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

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

Cell Rep. 2015 Jan 20;10(3):326-338. doi: 10.1016/j.celrep.2014.12.036. Epub 2015 Jan 15.

Authors

Manya Warrier¹, Diana M Shih², Amy C Burrows¹, Daniel Ferguson¹, Anthony D Gromovsky¹, Amanda L Brown¹, Stephanie Marshall¹, Allison McDaniel³, Rebecca C Schugar¹, Zeneng Wang¹, Jessica Sacks¹, Xin Rong⁴, Thomas de Aguiar Vallim², Jeff Chou³, Pavlina T Ivanova⁵, David S Myers⁵, H Alex Brown⁵, Richard G Lee⁶, Rosanne M Crooke⁶, Mark J Graham⁶, Xiuli Liu⁷, Paolo Parini⁸, Peter Tontonoz⁹, Aldon J Lusis², Stanley L Hazen¹, Ryan E Temel¹⁰, J Mark Brown¹¹

Affiliations

¹ Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA.
² Department of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Departments of Pathology and Biostatistics, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.
⁴ Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁵ Departments of Pharmacology and Biochemistry, The Vanderbilt Institute of Chemical Biology, Nashville, TN 37232, USA.
⁶ Cardiovascular Group, Antisense Drug Discovery, Isis Pharmaceuticals, Inc., Carlsbad, CA 92010, USA.
⁷ Department of Anatomical Pathology, Cleveland Clinic, Cleveland, OH 44195, USA.
⁸ Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institutet at Huddinge University Hospital, 141 86 Stockholm, Sweden.
⁹ Howard Hughes Medical Institute; Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹⁰ Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40536-0509, USA.
¹¹ Department of Cellular and Molecular Medicine, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA. Electronic address: brownm5@ccf.org.

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.

Abstract

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