The Effect of Different l‐Carnitine Administration Routes on the Development of Atherosclerosis in ApoE Knockout Mice
Abstract
Scope: l‐Carnitine (LC) is abundant in red meat and is widely added to health supplements and food. This study focuses on the adverse effects of oral supplementation of 1.3% LC in ApoE−/− mice and whether the parenteral administration of LC (subcutaneously, sub) has any impact on the development of atherosclerosis. Methods and results: Mice are randomly divided into three groups (n = 15). All mice are fed a high‐fat diet (HFD). The number of Ly6C hi monocytes; degree of atherosclerosis; plasma LC, γ‐butyrobetaine (γBB), and trimethylamine‐N‐oxide (TMAO) levels; and microbial community composition are analyzed. Compared with the HFD and HFD ± LC (sub) groups, the number of Ly6C hi monocytes, atherosclerotic plaque area, and plasma γBB and TMAO levels are increased in the HFD ± LC (oral) group (p < 0.001). Plasma LC levels in the HFD ± LC (sub) group are higher than those in other groups. The levels of γBB, TMAO, and Ly6C hi monocytes are positively correlated with atherosclerotic plaque area (p < 0.01), and TMAO is positively correlated with Bacteroidetes and negatively correlated with Firmicutes at the phylum level. Conclusion: In contrast with oral LC administration, subcutaneous LC administration, which bypasses its conversion to TMAO in the liver, does not have a detrimental effect on the development of atherosclerosis in male ApoE−/− mice. Taking LC parenterally may be preferable among patients who require LC supplementation.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the OCA trial for NASH, increased blood lipid levels were observed.
“in the OCA trial for NASH, additional metabolic derangements such as increased blood lipid levels were also observed, in contrast to the findings of other proof of concept studies152,153.”
From Dietary metabolism, the gut microbiome, and heart failure (2019) · cites this paper as [153]
Cites
Diversity of the Human Intestinal Microbial Flora
Eckburg, P. B., Bik, E. M., Bernstein, C. N., Purdom, E., Dethlefsen, L., Sargent, M., Gill, S. R., Nelson, K. E., & Relman, D. A. (2005) · Science · doi:10.1126/science.1110591 · Cited by 7,913 · see citing works
The gut microbiota as an environmental factor that regulates fat storage
Bäckhed, F., Ding, H., Wang, T., Hooper, L. V., Koh, G. Y., Nagy, A., Semenkovich, C. F., & Gordon, J. I. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0407076101 · Cited by 6,245 · see citing works
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 · see citing works
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 · see citing works
Self-citationIntestinal 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 3,402 · see citing works
Role of Endothelial Dysfunction in Atherosclerosis
Davignon, J., & Ganz, P. (2004) · Circulation · doi:10.1161/01.cir.0000131515.03336.f8 · Cited by 2,513 · see citing works
Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk
Zhu, W., Gregory, J. C., Org, E., Buffa, J. A., Gupta, N., Wang, Z., Li, L., Fu, X., Wu, Y., Mehrabian, M., et al. (2016) · Cell · doi:10.1016/j.cell.2016.02.011 · Cited by 1,968 · see citing works
Molecular physiology of reverse cholesterol transport.
