Dataset Information

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.

SUBMITTER: Warrier M

PROVIDER: S-EPMC4501903 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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

Warrier Manya M Shih Diana M DM Burrows Amy C AC Ferguson Daniel D Gromovsky Anthony D AD Brown Amanda L AL Marshall Stephanie S McDaniel Allison A Schugar Rebecca C RC Wang Zeneng Z Sacks Jessica J Rong Xin X Vallim Thomas de Aguiar TA Chou Jeff J Ivanova Pavlina T PT Myers David S DS Brown H Alex HA Lee Richard G RG Crooke Rosanne M RM Graham Mark J MJ Liu Xiuli X Parini Paolo P Tontonoz Peter P Lusis Aldon J AJ Hazen Stanley L SL Temel Ryan E RE Brown J Mark JM

Cell reports 20150115 3

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 cho ...[more]

PMID: 25600868

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Dataset Information

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

Publications

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

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