The TMAO-Generating Enzyme Flavin Monooxygenase 3 Is a Central Regulator of Cholesterol Balance
Open accessAbstract
Circulating levels of the gut microbe-derived metabolite trimethylamine-N-oxide (TMAO) have recently been linked to cardiovascular disease (CVD) risk. Here, we performed transcriptional profiling in mouse models of altered reverse cholesterol transport (RCT) and serendipitously identified the TMAO-generating enzyme flavin monooxygenase 3 (FMO3) as a powerful modifier of cholesterol metabolism and RCT. Knockdown of FMO3 in cholesterol-fed mice alters biliary lipid secretion, blunts intestinal cholesterol absorption, and limits the production of hepatic oxysterols and cholesteryl esters. Furthermore, FMO3 knockdown stimulates basal and liver X receptor (LXR)-stimulated macrophage RCT, thereby improving cholesterol balance. Conversely, FMO3 knockdown exacerbates hepatic endoplasmic reticulum (ER) stress and inflammation in part by decreasing hepatic oxysterol levels and subsequent LXR activation. FMO3 is thus identified as a central integrator of hepatic cholesterol and triacylglycerol metabolism, inflammation, and ER stress. These studies suggest that the gut microbiota-driven TMA/FMO3/TMAO pathway is a key regulator of lipid metabolism and inflammation.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
FMO3 inhibition causes side effects including hepatic inflammation.
“FMO3 inhibition is also accompanied by several untoward side effects, including hepatic inflammation”
From Non-lethal Inhibition of Gut Microbial Trimethylamine Production for the Treatment of Atherosclerosis (2015) · cites this paper as Warrier et al., 2015
Downregulation or knock-out of FMO3 leads to decreased levels of TMAO and is athero-protective, whereas increased expression of FMO3 leads to pro-atherogenic lipid profiles such as higher VLDL and LDL.
“downregulation or knock-out of FMO3 leads to decreased levels of TMAO and it is athero-protective in these models, whereas increased expression of FMO3 leads to pro-atherogenic lipid profiles (e.g., higher VLDL and LDL) [75,76].”
From Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target (2018) · cites this paper as [75]
FMO3, which is differentially regulated in male and female mice, is necessary but apparently not sufficient for the development of the diabetic phenotype.
“Taken together, these data suggest that FMO3, which is differentially regulated in male and female mice, is necessary but apparently not sufficient for the development of the diabetic phenotype.”
From Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target (2018) · cites this paper as [75]
Accumulation of TMA leads to trimethylaminuria, which is characterized by fishy odor and induces inflammation.
“Nevertheless, there could be several problems with this approach as an accumulation of TMA leads to trimethylaminuria, which is characterized by fishy odor (similar to rotten fish) and induce inflammation [18,75,99].”
From Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target (2018) · cites this paper as [75]
FMO3 knockdown altered intestinal cholesterol absorption, hepatic cholesterol ester storage, and macrophage reverse cholesterol transport in a dietary cholesterol-dependent manner.
“FMO3 knockdown altered several steps of cholesterol balance, including intestinal cholesterol absorption, hepatic cholesterol ester storage, and macrophage RCT in a dietary cholesterol-dependent manner (121).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [121]
FMO3 inhibition stimulated fecal neutral sterol loss and basal and liver X receptor-dependent macrophage reverse cholesterol transport.
“FMO3 inhibition stimulated fecal neutral sterol loss and basal and liver X receptor-dependent macrophage RCT (121).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [121]
FMO3 knockdown in C57Bl/6 female mice greatly reduced hepatic FMO3 expression, increased plasma TMA, and reduced TMAO.
“When C57Bl/6 female mice were fed either a low-or high-cholesterol diet, FMO3 knockdown greatly reduced hepatic FMO3 expression with corresponding increases in plasma TMA concentrations and reductions in TMAO concentrations (121).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [121]
Antibiotics eliminated the FMO3 substrate TMA and normalized intestinal cholesterol absorption and fecal neutral sterol loss in FMO3 antisense oligonucleotide-treated mice.
“The administration of antibiotics eliminated the FMO3 substrate TMA and normalized intestinal cholesterol absorption and fecal neutral sterol loss seen in FMO3 antisense oligonucleotide-treated mice (121).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [121]
Inhibiting FMO enzymes may not be ideal because it causes TMA accumulation, leading to fishy odor and inflammation as observed in antisense oligonucleotide-treated mice.
