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.
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA.
authors.forename: Manya
authors.initials: M
authors.lastname: Warrier
authors.affiliation: Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Diana M
authors.initials: DM
authors.lastname: Shih
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA.
authors.forename: Amy C
authors.initials: AC
authors.lastname: Burrows
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ferguson
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA.
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Gromovsky
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Brown
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Marshall
authors.affiliation: Departments of Pathology and Biostatistics, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: McDaniel
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Schugar
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA.
authors.forename: Zeneng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Sacks
authors.affiliation: Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Rong
authors.affiliation: Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Thomas de Aguiar
authors.initials: TA
authors.lastname: Vallim
authors.affiliation: Departments of Pathology and Biostatistics, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Chou
authors.affiliation: Departments of Pharmacology and Biochemistry, The Vanderbilt Institute of Chemical Biology, Nashville, TN 37232, USA.
authors.forename: Pavlina T
authors.initials: PT
authors.lastname: Ivanova
authors.affiliation: Departments of Pharmacology and Biochemistry, The Vanderbilt Institute of Chemical Biology, Nashville, TN 37232, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Myers
authors.affiliation: Departments of Pharmacology and Biochemistry, The Vanderbilt Institute of Chemical Biology, Nashville, TN 37232, USA.
authors.forename: H Alex
authors.initials: HA
authors.lastname: Brown
authors.affiliation: Cardiovascular Group, Antisense Drug Discovery, Isis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Lee
authors.affiliation: Cardiovascular Group, Antisense Drug Discovery, Isis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA.
authors.forename: Rosanne M
authors.initials: RM
authors.lastname: Crooke
authors.affiliation: Cardiovascular Group, Antisense Drug Discovery, Isis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Graham
authors.affiliation: Department of Anatomical Pathology, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Liu
authors.affiliation: Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet at Huddinge University Hospital, 141 86 Stockholm, Sweden.
authors.forename: Paolo
authors.initials: P
authors.lastname: Parini
authors.affiliation: Howard Hughes Medical Institute; Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Tontonoz
authors.affiliation: Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Aldon J
authors.initials: AJ
authors.lastname: Lusis
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA.
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
authors.affiliation: Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40536-0509, USA.
authors.forename: Ryan E
authors.initials: RE
authors.lastname: Temel
authors.affiliation: Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA. Electronic address: brownm5@ccf.org.
authors.forename: J Mark
authors.initials: JM
authors.lastname: Brown