO.
  • FMO3KO mouse model provides a tool to study TMAO-related cardiovascular disease without confounding ASO off-target effects.
Keywords:
atherosclerosisglucoselipid metabolismthrombosistrimethylamine N-oxide

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