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, Thomasde Aguiar Vallim, Jeff Chou, Pavlina T. Ivanova, David S. Myers, H. Alex Brown, Richard G. Lee, Rosanne M. Crooke, Mark J. GrahamXiuli Liu, Paolo Parini, Peter Tontonoz, Aldon J. Lusis, Stanley L. Hazen, Ryan E. Temel, J. Mark Brown

Research output: Contribution to journalArticlepeer-review

293 Scopus citations


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.

Original languageEnglish
Pages (from-to)326-338
Number of pages13
JournalCell Reports
Issue number3
StatePublished - Jan 20 2015

Bibliographical note

Funding Information:
This work was supported by NIH and Office of Dietary Supplements grants R00 HL096166 (J.M.B.), R01 HL122283 (J.M.B.), R01 HL103866 (S.L.H.), P20 HL113452 (S.L.H.), and U54 GM069338 (H.A.B.). Additional support was provided by American Heart Association grants 14POST18700001 (M.W.) and 14SDG18440015 (T.d.A.V.). Further support was provided by the Cleveland Clinic Foundation General Clinical Research Center of the Cleveland Clinic/Case Western Reserve University CTSA (1UL1RR024989). S.L.H is also partially supported by a gift from the Leonard Krieger Fund. The authors thank Stephen Milne for assistance with the glycerophospholipid mass spectrometry analysis. Some of the mass spectrometry studies were performed in the Lerner Research Institute Mass Spectrometry Core, with instruments partially supported by a Center of Innovation Award by AB Sciex.

Publisher Copyright:
© 2015 The Authors.

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology (all)


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