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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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In the citing paper
“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]
In the citing paper
“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 N -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [31]
In the citing paper
“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 N -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [31]
In the citing paper
“In these mice, increased plasma TMAO concentrations were inversely correlated with aortic lesion size (31).”
From Trimethylamine N -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [31]
In the citing paper
“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 N -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [31]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
Citations
Cites
A RAPID METHOD OF TOTAL LIPID EXTRACTION AND PURIFICATION
Bligh, E. G., & Dyer, W. J. (1959) · Canadian Journal of Biochemistry and Physiology · doi:10.1139/o59-099 · Cited by 54,751
A human gut microbial gene catalogue established by metagenomic sequencing
MetaHIT Consortium, Qin, J., Li, R., Raes, J., Arumugam, M., Burgdorf, K. S., Manichanh, C., Nielsen, T., Pons, N., Levenez, F., et al. (2010) · Nature · doi:10.1038/nature08821 · Cited by 11,624
Inflammation in atherosclerosis
Libby, P. (2002) · Nature · doi:10.1038/nature01323 · Cited by 8,315
Markwell, M. A. K., Haas, S. M., BIEBER, L. L., & Tolbert, N. E. (1978) · Analytical Biochemistry · doi:10.1016/0003-2697(78)90586-9 · Cited by 6,460
Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease
Wang, Z., Klipfell, E., Bennett, B. J., Koeth, R., Levison, B. S., DuGar, B., Feldstein, A. E., Britt, E. B., Fu, X., Chung, Y.-M., et al. (2011) · Nature · doi:10.1038/nature09922 · Cited by 5,597
Diversity, stability and resilience of the human gut microbiota
Lozupone, C. A., Stombaugh, J. I., Gordon, J. I., Jansson, J. K., & Knight, R. (2012) · Nature · doi:10.1038/nature11550 · Cited by 5,533
Metagenomic Analysis of the Human Distal Gut Microbiome
Gill, S. R., Pop, M., DeBoy, R. T., Eckburg, P. B., Turnbaugh, P. J., Samuel, B. S., Gordon, J. I., Relman, D. A., Fraser-Liggett, C. M., & Nelson, K. E. (2006) · Science · doi:10.1126/science.1124234 · Cited by 4,699
Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis
Koeth, R. A., Wang, Z., Levison, B. S., Buffa, J. A., Org, E., Sheehy, B. T., Britt, E. B., Fu, X., Wu, Y., Li, L., et al. (2013) · Nature Medicine · doi:10.1038/nm.3145 · Cited by 4,386
Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk
Tang, W. H. W., Wang, Z., Levison, B. S., Koeth, R. A., Britt, E. B., Fu, X., Wu, Y., & Hazen, S. L. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1109400 · Cited by 3,400
Beckman, J. A., Creager, M. A., & Libby, P. (2002) · JAMA · doi:10.1001/jama.287.19.2570 · Cited by 2,765
Bennett, B. J., Vallim, T. Q. D. A., Wang, Z., Shih, D. M., Meng, Y., Gregory, J., Allayee, H., Lee, R., Graham, M., Crooke, R., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2012.12.011 · Cited by 1,070
Cholesteryl Ester Transfer Protein
Barter, P. J., Brewer, H. B., Chapman, M. J., Hennekens, C. H., Rader, D. J., & Tall, A. R. (2003) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.0000054658.91146.64 · Cited by 868
Hypertension and the Pathogenesis of Atherosclerosis
Alexander, R. W. (1995) · Hypertension · doi:10.1161/01.hyp.25.2.155 · Cited by 785
Yu, X.-H., Fu, Y., Zhang, D., Yin, K., & Tang, C. (2013) · Clinica Chimica Acta · doi:10.1016/j.cca.2013.06.006 · Cited by 772
Interactions of gut microbiota with functional food components and nutraceuticals
Laparra, J. M., & Sanz, Y. (2010) · Pharmacological Research · doi:10.1016/j.phrs.2009.11.001 · Cited by 684
The contributory role of gut microbiota in cardiovascular disease
Tang, W. H. W., & Hazen, S. L. (2014) · Journal of Clinical Investigation · doi:10.1172/jci72331 · Cited by 641
Wang, Z., Tang, W. H. W., Buffa, J. A., Fu, X., Britt, E. B., Koeth, R. A., Levison, B. S., Fan, Y., Wu, Y., & Hazen, S. L. (2014) · European Heart Journal · doi:10.1093/eurheartj/ehu002 · Cited by 559
γ-Butyrobetaine Is a Proatherogenic Intermediate in Gut Microbial Metabolism of L-Carnitine to TMAO
Koeth, R. A., Levison, B. S., Culley, M. K., Buffa, J. A., Wang, Z., Gregory, J. C., Org, E., Wu, Y., Li, L., Smith, J. D., et al. (2014) · Cell Metabolism · doi:10.1016/j.cmet.2014.10.006 · Cited by 546
