Abstract 11747: The TMAO Generating Enzyme Flavin Monooxygenase 3 (FMO3) is a Novel Regulator of Cholesterol Balance
Circulating trimethylamine-N-oxide (TMAO) levels have recently been linked to cardiovascular disease (CVD) risk, but the mechanism underlying this association is unclear. Here we performed unbiased 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 inhibition stimulates basal and liver X receptor (LXR)-stimulated macrophage RCT, thereby improving cholesterol balance. Conversely, FMO3 knockdown exacerbates hepatic ER stress and inflammation by altering the LXR-Lpcat3-driven phospholipid remodeling pathway. FMO3 is thus identified as a novel integrator of hepatic lipid metabolism, inflammation, and ER stress. These studies suggest that the gut microbiota-driven TMAO pathway may promote CVD pathogenesis in part by reciprocally regulating lipid metabolism and inflammation.
Author Disclosures: M. Warrier: None. S. Marshall: None. A. McDaniel: None. Z. Wang: Employment; Significant; Cleveland Clinic. Ownership Interest; Significant; Liposciences, Proctor & Gamble. A.L. Brown: None. A.D. Gromovsky: None. J. Sacks: None. J. Chou: None. P.T. Ivanova: None. D.S. Myers: None. H. Brown: None. R.G. Lee: Employment; Significant; Employee of Isis Pharmaceuticals, Inc. R.M. Crooke: Employment; Significant; Employee of Isis Pharmaceutical, Inc. M.J. Graham: Employment; Significant; Employee of Isis Pharmaceuticals, Inc.. D.M. Shih: None. A.J. Lusis: None. P. Parini: None. S.L. Hazen: Employment; Significant; Cleveland Clinic. Research Grant; Significant; National Institutes of Health, Cleveland Heart Lab, Liposcience, Pfizer, Proctor & Gamble, Takeda. Ownership Interest; Modest; Esperion, Frants Biomarkers, Liposcience, Siemens. Consultant/Advisory Board; Modest; Eli Lilly, Merck, Pfizer. Consultant/Advisory Board; Significant; Cleveland Heart Lab, Esperion, Liposcience, Proctor & Gamble. Other; Significant; Abbott. R.E. Temel: Ownership Interest; Modest; Merck, Isis Pharmaceuticals. Consultant/Advisory Board; Modest; Liposcience. Other Research Support; Significant; Regulus Therapeutics. J.M. Brown: Employment; Significant; Cleveland Clinic. Research Grant; Significant; National Institutes of Health (R00-096166 & R01-122283).
This research has received full or partial funding support from the American Heart Association
- © 2014 by American Heart Association, Inc.