Fielding, C. J., & Fielding, P. E. (1995) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)39898-9 · Cited by 1,448 · see citing works
Symptomatic atherosclerosis is associated with an altered gut metagenome
Karlsson, F. H., Fåk, F., Nookaew, I., Tremaroli, V., Fagerberg, B., Petranovic, D., Bäckhed, F., & Nielsen, J. (2012) · Nature Communications · doi:10.1038/ncomms2266 · Cited by 1,371 · see citing works
Wang, Z., Roberts, A. B., Buffa, J. A., Levison, B. S., Zhu, W., Org, E., Gu, X., Huang, Y., Zamanian-Daryoush, M., Culley, M. K., et al. (2015) · Cell · doi:10.1016/j.cell.2015.11.055 · Cited by 1,317 · see citing works
Seldin, M. M., Meng, Y., Qi, H., Zhu, W., Wang, Z., Hazen, S. L., Lusis, A. J., & Shih, D. M. (2016) · Journal of the American Heart Association · doi:10.1161/jaha.115.002767 · Cited by 911 · see citing works
Flanagan, J. L., Simmons, P. A., Vehige, J., Willcox, M. D., & Garrett, Q. (2010) · Nutrition & Metabolism · doi:10.1186/1743-7075-7-30 · Cited by 611 · see citing works
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 · see citing works
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 · see citing works
Leuschner, F., Rauch, P. J., Ueno, T., Gorbatov, R., Marinelli, B. S., Lee, W. W., Dutta, P., Wei, Y., Robbins, C. S., Iwamoto, Y., et al. (2012) · The Journal of Experimental Medicine · doi:10.1084/jem.20111009 · Cited by 519 · see citing works
Extramedullary Hematopoiesis Generates Ly-6C high Monocytes That Infiltrate Atherosclerotic Lesions
Robbins, C. S., Chudnovskiy, A., Rauch, P. J., Figueiredo, J., Iwamoto, Y., Gorbatov, R., Etzrodt, M., Weber, G. F., Ueno, T., van Rooijen, N., et al. (2011) · Circulation · doi:10.1161/circulationaha.111.061986 · Cited by 483 · see citing works
Nagueh, S. F., Lakkis, N. M., Middleton, K. J., Franklin, J. L., & Spencer, W. H. (2004) · Circulation · doi:10.1161/01.cir.0000115644.35804.8b · Cited by 425 · see citing works
The TMAO-Generating Enzyme Flavin Monooxygenase 3 Is a Central Regulator of Cholesterol Balance
Warrier, M., Shih, D. M., Burrows, A. C., Ferguson, D., Gromovsky, A. D., Brown, A. L., Marshall, S., McDaniel, A., Schugar, R. C., Wang, Z., et al. (2015) · Cell Reports · doi:10.1016/j.celrep.2014.12.036 · Cited by 414 · see citing works
Flavin-containing monooxygenase 3 as a potential player in diabetes-associated atherosclerosis
Miao, J., Ling, A. V., Manthena, P. V., Gearing, M. E., Graham, M. J., Crooke, R. M., Croce, K. J., Esquejo, R. M., Clish, C. B., Morbid Obesity Study Group, et al. (2015) · Nature Communications · doi:10.1038/ncomms7498 · Cited by 368 · see citing works
Monocyte and macrophage heterogeneity in the heart
Nahrendorf, M., & Swirski, F. (2013) · Circulation Research · doi:10.1161/circresaha.113.300890 · Cited by 350 · see citing works
Pharmacokinetics of L-Carnitine
Evans, A. M., & Fornasini, G. (2003) · Clinical Pharmacokinetics · doi:10.2165/00003088-200342110-00002 · Cited by 303 · see citing works
Terpstra, A. H. M. (2004) · American Journal of Clinical Nutrition · doi:10.1093/ajcn/79.3.352 · Cited by 222 · see citing works
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 · see citing works
Dialysis-related carnitine disorder and levocarnitine pharmacology
Evans, A. M. (2003) · American Journal of Kidney Diseases · doi:10.1016/s0272-6386(03)00113-6 · Cited by 122 · see citing works
Pre-β HDL: structure and metabolism
Barrans, A., Jaspard‐Vinassa, B., Barbaras, R., Chap, H., Perret, B., & Collet, X. (1996) · Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metabolism · doi:10.1016/0005-2760(95)00236-7 · Cited by 89 · see citing works
