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

doi:10.1016/j.celrep.2014.12.036

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
pp. 326 – 338

Abstract

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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.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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