“Inhibiting FMO enzymes, however, may not be ideal as it causes accumulation of TMA, leading to a fishy odor and inflammation as observed in antisense oligonucleotide-treated mice (102, 121).”
From Trimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [121]
FMO3 knock down impairs trimethylamine transformation into trimethylamine N-oxide, reducing plasma trimethylamine N-oxide levels and restoring cholesterol balance.
“Consistent and complementary to these findings, FMO3 knock down has been shown to impair TMA transformation into TMAO, thus reducing plasma TMAO levels and concomitantly, restoring cholesterol balance114.”
From Gut microbiota and cardiovascular disease. (2020) · cites this paper as [114]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Smyth, G. K. (2004) · Statistical Applications in Genetics and Molecular Biology · doi:10.2202/1544-6115.1027 · Cited by 11,829 · 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
Self-citationIntestinal 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-citationLiving with Water Stress: Evolution of Osmolyte Systems
Yancey, P. H., Clark, M. E., Hand, S. C., Bowlus, R. D., & Somero, G. N. (1982) · Science · doi:10.1126/science.7112124 · Cited by 3,724 · see citing works
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 3,402 · see citing works
Self-citationNiacin in Patients with Low HDL Cholesterol Levels Receiving Intensive Statin Therapy
The AIM-HIGH Investigators (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1107579 · Cited by 2,911 · see citing works
Effects of dalcetrapib in patients with a recent acute coronary syndrome
Schwartz, G. G., Olsson, A. G., Abt, M., Ballantyne, C. M., Barter, P. J., Brumm, J., Chaitman, B. R., Holme, I. M., Kallend, D., Leiter, L. A., et al. (2012) · New England Journal of Medicine · doi:10.1056/nejmoa1206797 · Cited by 2,022 · see citing works
Niemann-Pick C1 Like 1 Protein Is Critical for Intestinal Cholesterol Absorption
Altmann, S. W., Davis, H. R., Zhu, L.-J., Yao, X., Hoos, L. M., Tetzloff, G. G., Iyer, S. P. N., Maguire, M., Golovko, A., Zeng, M., et al. (2004) · Science · doi:10.1126/science.1093131 · Cited by 1,781 · see citing works
A proteolytic pathway that controls the cholesterol content of membranes, cells, and blood
Brown, M. S., & Goldstein, J. L. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.20.11041 · Cited by 1,327 · see citing works
Go, A. S., Mozaffarian, D., Roger, V. L., Benjamin, E. J., Berry, J. D., Borden, W. B., Bravata, D. M., Dai, S., Ford, E. S., Fox, C. S., et al. (2013) · Circulation · doi:10.1161/cir.0b013e318282ab8f · Cited by 1,294 · see citing works
Reciprocal regulation of inflammation and lipid metabolism by liver X receptors
Joseph, S. B., Castrillo, A., Laffitte, B. A., Mangelsdorf, D. J., & Tontonoz, P. (2003) · Nature Medicine · doi:10.1038/nm820 · Cited by 1,158 · see citing works
Self-citationBennett, 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 · see citing works
Self-citationDisruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion
Yu, L., Hammer, R. E., Li-Hawkins, J., von Bergmann, K., Lütjohann, D., Cohen, J. C., & Hobbs, H. H. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.252582399 · Cited by 706 · see citing works
Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme
Craciun, S., & Balskus, E. P. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1215689109 · Cited by 701 · see citing works
Liver X Receptor Signaling Pathways in Cardiovascular Disease
Tontonoz, P., & Mangelsdorf, D. J. (2003) · Molecular Endocrinology · doi:10.1210/me.2003-0061 · Cited by 633 · see citing works
Self-citationNuclear receptor transrepression pathways that regulate inflammation in macrophages and T cells
