Cell Reports
(Jan 2015)
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,
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
Affiliations
Manya Warrier
Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA
Diana M. Shih
Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Amy C. Burrows
Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA
Daniel Ferguson
Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA
Anthony D. Gromovsky
Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA
Amanda L. Brown
Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA
Stephanie Marshall
Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA
Allison McDaniel
Departments of Pathology and Biostatistics, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
Rebecca C. Schugar
Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA
Zeneng Wang
Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA
Jessica Sacks
Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA
Xin Rong
Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Thomas de Aguiar Vallim
Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Jeff Chou
Departments of Pathology and Biostatistics, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
Pavlina T. Ivanova
Departments of Pharmacology and Biochemistry, The Vanderbilt Institute of Chemical Biology, Nashville, TN 37232, USA
David S. Myers
Departments of Pharmacology and Biochemistry, The Vanderbilt Institute of Chemical Biology, Nashville, TN 37232, USA
H. Alex Brown
Departments of Pharmacology and Biochemistry, The Vanderbilt Institute of Chemical Biology, Nashville, TN 37232, USA
Richard G. Lee
Cardiovascular Group, Antisense Drug Discovery, Isis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA
Rosanne M. Crooke
Cardiovascular Group, Antisense Drug Discovery, Isis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA
Mark J. Graham
Cardiovascular Group, Antisense Drug Discovery, Isis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA
Xiuli Liu
Department of Anatomical Pathology, Cleveland Clinic, Cleveland, OH 44195, USA
Paolo Parini
Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet at Huddinge University Hospital, 141 86 Stockholm, Sweden
Peter Tontonoz
Howard Hughes Medical Institute
Aldon J. Lusis
Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
Stanley L. Hazen
Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA
Ryan E. Temel
Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40536-0509, USA
J. Mark Brown
Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA
DOI
https://doi.org/10.1016/j.celrep.2014.12.036
Journal volume & issue
Vol. 10,
no. 3
Abstract
Read online
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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