Tangirala, R. K., Rubin, E. M., & Palinski, W. (1995) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)39713-3 · Cited by 514
Severe atherosclerosis in transgenic mice expressing simian cholesteryl ester transfer protein
Marotti, K. R., Castle, C. K., Boyle, T. P., Lin, A. H., Murray, R. W., & Melchior, G. W. (1993) · Nature · doi:10.1038/364073a0 · Cited by 444
Nabel, E. G. (2003) · New England Journal of Medicine · doi:10.1056/nejmra035098 · Cited by 431
de la Llera-Moya, M., Drazul‐Schrader, D., Asztalos, B. F., Cuchel, M., Rader, D. J., & Rothblat, G. H. (2010) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.109.199158 · Cited by 385
Self-citationProgramming infant gut microbiota: influence of dietary and environmental factors
Marques, T. M., Wall, R., Ross, R. P., Fitzgerald, G. F., Ryan, C. A., & Stanton, C. (2010) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2010.03.020 · Cited by 326
Huang, Y. J., & Boushey, H. A. (2015) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2014.11.011 · Cited by 280
Gut microbiota and diabetes: from pathogenesis to therapeutic perspective
Burcelin, R., Sérino, M., Chabo, C., Blasco‐Baqué, V., & Amar, J. (2011) · Acta Diabetologica · doi:10.1007/s00592-011-0333-6 · Cited by 270
The macrophage scavenger receptor at 30 years of age: current knowledge and future challenges
Greaves, D. R., & Gordon, S. (2008) · Journal of Lipid Research · doi:10.1194/jlr.r800066-jlr200 · Cited by 248
Plump, A. S., Masucci-Magoulas, L., Bruce, C., Bisgaier, C. L., Breslow, J. L., & Tall, A. R. (1999) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.19.4.1105 · Cited by 222
DiNicolantonio, J. J., Lavie, C. J., Fares, H., Menezes, A. R., & O'Keefe, J. H. (2013) · Mayo Clinic Proceedings · doi:10.1016/j.mayocp.2013.02.007 · Cited by 217 · cited 4×
“and CVD [7,19,24,25].”
InfluentialExploring gut microbes in human health and disease: Pushing the envelope
Sun, J., & Chang, E. B. (2014) · Genes & Diseases · doi:10.1016/j.gendis.2014.08.001 · Cited by 191
Supplementation of l-carnitine in athletes: does it make sense?
Karlic, H., & Lohninger, A. (2004) · Nutrition · doi:10.1016/j.nut.2004.04.003 · Cited by 175
van der Hoorn, J. W. A., de Haan, W., Berbée, J. F. P., Havekes, L. M., Jukema, J. W., Rensen, P. C. N., & Princen, H. M. G. (2008) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.108.171363 · Cited by 172
Gut microbiota metabolism of l-carnitine and cardiovascular risk
Ussher, J. R., Lopaschuk, G. D., & Arduini, A. (2013) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2013.10.013 · Cited by 172
Role of carnitine in fatty acid metabolism of normal and ischemic myocardium
Opie, L. H. (1979) · American Heart Journal · doi:10.1016/0002-8703(79)90440-x · Cited by 151
Measuring the stability of partly folded proteins using TMAO
Mello, C. C., & Barrick, D. (2003) · Protein Science · doi:10.1110/ps.0372903 · Cited by 151
Tanigawa, H., Billheimer, J. T., Tohyama, J., Zhang, Y., Rothblat, G. H., & Rader, D. J. (2007) · Circulation · doi:10.1161/circulationaha.107.704254 · Cited by 149
Carnitine in metabolic disease: Potential for pharmacological intervention
Arduini, A., Bonomini, M., Savica, V., Amato, A., & Zammit, V. A. (2008) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2008.08.008 · Cited by 88
Levocarnitine Administration in Elderly Subjects with Rapid Muscle Fatigue
Pistone, G., Marino, A. D., Leotta, C., Dell'Arte, S., Finocchiaro, G., & Malaguarnera, M. (2003) · Drugs & Aging · doi:10.2165/00002512-200320100-00004 · Cited by 86
Role of urea and methylamines in buoyancy of elasmobranchs
Withers, P. C., Morrison, G., Hefter, G. T., & Pang, T.-S. (1994) · Journal of Experimental Biology · doi:10.1242/jeb.188.1.175 · Cited by 85
Fukami, K., Yamagishi, S.-I., Sakai, K., Kaida, Y., Yokoro, M., Ueda, S., Wada, Y., Takeuchi, M., Shimizu, M., Yamazaki, H., et al. (2015) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0000000000000197 · Cited by 84
Regulation of Mouse Liver Flavin-Containing Monooxygenases 1 and 3 by Sex Steroids
Falls, J. G., Ryu, D., Cao, Y., Levi, P. E., & Hodgson, E. (1997) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.1997.9965 · Cited by 83
de Haan, W., van der Hoogt, C. C., Westerterp, M., Hoekstra, M., Dallinga‐Thie, G. M., Princen, H. M. G., Romijn, J. A., Jukema, J. W., Havekes, L. M., & Rensen, P. C. N. (2007) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2007.08.001 · Cited by 82
Orphenadrine and methimazole inhibit multiple cytochrome P450 enzymes in human liver microsomes.
