Genetic Deficiency of Flavin-Containing Monooxygenase 3 ( Fmo3 ) Protects Against Thrombosis but Has Only a Minor Effect on Plasma Lipid Levels—Brief Report
Open accessAbstract
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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Multiple studies have confirmed through genetic gain and loss of function studies in mice that manipulation of trimethylamine and trimethylamine N-oxide levels in vivo alters platelet responsiveness, rate of clot generation, and thrombosis potential.
“Multiple studies have confirmed through both genetic gain (as global FMO3 transgene) and loss (via anti-sense oligonucleotide to FMO3, and via global FMO3 knock out) of function studies in mice that manipulation of TMA and TMAO levels in vivo alters platelet responsiveness, rate of clot generation, and thrombosis potential83, 84, 119.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [119]
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- Authors
- Shih, D. M., Zhu, W., Schugar, R. C., Meng, Y., Jia, X., Miikeda, A., Wang, Z., Zieger, M., Lee, R., Graham, M., Allayee, H., Cantor, R. M., Mueller, C., Brown, J. M., Hazen, S. L., & Lusis, A. J.
- Affiliations
- University of California, Los Angeles (US)
- Cleveland Clinic (US)
- University of Massachusetts Chan Medical School (US)
- Ionis Pharmaceuticals (United States) (US)
- University of Southern California (US)
- ORCID
- Venue
- Arteriosclerosis, Thrombosis, and Vascular Biology
- Published
- 2019-06
- Volume
- 39
- Issue
- 6
- Pages
- 1045-1054
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- PMC
- PMC6531332
- OpenAlex
- W2937246795
- Cited by
- 67
- References
- 30
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 8 · 2023: 10 · 2022: 12 · 2021: 10 · 2020: 11 · 2019: 1
- FWCI
- 8.56
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- The Journal of the American Medical Association (JAMA) Network (American Medical Association) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Cleveland Clinic
- National Institutes of Health (5r01dk098252-08)
- National Institute on Alcohol Abuse and Alcoholism (P50AA024333)
- National Heart, Lung, and Blood Institute (P01HL131471, P01HL030568, R01HL133169, R01HL126827, R01HL103866, R01HL071776, R01HL122283, P01HL028481)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK098252)
- National Institute of Neurological Disorders and Stroke (R01NS088689)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Paraoxonase enzyme and polymorphisms
- Keywords
- FMO3, trimethylamine N-oxide, thrombosis, plasma lipids, Ldlr knockout mice, antisense oligonucleotide knockdown, off-target effects, atherosclerosis, cardiovascular risk
- MeSH terms
- Animals, Choline, Disease Models, Animal, Methylamines, Mice, Inbred C57BL, Oxygenases, Random Allocation, Reference Values, Thrombosis, Polymerase Chain Reaction, Mice, Knockout, Atherosclerosis, Lipid Metabolism, Mice
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