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.
Digital Object Identifier (DOI)
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.
Warrier, Manya; Shih, Diana M.; Burrows, Amy C.; Ferguson, Daniel; Gromovsky, Anthony D.; Brown, Amanda L.; Marshall, Stephanie; McDaniel, Allison; Schugar, Rebecca C.; Wang, Zeneng; Sacks, Jessica; Rong, Xin; Vallim, Thomas de Aguiar; Chou, Jeff; Ivanova, Pavlina T.; Myers, David S.; Brown, H. Alex; Lee, Richard G.; Crooke, Rosanne M.; Graham, Mark J.; Liu, Xiuli; Parini, Paolo; Tontonoz, Peter; Lusis, Aldon J.; Hazen, Stanley L.; Temel, Ryan E.; and Brown, J. Mark, "The TMAO-Generating Enzyme Flavin Monooxygenase 3 Is a Central Regulator of Cholesterol Balance" (2015). Saha Cardiovascular Research Center Faculty Publications. 17.
Document S1. Supplemental Experimental Procedures and Figures S1–S5.
mmc2.xlsx (1352 kB)
Table S1. Differentially Expressed Genes in Acute and Chronic Mouse Models of TICE Stimulation, Related to Figure 1.
mmc3.xlsx (13 kB)
Table S2. Differentially Expressed Genes Shared in Both Acute and Chronic Mouse Models of TICE Stimulation, Related to Figure 1.
mmc4.xlsx (12122 kB)
Table S3. Complete Microarray Data Set from the Acute Mouse Model of TICE Stimulation: Control ASO versus ACAT2 ASO, Related to Figure 1.
mmc5.xlsx (13123 kB)
Table S4. Complete Microarray Data Set from the Chronic Mouse Model of TICE Stimulation: WT versus NPC1L1 Liver Transgenic, Related to Figure 1.
mmc6.pdf (10516 kB)
Document S2. Article plus Supplemental Information.