The TMAO-Generating Enzyme Flavin Monooxygenase 3 Is a Central Regulator of Cholesterol Balance

Manya Warrier; Diana M. Shih; Amy C. Burrows; Daniel Ferguson; Anthony D. Gromovsky; Amanda L. Brown; Stephanie Marshall; Allison McDaniel; Rebecca C. Schugar; Zeneng Wang; Jessica Sacks; Xin Rong; Thomasde Aguiar Vallim; Jeff Chou; Pavlina T. Ivanova; David S. Myers; H. Alex Brown; Richard G. Lee; Rosanne M. Crooke; Mark J. Graham; Xiuli Liu; Paolo Parini; Peter Tontonoz; Aldon J. Lusis; Stanley L. Hazen; Ryan E. Temel; J. Mark Brown

doi:10.1016/j.celrep.2014.12.036

The TMAO-Generating Enzyme Flavin Monooxygenase 3 Is a Central Regulator of Cholesterol Balance

Manya Warrier, Diana M. Shih, Amy C. Burrows, Daniel Ferguson, Anthony D. Gromovsky, Amanda L. Brown, Stephanie Marshall, Allison McDaniel, Rebecca C. Schugar, Zeneng Wang, Jessica Sacks, Xin Rong, Thomasde Aguiar Vallim, Jeff Chou, Pavlina T. Ivanova, David S. Myers, H. Alex Brown, Richard G. Lee, Rosanne M. Crooke, Mark J. GrahamXiuli Liu, Paolo Parini, Peter Tontonoz, Aldon J. Lusis, Stanley L. Hazen, Ryan E. Temel, J. Mark Brown

Research output: Contribution to journal › Article › peer-review

336 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	326-338
Number of pages	13
Journal	Cell Reports
Volume	10
Issue number	3
DOIs	https://doi.org/10.1016/j.celrep.2014.12.036
State	Published - Jan 20 2015

Bibliographical note

Publisher Copyright:
© 2015 The Authors.

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.celrep.2014.12.036

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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. A., Chou, J., Ivanova, P. T., Myers, D. S., Brown, H. A., Lee, R. G., Crooke, R. M., ... Brown, J. M. (2015). The TMAO-Generating Enzyme Flavin Monooxygenase 3 Is a Central Regulator of Cholesterol Balance. Cell Reports, 10(3), 326-338. https://doi.org/10.1016/j.celrep.2014.12.036

@article{d8f49e9f153f464eadba1a4c8a283248,

title = "The TMAO-Generating Enzyme Flavin Monooxygenase 3 Is a Central Regulator of Cholesterol Balance",

abstract = "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.",

author = "Manya Warrier and Shih, {Diana M.} and Burrows, {Amy C.} and Daniel Ferguson and Gromovsky, {Anthony D.} and Brown, {Amanda L.} and Stephanie Marshall and Allison McDaniel and Schugar, {Rebecca C.} and Zeneng Wang and Jessica Sacks and Xin Rong and Vallim, {Thomasde Aguiar} and Jeff Chou and Ivanova, {Pavlina T.} and Myers, {David S.} and Brown, {H. Alex} and Lee, {Richard G.} and Crooke, {Rosanne M.} and Graham, {Mark J.} and Xiuli Liu and Paolo Parini and Peter Tontonoz and Lusis, {Aldon J.} and Hazen, {Stanley L.} and Temel, {Ryan E.} and Brown, {J. Mark}",

note = "Publisher Copyright: {\textcopyright} 2015 The Authors.",

year = "2015",

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Warrier, M, Shih, DM, Burrows, AC, Ferguson, D, Gromovsky, AD, Brown, AL, Marshall, S, McDaniel, A, Schugar, RC, Wang, Z, Sacks, J, Rong, X, Vallim, TA, Chou, J, Ivanova, PT, Myers, DS, Brown, HA, Lee, RG, Crooke, RM, Graham, MJ, Liu, X, Parini, P, Tontonoz, P, Lusis, AJ, Hazen, SL, Temel, RE & Brown, JM 2015, 'The TMAO-Generating Enzyme Flavin Monooxygenase 3 Is a Central Regulator of Cholesterol Balance', Cell Reports, vol. 10, no. 3, pp. 326-338. https://doi.org/10.1016/j.celrep.2014.12.036

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T1 - The TMAO-Generating Enzyme Flavin Monooxygenase 3 Is a Central Regulator of Cholesterol Balance

AU - Warrier, Manya

AU - Shih, Diana M.

AU - Burrows, Amy C.

AU - Ferguson, Daniel

AU - Gromovsky, Anthony D.

AU - Brown, Amanda L.

AU - Marshall, Stephanie

AU - McDaniel, Allison

AU - Schugar, Rebecca C.

AU - Wang, Zeneng

AU - Sacks, Jessica

AU - Rong, Xin

AU - Vallim, Thomasde Aguiar

AU - Chou, Jeff

AU - Ivanova, Pavlina T.

AU - Myers, David S.

AU - Brown, H. Alex

AU - Lee, Richard G.

AU - Crooke, Rosanne M.

AU - Graham, Mark J.

AU - Liu, Xiuli

AU - Parini, Paolo

AU - Tontonoz, Peter

AU - Lusis, Aldon J.

AU - Hazen, Stanley L.

AU - Temel, Ryan E.

AU - Brown, J. Mark

PY - 2015/1/20

Y1 - 2015/1/20

N2 - 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.

AB - 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.

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JO - Cell Reports

JF - Cell Reports

IS - 3

ER -

The TMAO-Generating Enzyme Flavin Monooxygenase 3 Is a Central Regulator of Cholesterol Balance

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

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