Journal
CELL REPORTS
Volume 10, Issue 3, Pages 326-338Publisher
CELL PRESS
DOI: 10.1016/j.celrep.2014.12.036
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Funding
- NIH
- Office of Dietary Supplements [R00 HL096166, R01 HL122283, R01 HL103866, P20 HL113452, U54 GM069338]
- American Heart Association [14POST18700001, 14SDG18440015]
- Cleveland Clinic Foundation General Clinical Research Center of the Cleveland Clinic/Case Western Reserve University CTSA [1UL1RR024989]
- Leonard Krieger Fund
- Center of Innovation Award by AB Sciex
- Cleveland Heart Lab
- Esperion
- Liposciences
- Proctor Gamble
- Roche
- Takeda
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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.
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