Glass, C. K., & Saijo, K. (2010) · Nature Reviews Immunology · doi:10.1038/nri2748 · Cited by 619 · see citing works
The role of reverse cholesterol transport in animals and humans and relationship to atherosclerosis
Rader, D. J., Alexander, E. T., Weibel, G. L., Billheimer, J. T., & Rothblat, G. H. (2008) · Journal of Lipid Research · doi:10.1194/jlr.r800088-jlr200 · Cited by 597 · 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
Self-citationGrefhorst, A., Elzinga, B. M., Voshol, P. J., Plösch, T., Kok, T., Bloks, V. W., van der Sluijs, F. H., Havekes, L. M., Romijn, J. A., Verkade, H. J., et al. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m204887200 · Cited by 502 · see citing works
ABCG5 and ABCG8 Are Obligate Heterodimers for Protein Trafficking and Biliary Cholesterol Excretion
Graf, G. A., Yu, L., Li, W., Gerard, R. D., Tuma, P. L., Cohen, J. C., & Hobbs, H. H. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m310223200 · Cited by 474 · see citing works
Temel, R. E., Tang, W., Ma, Y., Rudel, L. L., Willingham, M. C., Ioannou, Y. A., Davies, J. P., Nilsson, L.-M., & Yu, L. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30060 · Cited by 368 · see citing works
Self-citationHUMAN FLAVIN-CONTAINING MONOOXYGENASES
Cashman, J. R., & Zhang, J. (2006) · The Annual Review of Pharmacology and Toxicology · doi:10.1146/annurev.pharmtox.46.120604.141043 · Cited by 333 · see citing works
Rong, X., Albert, C. J., Hong, C., Duerr, M. A., Chamberlain, B. T., Tarling, E. J., Ito, A., Gao, J., Wang, B., Edwards, P. A., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.10.002 · Cited by 316 · see citing works
Self-citationSaturated Fatty Acids Induce c-Src Clustering within Membrane Subdomains, Leading to JNK Activation
Holzer, R. G., Park, E., Li, N., Tran, H., Chen, M. F., Choi, C., Solinas, G., & Karin, M. (2011) · Cell · doi:10.1016/j.cell.2011.08.034 · Cited by 284 · see citing works
Control of Cholesterol Turnover in the Mouse
Dietschy, J. M., & Turley, S. D. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.r100057200 · Cited by 265 · see citing works
Schwarz, M., Russell, D. W., Dietschy, J. M., & Turley, S. D. (1998) · Journal of Lipid Research · doi:10.1016/s0022-2275(20)32171-4 · Cited by 258 · see citing works
Cholic acid mediates negative feedback regulation of bile acid synthesis in mice
Li-Hawkins, J., Gåfvels, M., Olin, M., Lund, E. G., Andersson, U., Schuster, G., Björkhem, I., Russell, D. W., & Eggertsen, G. (2002) · Journal of Clinical Investigation · doi:10.1172/jci0216309 · Cited by 227 · see citing works
Activation of the Liver X Receptor Stimulates Trans-intestinal Excretion of Plasma Cholesterol
van der Veen, J. N., van Dijk, T. H., Vrins, C. L. J., van Meer, H., Havinga, R., Bijsterveld, K., Tietge, U. J. F., Groen, A. K., & Kuipers, F. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.014860 · Cited by 213 · see citing works
van der Velde, A. E., Vrins, C. L. J., van den Oever, K., Kunne, C., Elferink, R. P. J. O., Kuipers, F., & Groen, A. K. (2007) · Gastroenterology · doi:10.1053/j.gastro.2007.06.019 · Cited by 199 · see citing works
Synchronous Evolution of an Odor Biosynthesis Pathway and Behavioral Response
Li, Q., Korzan, W. J., Ferrero, D. M., Chang, R. B., Roy, D. S., Buchi, M., Lemon, J. K., Kaur, A. W., Stowers, L., Fendt, M., et al. (2012) · Current Biology · doi:10.1016/j.cub.2012.10.047 · Cited by 190 · see citing works
May, C. L., Berger, J., Lespine, A., Pillot, B., Prieur, X., Letessier, E., Hussain, M. M., Collet, X., Cariou, B., & Costet, P. (2013) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.112.300263 · Cited by 181 · see citing works
Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study
Voight, B. F., Peloso, G. M., Orho-Melander, M., Frikke-Schmidt, R., Barbalic, M., Jensen, M. K., Hindy, G., Hólm, H., Ding, E. L., Johnson, T., et al. (2012) · The Lancet · doi:10.1016/s0140-6736(12)60312-2 · Cited by 148 · see citing works
Khovidhunkit, W., Moser, A. H., Shigenaga, J. K., Grünfeld, C., & Feingold, K. R. (2003) · Journal of Lipid Research · doi:10.1194/jlr.m300100-jlr200 · Cited by 142 · see citing works
The Serine Hydrolase ABHD6 Is a Critical Regulator of the Metabolic Syndrome
Thomas, G., Betters, J. L., Lord, C. C., Brown, A. L., Marshall, S., Ferguson, D., Sawyer, J. K., Davis, M. A., Melchior, J., Blume, L. C., et al. (2013) · Cell Reports · doi:10.1016/j.celrep.2013.08.047 · Cited by 129 · see citing works
Self-citationHuman Trace Amine-Associated Receptor TAAR5 Can Be Activated by Trimethylamine
Wallrabenstein, I., Kuklan, J., Weber, L., Zborala, S., Werner, M., Altmüller, J., Becker, C., Schmidt, A., Hatt, H., Hummel, T., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0054950 · Cited by 122 · see citing works
Biliary Sterol Secretion Is Not Required for Macrophage Reverse Cholesterol Transport
Temel, R. E., Sawyer, J. K., Yu, L., Lord, C. C., Degirolamo, C., McDaniel, A. L., Marshall, S., Wang, N., Shah, R., Rudel, L. L., et al. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2010.05.011 · Cited by 110 · see citing works
Self-citationVoshol, P. J., Havinga, R., Wolters, H., Ottenhoff, R., Princen, H. M. G., Elferink, R. P. J. O., Groen, A. K., & Kuipers, F. (1998) · Gastroenterology · doi:10.1016/s0016-5085(98)70323-3 · Cited by 93 · see citing works
Wiersma, H., Gatti, A., Nijstad, N., et al. (2009) · Hepatology · doi:10.1002/hep.23112 · Cited by 90 · see citing works
Metaorganismal nutrient metabolism as a basis of cardiovascular disease
Brown, J. M., & Hazen, S. L. (2014) · Current Opinion in Lipidology · doi:10.1097/mol.0000000000000036 · Cited by 80 · see citing works
Self-citationRole of flavin-containing monooxgenase in drug development
Cashman, J. R. (2008) · Expert Opinion on Drug Metabolism & Toxicology · doi:10.1517/17425250802522188 · Cited by 79 · see citing works
Biliary and nonbiliary contributions to reverse cholesterol transport
Temel, R. E., & Brown, J. M. (2012) · Current Opinion in Lipidology · doi:10.1097/mol.0b013e3283508c21 · Cited by 73 · see citing works
Self-citationSehayek, E., & Hazen, S. L. (2008) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.108.165803 · Cited by 64 · see citing works
Self-citationBusby, M. G., Fischer, L. M., da Costa, K.-A., Thompson, D., Mar, M.-H. H., & Zeisel, S. H. (2004) · Journal of the American Dietetic Association · doi:10.1016/j.jada.2004.09.027 · Cited by 61 · see citing works
Advances in Understanding the Pharmacological Properties of Antisense Oligonucleotides
Crooke, S. T. (1997) · Advances in pharmacology · doi:10.1016/s1054-3589(08)60136-2 · Cited by 58 · see citing works
Abcg5/8 Independent Biliary Cholesterol Excretion in Atp8b1-Deficient Mice
Groen, A., Kunne, C., Jongsma, G., et al. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.02.097 · Cited by 50 · see citing works
Ezetimibe stimulates faecal neutral sterol excretion depending on abcg8 function in mice
Jakulj, L., Vissers, M. N., van Roomen, C. P., et al. (2010) · FEBS Letters · doi:10.1016/j.febslet.2010.07.035 · Cited by 47 · see citing works
Hepatic Flavin-Containing Monooxygenase Gene Regulation in Different Mouse Inflammation Models
Zhang, J., Chaluvadi, M. R., Reddy, R. R., et al. (2008) · Drug Metabolism and Disposition · doi:10.1124/dmd.108.025338 · Cited by 42 · see citing works