Shang, R., Sun, Z., & Li, H. (2014) · BMC Cardiovascular Disorders · doi:10.1186/1471-2261-14-88 · Cited by 66 · see citing works
Self-citationZambrano, S. S., Blanca, A. J., Ruiz-Armenta, M. V., Miguel‐Carrasco, J. L., Arévalo, M., Vázquez, M. J., Mate, A., & Vázquez, C. M. (2013) · Biochemical Pharmacology · doi:10.1016/j.bcp.2012.12.021 · Cited by 60 · see citing works
l-Carnitine attenuates oxidative stress in hypertensive rats
Gómez-Amores, L., Mate, A., Miguel‐Carrasco, J. L., Jiménez, L., Jos, A. M., Cameán, A. M., Revilla, E., Santa‐María, C., & Vázquez, C. M. (2006) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2006.10.004 · Cited by 58 · see citing works
Williams, H. J., Fisher, E. A. A., & Greaves, D. R. (2012) · Journal of Innate Immunity · doi:10.1159/000336618 · Cited by 53 · see citing works
Blanca, A. J., Ruiz-Armenta, M. V., Zambrano, S. S., Miguel‐Carrasco, J. L., Arias, J. L., Arévalo, M., Mate, A., Aramburu, Ó., & Vázquez, C. M. (2015) · Toxicology Letters · doi:10.1016/j.toxlet.2015.11.007 · Cited by 44 · see citing works
Cui, J., Das, D. K., Bertelli, A., & Tósaki, Á. (2003) · Molecular and Cellular Biochemistry · doi:10.1023/a:1027368018064 · Cited by 37 · see citing works
L-carnitine for the Treatment of Acute Myocardial Infarction
DiNicolantonio, J. J., Niazi, A. K., McCarty, M. F., Lavie, C. J., Liberopoulos, E. N., & O’Keefe, J. H. (2014) · Reviews in Cardiovascular Medicine · doi:10.3909/ricm0710 · Cited by 36 · see citing works
Ogita, M., Miyauchi, K., Miyazaki, T., Naito, R., Konishi, H., Tsuboi, S., Dohi, T., Kasai, T., Yokoyama, T., Okazaki, S., et al. (2013) · Heart and Vessels · doi:10.1007/s00380-013-0330-5 · Cited by 33 · see citing works
Serati, A. R., Motamedi, M. R., Emami, S., Varedi, P., & Movahed, M. R. (2010) · Cardiology · doi:10.1159/000318810 · Cited by 26 · see citing works
Metabolism of L(−)-carnitine by Enterobacteriaceae under aerobic conditions
Elßner, T., Preusser-Kunze, A., Wagner, U., & Kleber, H. ‐. (1999) · FEMS Microbiology Letters · doi:10.1111/j.1574-6968.1999.tb13582.x · Cited by 23 · see citing works
Role of Supplementary L -Carnitine in Exercise and Exercise Recovery
Huang, A., & Owen, K. Q. (2012) · Medicine and sport science/Medicine and sport · doi:10.1159/000341934 · Cited by 21 · see citing works
Metabolism of L(−)-carnitine by Enterobacteriaceae under aerobic conditions
Elßner, T. (1999) · FEMS Microbiology Letters · doi:10.1016/s0378-1097(99)00151-2 · Cited by 19 · see citing works
Fukami, K., Yamagishi, S., Sakai, K., Nasu, M., & Okuda, S. (2014) · Clinical Kidney Journal · doi:10.1093/ckj/sfu082 · Cited by 17 · see citing works
Liao, J. K. (2008) · Current Atherosclerosis Reports · doi:10.1007/s11883-008-0043-x · Cited by 7 · see citing works
HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events.
Liao, J. K. (2008) · PubMed · Cited by 5 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Dietary metabolism, the gut microbiome, and heart failure
Tang, W. H. W., Li, D. Y., & Hazen, S. L. (2019) · Nature Reviews Cardiology · doi:10.1038/s41569-018-0108-7 · Cited by 789 · see citing works
Trimethylamine-N-Oxide (TMAO) Predicts Cardiovascular Mortality in Peripheral Artery Disease
Roncal, C., Martínez-Aguilar, E., Orbe, J., Ravassa, S., Fernández‐Montero, A., Saenz‐Pipaon, G., Ugarte, A., de Mendoza, A. E., Rodríguez, J. A., Fernandez-Alonso, S., et al. (2019) · Scientific Reports · doi:10.1038/s41598-019-52082-z · Cited by 160 · see citing works
Trimethylamine N-Oxide in Relation to Cardiometabolic Health—Cause or Effect?
