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

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-g...

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Main Authors: 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, Thomas de 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
Format: Article
Language:English
Published: Elsevier 2015-01-01
Series:Cell Reports
Online Access:http://www.sciencedirect.com/science/article/pii/S2211124714010651
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author 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
Thomas de 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
spellingShingle 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
Thomas de 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
The TMAO-Generating Enzyme Flavin Monooxygenase 3 Is a Central Regulator of Cholesterol Balance
Cell Reports
author_facet 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
Thomas de 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
author_sort Manya Warrier
title The TMAO-Generating Enzyme Flavin Monooxygenase 3 Is a Central Regulator of Cholesterol Balance
title_short The TMAO-Generating Enzyme Flavin Monooxygenase 3 Is a Central Regulator of Cholesterol Balance
title_full The TMAO-Generating Enzyme Flavin Monooxygenase 3 Is a Central Regulator of Cholesterol Balance
title_fullStr The TMAO-Generating Enzyme Flavin Monooxygenase 3 Is a Central Regulator of Cholesterol Balance
title_full_unstemmed The TMAO-Generating Enzyme Flavin Monooxygenase 3 Is a Central Regulator of Cholesterol Balance
title_sort tmao-generating enzyme flavin monooxygenase 3 is a central regulator of cholesterol balance
publisher Elsevier
series Cell Reports
issn 2211-1247
publishDate 2015-01-01
description 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.
url http://www.sciencedirect.com/science/article/pii/S2211124714010651
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spelling doaj-a4273ef0fd5b4cb38f7e399803e887fb2020-11-24T21:55:28ZengElsevierCell Reports2211-12472015-01-0110332633810.1016/j.celrep.2014.12.036The TMAO-Generating Enzyme Flavin Monooxygenase 3 Is a Central Regulator of Cholesterol BalanceManya Warrier0Diana M. Shih1Amy C. Burrows2Daniel Ferguson3Anthony D. Gromovsky4Amanda L. Brown5Stephanie Marshall6Allison McDaniel7Rebecca C. Schugar8Zeneng Wang9Jessica Sacks10Xin Rong11Thomas de Aguiar Vallim12Jeff Chou13Pavlina T. Ivanova14David S. Myers15H. Alex Brown16Richard G. Lee17Rosanne M. Crooke18Mark J. Graham19Xiuli Liu20Paolo Parini21Peter Tontonoz22Aldon J. Lusis23Stanley L. Hazen24Ryan E. Temel25J. Mark Brown26Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USADepartment of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USADepartment of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USADepartment of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USADepartment of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USADepartment of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USADepartment of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USADepartments of Pathology and Biostatistics, Wake Forest School of Medicine, Winston-Salem, NC 27157, USADepartment of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USADepartment of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USADepartment of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USADepartment of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USADepartment of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USADepartments of Pathology and Biostatistics, Wake Forest School of Medicine, Winston-Salem, NC 27157, USADepartments of Pharmacology and Biochemistry, The Vanderbilt Institute of Chemical Biology, Nashville, TN 37232, USADepartments of Pharmacology and Biochemistry, The Vanderbilt Institute of Chemical Biology, Nashville, TN 37232, USADepartments of Pharmacology and Biochemistry, The Vanderbilt Institute of Chemical Biology, Nashville, TN 37232, USACardiovascular Group, Antisense Drug Discovery, Isis Pharmaceuticals, Inc., Carlsbad, CA 92010, USACardiovascular Group, Antisense Drug Discovery, Isis Pharmaceuticals, Inc., Carlsbad, CA 92010, USACardiovascular Group, Antisense Drug Discovery, Isis Pharmaceuticals, Inc., Carlsbad, CA 92010, USADepartment of Anatomical Pathology, Cleveland Clinic, Cleveland, OH 44195, USAClinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet at Huddinge University Hospital, 141 86 Stockholm, SwedenHoward Hughes Medical InstituteDepartment of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USADepartment of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USASaha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40536-0509, USADepartment of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USACirculating 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.http://www.sciencedirect.com/science/article/pii/S2211124714010651