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

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293 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

Funding Information:
This work was supported by NIH and Office of Dietary Supplements grants R00 HL096166 (J.M.B.), R01 HL122283 (J.M.B.), R01 HL103866 (S.L.H.), P20 HL113452 (S.L.H.), and U54 GM069338 (H.A.B.). Additional support was provided by American Heart Association grants 14POST18700001 (M.W.) and 14SDG18440015 (T.d.A.V.). Further support was provided by the Cleveland Clinic Foundation General Clinical Research Center of the Cleveland Clinic/Case Western Reserve University CTSA (1UL1RR024989). S.L.H is also partially supported by a gift from the Leonard Krieger Fund. The authors thank Stephen Milne for assistance with the glycerophospholipid mass spectrometry analysis. Some of the mass spectrometry studies were performed in the Lerner Research Institute Mass Spectrometry Core, with instruments partially supported by a Center of Innovation Award by AB Sciex.

Publisher Copyright:
© 2015 The Authors.

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology (all)

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

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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 = "Funding Information: This work was supported by NIH and Office of Dietary Supplements grants R00 HL096166 (J.M.B.), R01 HL122283 (J.M.B.), R01 HL103866 (S.L.H.), P20 HL113452 (S.L.H.), and U54 GM069338 (H.A.B.). Additional support was provided by American Heart Association grants 14POST18700001 (M.W.) and 14SDG18440015 (T.d.A.V.). Further support was provided by the Cleveland Clinic Foundation General Clinical Research Center of the Cleveland Clinic/Case Western Reserve University CTSA (1UL1RR024989). S.L.H is also partially supported by a gift from the Leonard Krieger Fund. The authors thank Stephen Milne for assistance with the glycerophospholipid mass spectrometry analysis. Some of the mass spectrometry studies were performed in the Lerner Research Institute Mass Spectrometry Core, with instruments partially supported by a Center of Innovation Award by AB Sciex. Publisher Copyright: {\textcopyright} 2015 The Authors.",

year = "2015",

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doi = "10.1016/j.celrep.2014.12.036",

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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

TY - JOUR

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

N1 - Funding Information: This work was supported by NIH and Office of Dietary Supplements grants R00 HL096166 (J.M.B.), R01 HL122283 (J.M.B.), R01 HL103866 (S.L.H.), P20 HL113452 (S.L.H.), and U54 GM069338 (H.A.B.). Additional support was provided by American Heart Association grants 14POST18700001 (M.W.) and 14SDG18440015 (T.d.A.V.). Further support was provided by the Cleveland Clinic Foundation General Clinical Research Center of the Cleveland Clinic/Case Western Reserve University CTSA (1UL1RR024989). S.L.H is also partially supported by a gift from the Leonard Krieger Fund. The authors thank Stephen Milne for assistance with the glycerophospholipid mass spectrometry analysis. Some of the mass spectrometry studies were performed in the Lerner Research Institute Mass Spectrometry Core, with instruments partially supported by a Center of Innovation Award by AB Sciex. Publisher Copyright: © 2015 The Authors.

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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DO - 10.1016/j.celrep.2014.12.036

M3 - Article

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VL - 10

SP - 326

EP - 338

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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