Papandreou, C., Moré, M. I., & Bellamine, A. (2020) · Nutrients · doi:10.3390/nu12051330 · Cited by 150 · see citing works
Mamic, P., Chaikijurajai, T., & Tang, W. H. W. (2020) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2020.12.001 · Cited by 99 · see citing works
Farhangi, M. A., Vajdi, M., & Asghari-Jafarabadi, M. (2020) · Nutrition Journal · doi:10.1186/s12937-020-00592-2 · Cited by 72 · see citing works
Elevated plasma trimethylamine-N-oxide levels are associated with diabetic retinopathy
Liu, W., Wang, C., Xia, Y., Xia, W. T., Liu, G., Ren, C., Gu, Y., Li, X., & Lu, P. (2020) · Acta Diabetologica · doi:10.1007/s00592-020-01610-9 · Cited by 64 · see citing works
Farhangi, M. A., & Vajdi, M. (2020) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2020.1770199 · Cited by 59 · see citing works
Samulak, J. J., Sawicka, A. K., Hartmane, D., Grı̄nberga, S., Pugovičs, O., Łysiak−Szydłowska, W., & Olek, R. A. (2018) · Annals of Nutrition and Metabolism · doi:10.1159/000495037 · Cited by 54 · see citing works
Yu, Z., Zhang, L., Jiang, X., Xue, C., Chi, N., Zhang, T., & Wang, Y. (2020) · Journal of Food Science · doi:10.1111/1750-3841.15186 · Cited by 47 · see citing works
He, Z., Hao, W., Kwek, E., Lei, L., Liu, J., Zhu, H., Ma, K. Y., Zhao, Y., Ho, H., He, W., et al. (2019) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.9b06753 · Cited by 46 · see citing works
Self-citationAssociation between dietary patterns and cardiovascular diseases: A review
Lu, L., Jing, W., Qian, W., Fan, L., & Cheng, J. (2024) · Current Problems in Cardiology · doi:10.1016/j.cpcardiol.2024.102412 · Cited by 40 · see citing works
Gut macrobiotic and its metabolic pathways modulate cardiovascular disease
Zhu, J., Lyu, J., Zhao, R., Liu, G., & Wang, S. (2023) · Frontiers in Microbiology · doi:10.3389/fmicb.2023.1272479 · Cited by 30 · see citing works
Trimethylamine N-Oxide in Aquatic Foods
Li, X., Wang, C., Yanagita, T., Xue, C., Zhang, T., & Wang, Y. (2024) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.4c01974 · Cited by 28 · see citing works
Gao, X., Sun, G., Randell, E. W., Tian, Y., & Zhou, H. (2020) · Food & Function · doi:10.1039/d0fo01743d · Cited by 27 · see citing works
Olek, R. A., Samulak, J. J., Sawicka, A. K., Hartmane, D., Grı̄nberga, S., Pugovičs, O., & Łysiak−Szydłowska, W. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/6247169 · Cited by 27 · see citing works
Senesi, P., Ferrulli, A., Luzi, L., & Terruzzi, I. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22157772 · Cited by 26 · see citing works
He, Z., Lei, L., Kwek, E., Zhao, Y., Liu, J., Hao, W., Zhu, H., Liang, N. N., Ma, K. Y., Ho, H., et al. (2018) · Journal of Functional Foods · doi:10.1016/j.jff.2018.10.022 · Cited by 26 · see citing works
Self-citationZhang, H., & Yao, G. (2022) · European Journal of Clinical Nutrition · doi:10.1038/s41430-022-01104-7 · Cited by 20 · see citing works
PARASKEVAIDIS, I. A., Briasoulis, Α., & Tsougos, E. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25031716 · Cited by 16 · see citing works
Heart Failure and Gut Microbiota: What Is Cause and Effect?