Aerobic TMAO respiration in Escherichia coli
Ansaldi, M., Théraulaz, L., Baraquet, C., Panis, G., & Méjean, V. (2007) · Molecular Microbiology · doi:10.1111/j.1365-2958.2007.05936.x · Cited by 40 · see citing works
Flavin-containing monooxygenase activity can be inhibited by nitric oxide-mediated S-nitrosylation
Ryu, S.-D., Yi, H.-G., Cha, Y., Kang, J., Kang, J.-S., Jeon, Y.-C., Park, H.-K., Yu, T.-M., Lee, J., & Park, C. (2004) · Life Sciences · doi:10.1016/j.lfs.2004.05.018 · Cited by 32 · see citing works
Marshall, S., Gromovsky, A. D., Kelley, K. L., Davis, M. A., Wilson, M. D., Lee, R. G., Crooke, R. M., Graham, M. J., Rudel, L. L., Brown, J. M., et al. (2014) · PLoS ONE · doi:10.1371/journal.pone.0098953 · Cited by 30 · see citing works
Self-citationRyu, S.-D., Kang, J., Yi, H.-G., Nahm, C. H., & Park, C. (2004) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.09.065 · Cited by 12 · see citing works
Flagged first, then by citations
Research works printed but not linked: 4
- Brufau G Groen AK Kuipers F Reverse cholesterol transport revisited: contribution of biliary versus intestinal cholesterol excretion Arterioscler. Thromb. Vasc. Biol 2011 31 1726 1733 21571685
- Rader DJ Tall AR The not-so-simply HDL story: Is it time to revise the HDL cholesterol hypothesis? Nat. Med 2012 18 1344 1346 22961164
- Rosenson RS Brewer HB Jr Davidson WS Fayad ZA Fuster V Goldstein J Hellerstein M Jiang XC Phillips MC Rader DJ Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport Circulation 2012 125 1905 1919 22508840 PMC4159082
- Temel RE Tang W Ma Y Rudel LL Willingham MC Ioannou YA Davies JP Nilsson LM Yu L Hepatic Niemann-Pick C1-like 1 regulates biliary cholesterol concentrations and is a target of ezetimibe J. Clin. Invest 2007 117 1968 1978 17571164 PMC1888567
Cited by
Sorted by citations
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
Self-citationWang, 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
Self-citationGut microbiota and cardiovascular disease.
Witkowski, M., Weeks, T. L., & Hazen, S. L. (2020) · Circulation Research · doi:10.1161/circresaha.120.316242 · Cited by 1,051 · see citing works
Self-citationJaneiro, M., Ramírez, M., Milagro, F., Martínez, J., & Solas, M. (2018) · Nutrients · doi:10.3390/nu10101398 · Cited by 631 · see citing works
Schiattarella, G. G., Sannino, A., Toscano, E., Giugliano, G., Gargiulo, G., Franzone, A., Trimarco, B., Esposito, G., & Perrino, C. (2017) · European Heart Journal · doi:10.1093/eurheartj/ehx342 · Cited by 563 · see citing works
Development of a gut microbe–targeted nonlethal therapeutic to inhibit thrombosis potential
Roberts, A. B., Gu, X., Buffa, J. A., Hurd, A. G., Wang, Z., Zhu, W., Gupta, N., Skye, S. M., Cody, D. B., Levison, B. S., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0128-1 · Cited by 552 · see citing works
Self-citationHeianza, Y., Ma, W., Manson, J. E., Rexrode, K. M., & Qi, L. (2017) · Journal of the American Heart Association · doi:10.1161/jaha.116.004947 · Cited by 544 · see citing works
Wang, Z., Bergeron, N., Levison, B. S., Li, X. S., Chiu, S., Jia, X., Koeth, R. A., Li, L., Wu, Y., Tang, W. H. W., et al. (2019) · European Heart Journal · doi:10.1093/eurheartj/ehy799 · Cited by 496 · see citing works
Self-citationTrimethylamine <i>N</i> -Oxide, the Microbiome, and Heart and Kidney Disease
Zeisel, S. H., & Warrier, M. (2017) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071816-064732 · Cited by 475 · see citing works
Self-citationLi, X. S., Obeid, S., Klingenberg, R., Gencer, B., Mach, F., Räber, L., Windecker, S., Rodondi, N., Nanchen, D., Muller, O., et al. (2017) · European Heart Journal · doi:10.1093/eurheartj/ehw582 · Cited by 479 · see citing works
