L-Carnitine intake and high trimethylamine N-oxide plasma levels correlate with low aortic lesions in ApoE−/− transgenic mice expressing CETP
Open accessAbstract
OBJECTIVE: Dietary l-carnitine can be metabolized by intestinal microbiota to trimethylamine, which is absorbed by the gut and further oxidized to trimethylamine N-oxide (TMAO) in the liver. TMAO plasma levels have been associated with atherosclerosis development in ApoE(-/-) mice. To better understand the mechanisms behind this association, we conducted in vitro and in vivo studies looking at the effect of TMAO on different steps of atherosclerotic disease progression. METHODS: J774 mouse macrophage cells were used to evaluate the effect of TMAO on foam cell formation. Male ApoE(-/-) mice transfected with human cholesteryl ester transfer protein (hCETP) were fed l-carnitine and/or methimazole, a flavin monooxygenase 3 (FMO3) inhibitor that prevents the formation of TMAO. Following 12 week treatment, l-carnitine and TMAO plasma levels, aortic lesion development, and lipid profiles were determined. RESULTS: TMAO at concentrations up to 10-fold the Cmax reported in humans did not affect in vitro foam cell formation. In ApoE(-/-)mice expressing hCETP, high doses of l-carnitine resulted in a significant increase in plasma TMAO levels. Surprisingly, and independently from treatment group, TMAO levels inversely correlated with aortic lesion size in both aortic root and thoracic aorta. High TMAO levels were found to significantly correlate with smaller aortic lesion area. Plasma lipid and lipoprotein levels did not change with treatment nor with TMAO levels, suggesting that the observed effects on lesion area were independent from lipid changes. CONCLUSION: These findings suggest that TMAO slows aortic lesion formation in this mouse model and may have a protective effect against atherosclerosis development in humans.
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TMAO shows positive effects against atherosclerosis in ApoE−/− transgenic mice expressing cholesteryl ester transfer protein CETP.
“even TMAO showed positive effects against atherosclerosis in ApoE−/− transgenic mice expressing cholesteryl ester transfer protein CETP [70].”
From Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target (2018) · cites this paper as [70]
Feeding L-carnitine to Apoe-/- transgenic mice overexpressing human CETP increased plasma TMAO.
“Feeding L-carnitine to Apo e -/- transgenic mice overexpressing human cholesterol ester transfer protein (CETP) caused increased plasma TMAO concentrations in these mice, but this elevated TMAO was inversely correlated with aortic lesion size (31).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [31]
The effects of TMAO on atherogenesis are completely opposite in Apoe-/- transgenic mice overexpressing human CETP.
“As discussed above in Section 5.1.2,the effects of TMAO on atherogenesis are completely opposite when Apo e -/-transgenic mice overexpressing human CETP are studied.”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [31]
In those CETP-overexpressing mice, increased plasma TMAO was inversely correlated with aortic lesion size.
“In these mice, increased plasma TMAO concentrations were inversely correlated with aortic lesion size (31).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [31]
In those CETP-overexpressing mice, elevated TMAO was inversely correlated with aortic lesion size.
“Feeding L-carnitine to Apo e -/- transgenic mice overexpressing human cholesterol ester transfer protein (CETP) caused increased plasma TMAO concentrations in these mice, but this elevated TMAO was inversely correlated with aortic lesion size (31).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [31]
TMAO at concentrations up to 10-fold the Cmax reported in humans did not affect in vitro foam cell formation in apoE−/− mice transfected with human cholesteryl ester transfer protein.
“On the contrary, Collins et al. showed that TMAO at concentrations up to 10-fold the Cmax reported in humans did not affect in vitro foam cell formation in apoE−/− mice transfected with human cholesteryl ester transfer protein [41].”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [41]
TMAO levels were inversely correlated with atherosclerotic lesion size in aorta.
“Surprisingly, TMAO levels were inversely correlated with atherosclerotic lesion size in aorta.”
From Trimethylamine N-oxide: the good, the bad and the unknown. (2016) · cites this paper as [41]
Most fish do not contain TMAO, just as most fish do not contain significant amounts of omega-3 fatty acids.
“In fact, most fish do not contain TMAO, just as most fish do not contain significant amounts of omega-3 fatty acids163,164.”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [164]
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- Authors
- Collins, H. L., Drazul-Schrader, D., Sulpizio, A. C., Koster, P. D., Williamson, Y., Adelman, S. J., Owen, K., Sanli, T., & Bellamine, A.
- Affiliations
- Lonza (United States) (US)
- KGK Synergize (Canada) (CA)
- Corresponding author
- Bellamine, Aouatef
- Venue
- Atherosclerosis
- Publisher
- Elsevier BV
- Published
- 2016-01
- Volume
- 244
- Pages
- 29-37
- ISSN
- 0021-9150 (ISSN-L)
- OpenAlex
- W2211887163
- Cited by
- 189
- References
- 64
- Citations by year
- 2026: 10 · 2025: 8 · 2024: 11 · 2023: 14 · 2022: 31 · 2021: 27 · 2020: 22 · 2019: 22 · 2018: 19 · 2017: 13 · 2016: 12
- FWCI
- 7.21
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Atherosclerosis (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Keywords
- L-carnitine, trimethylamine N-oxide, aortic lesions, ApoE-deficient mice, cholesteryl ester transfer protein, methimazole, flavin monooxygenase 3, gut microbiota, foam cell formation, macrophages
- MeSH terms
- Animals, Apolipoproteins E, Carnitine, Cells, Cultured, Disease Models, Animal, Humans, Macrophages, Male, Methylamines, Mice, Knockout, Disease Progression, Atherosclerosis, Mice, Cholesterol Ester Transfer Proteins
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