Shen, S., Tian, B., Haizhu, Z., Wang, Y., Li, T., & Cao, Y. (2025) · Research · doi:10.34133/research.0610 · Cited by 18 · see citing works
Human Gut Microbiota in Heart Failure: Trying to Unmask an Emerging Organ
PARASKEVAIDIS, I. A., Xanthopoulos, A. V., Tsougos, E., & Triposkiadis, F. K. (2023) · Biomedicines · doi:10.3390/biomedicines11092574 · Cited by 13 · see citing works
Guimarães, V. H. D., Marinho, B. M., Motta‐Santos, D., Mendes, G. D. R. L., & Santos, S. H. S. (2022) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2022.109252 · Cited by 13 · see citing works
Interventions for non-alcoholic liver disease: a gut microbial metabolites perspective
Guo, J., Shi, C., Zhang, Q., Deng, W., Zhang, L., Chen, Q., Zhang, D., & Gong, Z. (2022) · Therapeutic Advances in Gastroenterology · doi:10.1177/17562848221138676 · Cited by 12 · see citing works
The origin of trimethylamine- N-oxide (TMAO) and its role in development of atherosclerosis
He, Z., & Chen, Z. (2018) · Journal of Food Bioactives · doi:10.31665/jfb.2018.2138 · Cited by 12 · see citing works
Wang, C., Duan, X., Li, X., Yang, J., Xue, C., Yanagita, T., Zhang, T., & Wang, Y. (2023) · Food Science and Human Wellness · doi:10.26599/fshw.2022.9250054 · Cited by 9 · see citing works
Kilic, E., & Başaran, P. (2025) · Nutrients · doi:10.3390/nu17233787 · Cited by 10 · see citing works
Levocarnitine does not impair chemotherapy cytotoxicity against acute lymphoblastic leukemia
Sea, J. L., Orgel, E., Chen, T., Paszkiewicz, R. L., Krall, A. S., Oberley, M. J., Stiles, L., & Mittelman, S. D. (2019) · Leukemia & lymphoma/Leukemia and lymphoma · doi:10.1080/10428194.2019.1666379 · Cited by 3 · see citing works
Nergiz‐Unal, R., & Gönen, B. (2021) · Akdeniz Medical Journal · doi:10.53394/akd.982129 · Cited by 1 · see citing works
Chong, L., Rampersaud, H., Rao, D. A., Gujare, I., Makhijani, A., Kim, D., Levy, E., Beatty, B. L., & Kobayashi, S. (2026) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00584.2026
- Authors
- Zhao, Y., Yang, N., Gao, J., Li, H., Cai, W., Zhang, X., Ma, Y., Niu, X., Yang, G., Zhou, X., & Li, Y.
- Affiliations
- Tianjin First Center Hospital (CN)
- Pingjin Hospital (CN)
- Tianjin Key Laboratory of Cardiovascular Remodeling and Target Organ Injury Pingjin Hospital Heart Center Logistics University of PAPF Tianjin China
- Corresponding author
- Zhou, Xin
- Li, Yuming
- Venue
- Molecular Nutrition & Food Research
- Publisher
- Wiley
- Published
- 2018-02-05
- Volume
- 62
- Issue
- 5
- ISSN
- 1613-4125 (ISSN-L)
- 1613-4133
- OpenAlex
- W2769548116
- Cited by
- 29
- References
- 40
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 3 · 2023: 3 · 2022: 3 · 2021: 2 · 2020: 7 · 2019: 4 · 2018: 4
- FWCI
- 1.86
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Molecular Nutrition & Food Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (81570335)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Health Sciences › Nursing › Nutrition and Dietetics › Fatty Acid Research and Health
- Keywords
- L-carnitine, atherosclerosis, ApoE-deficient mice, high-fat diet, parenteral administration, oral supplementation, Ly6Chi monocytes, atherosclerotic plaque, trimethylamine N-oxide, gamma-butyrobetaine, gut microbiota, Bacteroidetes, Firmicutes, dietary supplementation
- MeSH terms
- Administration, Oral, Animals, Apolipoproteins E, Carnitine, Humans, Injections, Subcutaneous, Lipids, Methylamines, Monocytes, Oxygenases, Mice, Knockout, Atherosclerosis, Mice, Diet, High-Fat
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