Self-citationOrgan, C. L., Otsuka, H., Bhushan, S., Wang, Z., Bradley, J., Trivedi, R., Polhemus, D. J., Tang, W. H. W., Wu, Y., Hazen, S. L., et al. (2016) · Circulation: Heart Failure · doi:10.1161/circheartfailure.115.002314 · Cited by 382 · see citing works
Self-citationFlavin-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
Self-citationFennema, D., Phillips, I. R., & Shephard, E. A. (2016) · Drug Metabolism and Disposition · doi:10.1124/dmd.116.070615 · Cited by 355 · see citing works
Trimethylamine-N-Oxide Instigates NLRP3 Inflammasome Activation and Endothelial Dysfunction
Boini, K. M., Hussain, T., Li, P.-L., & Koka, S. S. (2017) · Cellular Physiology and Biochemistry · doi:10.1159/000484623 · Cited by 302 · see citing works
Schugar, R. C., Shih, D. M., Warrier, M., Helsley, R. N., Burrows, A., Ferguson, D., Brown, A. L., Gromovsky, A. D., Heine, M., Chatterjee, A., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.05.077 · Cited by 291 · see citing works
Self-citationTrimethylamine-N-oxide (TMAO)-induced atherosclerosis is associated with bile acid metabolism
Ding, L., Chang, M., Guo, Y., Zhang, L., Xue, C., Yanagita, T., Zhang, T., & Wang, Y. (2018) · Lipids in Health and Disease · doi:10.1186/s12944-018-0939-6 · Cited by 250 · see citing works
Rohrmann, S., Linseisen, J., Allenspach, M., von Eckardstein, A., & Müller, D. (2016) · The Journal of Nutrition · doi:10.3945/jn.115.220103 · Cited by 197 · see citing works
Kim, R. B., Morse, B. L., Djurdjev, O., Tang, M., Muirhead, N., Barrett, B., Holmes, D. T., Madore, F., Clase, C. M., Rigatto, C., et al. (2016) · Kidney International · doi:10.1016/j.kint.2016.01.014 · Cited by 179 · see citing works
Trimethylamine <i>N</i> ‐Oxide and Mortality Risk in Patients With Peripheral Artery Disease
Senthong, V., Wang, Z., Fan, Y., Wu, Y., Hazen, S. L., & Tang, W. H. W. (2016) · Journal of the American Heart Association · doi:10.1161/jaha.116.004237 · Cited by 175 · see citing works
Self-citationZhu, W., Buffa, J. A., Wang, Z., Warrier, M., Schugar, R., Shih, D. M., Gupta, N., Gregory, J. C., Org, E., Fu, X., et al. (2018) · Journal of Thrombosis and Haemostasis · doi:10.1111/jth.14234 · Cited by 161 · see citing works
Self-citationTMAO is Associated with Mortality: Impact of Modestly Impaired Renal Function
Gruppen, E. G., Garcia, E., Connelly, M. A., Jeyarajah, E. J., Otvos, J. D., Bakker, S. J. L., & Dullaart, R. P. F. (2017) · Scientific Reports · doi:10.1038/s41598-017-13739-9 · Cited by 146 · see citing works
Molecular mechanisms in liver repair and regeneration: from physiology to therapeutics
Ma, X., Huang, T., Chen, X., Li, Q., Liao, M., Fu, L., Huang, J., Yuan, K., Wang, Z., & Zeng, Y. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02104-8 · Cited by 133 · see citing works
Self-citationHartiala, J. A., Wilson Tang, W. H., Wang, Z., Crow, A. L., Stewart, A. F. R., Roberts, R., McPherson, R., Erdmann, J., Willenborg, C., Hazen, S. L., et al. (2016) · Nature Communications · doi:10.1038/ncomms10558 · Cited by 130 · see citing works
Self-citationObeid, R., Awwad, H. M., Rabagny, Y., Graeber, S., Herrmann, W., & Geisel, J. (2016) · The American Journal of Clinical Nutrition · doi:10.3945/ajcn.115.121269 · Cited by 117 · see citing works
Dumas, M.-E., Rothwell, A. R., Hoyles, L., Aranias, T., Chilloux, J., Calderari, S., Noll, E. M., Péan, N., Boulangé, C. L., Blancher, C., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.06.039 · Cited by 114 · see citing works
“, 2013) and was shown to play a central role in the regulation of cholesterol balance and glucose homeostasis (Warrier et al., 2015).”