Guo, Z., Raeissi, S., White, R. B., & Stevens, J. C. (1997) · PubMed · Cited by 82
A complex microworld in the gut: Gut microbiota and cardiovascular disease connectivity
Howitt, M. R., & Garrett, W. S. (2012) · Nature Medicine · doi:10.1038/nm.2895 · Cited by 78
Falls, J. G., Blake, B. L., Cao, Y., Levi, P. E., & Hodgson, E. (1995) · Journal of Biochemical and Molecular Toxicology · doi:10.1002/jbt.2570100308 · Cited by 78
New Aspects on the Metabolic role of Intestinal Microbiota in the Development of Atherosclerosis
Drosos, I., Tavridou, A., & Kolios, G. C. (2015) · Metabolism · doi:10.1016/j.metabol.2015.01.007 · Cited by 67
L -carnitine prevents the progression of atherosclerotic lesions in hypercholesterolaemic rabbits
Sayed‐Ahmed, M. M., Khattab, M. M., Gad, M. Z., & Mostafa, N. (2001) · Pharmacological Research · doi:10.1006/phrs.2001.0852 · Cited by 66
Chemical Chaperones Mitigate Experimental Asthma by Attenuating Endoplasmic Reticulum Stress
Makhija, L., Krishnan, V., Rehman, R., Chakraborty, S., Maity, S., Mabalirajan, U., Chakraborty, K., Ghosh, B., & Agrawal, A. (2013) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2013-0320oc · Cited by 58
Madan, M., Bishayi, B., Hoge, M., Messas, E., & Amar, S. (2006) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2006.02.026 · Cited by 54
The Pathogenesis of Foam Cell Formation
Jones, N. L., Reagan, J. W., & Willingham, M. C. (2000) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.20.3.773 · Cited by 48
Nutritional factors in the prevention and management of coronary artery disease and heart failure
Das, U. N. (2014) · Nutrition · doi:10.1016/j.nut.2014.08.011 · Cited by 44
Spagnoli, L. G., Orlandi, A., Marino, B., Mauriello, A., de Angelis, C., & Ramacci, M. T. (1995) · Atherosclerosis · doi:10.1016/0021-9150(94)05460-z · Cited by 41
Xie, F., Zhou, X., Genter, M. B., Behr, M., Gu, J., & Ding, X. (2011) · Drug Metabolism and Disposition · doi:10.1124/dmd.110.037895 · Cited by 37
Gut microbiota: An environmental risk factor for cardiovascular disease
Stock, J. K. (2013) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2013.05.019 · Cited by 36
Gong, B., Zhang, L.-Y., Pang, C.-P., Lam, D. S.-C., & Yam, G. H. (2009) · PubMed Central · Cited by 35
Methimazole protection against oxidative stress induced by hyperthyroidism in Graves disease.
Sewerynek, J., Wiktorska, J. A., Nowak, D., & Lewiñski, A. (2000) · PubMed · Cited by 27
Jawień, J., Totoń‐Żurańska, J., Kuś, K., Pawlowska, M., Olszanecki, R., & Korbut, R. (2012) · Medical Science Monitor · doi:10.12659/msm.883478 · Cited by 19
Özçelik, A. T., Demirdöğen, B. C., Demirkaya, Ş., & Adalı, O. (2013) · Gene · doi:10.1016/j.gene.2013.03.010 · Cited by 16
[The biological function of L-carnitine and its content in the particular food examples].
Rospond, B., & Chłopicka, J. (2013) · PubMed · Cited by 13
Anti-Inflammatory Action of Methimazole
Lagorce, J. F., Moulard, T., Rousseau, A., Comby, F., Buxeraud, J., & Raby, C. (2008) · Pharmacology · doi:10.1159/000139525 · Cited by 12
Bell, F. P., Raymond, T. L., & Patnode, C. L. (1987) · Comparative Biochemistry and Physiology Part B Comparative Biochemistry · doi:10.1016/0305-0491(87)90056-3 · Cited by 10
Risk Factors for Cardiovascular Disease: A Cautionary Tale of Diet–Microbiome Interactions
Miller, M. J. S. (2013) · Journal of the American College of Nutrition · doi:10.1080/07315724.2013.799982 · Cited by 7
Research works printed but not linked: 1
- Gulewitsch, 1905, Zur Kenntnis der Extraktionsstoffe der Muskeln. 2. Mitteilungenüber das Carnitin (extracted substances in muscle, report on carnitine), Physiol. Chem., 45
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Postler, T. S., & Ghosh, S. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.05.008 · Cited by 876
“Cell Metabolism 26, July 5, 2017 15 Review Ghoshal, S., Witta, J., Zhong, J., de Villiers, W., and Eckhardt, E. (2009).”
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Metadata
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › 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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