BackgroundTan, Y., Sheng, Z., Zhou, P., Liu, C., Zhao, H., Song, L., Li, J., Zhou, J., Chen, Y., Wang, L., et al. (2019) · Circulation: Cardiovascular Interventions · doi:10.1161/circinterventions.118.007281 · Cited by 113 · see citing works
Ryan, P. M., London, L. E. E., Bjorndahl, T. C., Mandal, R., Murphy, K., Fitzgerald, G. F., Shanahan, F., Ross, R. P., Wishart, D. S., Caplice, N. M., et al. (2017) · Microbiome · doi:10.1186/s40168-017-0246-x · Cited by 97 · see citing works
Shih, D. M., Zhu, W., Schugar, R. C., Meng, Y., Jia, X., Miikeda, A., Wang, Z., Zieger, M., Lee, R., Graham, M., et al. (2019) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.119.312592 · Cited by 67 · see citing works
Self-citationRobinson-Cohen, C., Newitt, R., Shen, D. D., Rettie, A. E., Kestenbaum, B. R., Himmelfarb, J., & Yeung, C. K. (2016) · PLOS ONE · doi:10.1371/journal.pone.0161074 · Cited by 63 · see citing works
The Role of Microbiota in Cardiovascular Risk: Focus on Trimethylamine Oxide
Al-Rubaye, H., Perfetti, G., & Kaski, J.-C. (2019) · Current Problems in Cardiology · doi:10.1016/j.cpcardiol.2018.06.005 · Cited by 43 · see citing works
Yang, S., Li, D., Yu, Z., Li, Y., & Wu, M. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.709629 · Cited by 40 · see citing works
Trimethylamine-N-oxide and its biological variations in vegetarians.
Obeid, R., Awwad, H. M., Keller, M., & Geisel, J. (2017) · European Journal of Nutrition · doi:10.1007/s00394-016-1295-9 · Cited by 38 · see citing works
Functional food addressing heart health: do we have to target the gut microbiota?
Ryan, P. M., Ross, R. P., Fitzgerald, G. F., Caplice, N. M., & Stanton, C. (2015) · Current Opinion in Clinical Nutrition and Metabolic Care · doi:10.1097/mco.0000000000000224 · Cited by 28 · see citing works
Zhao, Y., Yang, N., Gao, J., Li, H., Cai, W., Zhang, X., Ma, Y., Niu, X., Yang, G., Zhou, X., et al. (2018) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201700299 · Cited by 29 · see citing works
- Authors
- 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., Sacks, J., Rong, X., Vallim, T. D. A., Chou, J., Ivanova, P. T., Myers, D. S., Brown, H. A., Lee, R. G., Crooke, R. M., Graham, M. J., Liu, X., Parini, P., Tontonoz, P., Lusis, A. J., Hazen, S. L., Temel, R. E., & Brown, J. M.
- Affiliations
- Cleveland Clinic (US)
- University of California, Los Angeles (US)
- Wake Forest University Health Sciences (US)
- Vanderbilt University (US)
- Ionis Pharmaceuticals (United States) (US)
- Karolinska Institutet (SE)
- Howard Hughes Medical Institute (US)
- University of Kentucky (US)
- Corresponding author
- Brown, J. Mark
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2015-01
- Volume
- 10
- Issue
- 3
- Pages
- 326-338
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC4501903
- OpenAlex
- W2046316092
- Cited by
- 414
- References
- 51
- Citations by year
- 2026: 24 · 2025: 24 · 2024: 31 · 2023: 38 · 2022: 45 · 2021: 48 · 2020: 43 · 2019: 33 · 2018: 39 · 2017: 32 · 2016: 39 · 2015: 18
- FWCI
- 43.34
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UKnowledge (University of Kentucky) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institutes of Health (UL1TR000439)
- National Heart, Lung, and Blood Institute (R00HL096166, T32HL091797, P20HL113452, R01HL066088, R01HL103866, R01HL122283)
- National Institute of General Medical Sciences (U54GM069338)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK063491)
- National Center for Research Resources (UL1RR024989)
- National Center for Advancing Translational Sciences
- Topics
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Keywords
- trimethylamine N-oxide, flavin monooxygenase 3, reverse cholesterol transport, cholesterol metabolism, gut microbiota, liver X receptor, endoplasmic reticulum stress, intestinal cholesterol absorption, biliary lipid secretion, macrophages, cardiovascular risk, inflammation, triglyceride metabolism
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
