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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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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 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. To identify potential regulators of macrophage reverse cholesterol transport (RCT), liver was isolated from two independent mouse models where the non-biliary RCT pathway known as transintestinal cholesterol excretion (TICE) was either chronically (NPC1L1-liver-transgenic mice) or acutely (ACAT2 antisense oligonucleotide treatment) stimulated. Total RNA was isolated and gene expression levels were profiled on the Affymetrix GeneAtlas MG-430 PM Array Strip (Affymetrix; Santa Clara, CA, USA)

ORGANISM(S): Mus musculus

SUBMITTER: Jeff Chou

PROVIDER: E-GEOD-64326 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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The TMAO Generating Enzyme Flavin Monooxygenase 3 is a Central Regulator of Cholesterol Balance

Project description: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 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.

2014-12-19 | GSE64326 | GEO

Feedback regulation of cholesterol metabolism by LeXis, a lipid-responsive non-coding RNA

Project description:Abstract: The LXR and SREBP transcription factors are key regulators of cellular and systemic cholesterol homeostasis. The molecular mechanisms that integrate these pathways are incompletely understood. Here we show that ligand activation of LXRs in liver not only promotes cholesterol efflux, but also simultaneously inhibits cholesterol biosynthesis. We further identify the long non-coding RNA LeXis as an unexpected mediator of this effect. LeXis is robustly induced in mouse liver in response to western diet feeding or pharmacologic LXR activation. Expression of LeXis in liver inhibits cholesterol biosynthesis and lowers plasma cholesterol levels. Reciprocally, knockdown of LeXis increases hepatic cholesterol content and raises plasma cholesterol levels. LeXis interacts with the heterogeneous nuclear ribonucleoprotein Raly and regulates its binding to cholesterol biosynthetic gene promoters. These studies outline a regulatory role for a non-coding RNA in lipid metabolism and advance our understanding of the mechanisms orchestrating systemic sterol homeostasis. Global RNA expression from primary hepatocytes treated with or without GW3965 were compared by RNA-Seq.

2016-02-10 | E-GEOD-77793 | biostudies-arrayexpress

Gene expression levels after TMAO treatment

Project description:TMAO is gut microbiota dependent metabolite catalyzed by monooxygenase FMO3 from TMA. TMAO is positively assocaited with different metabolic diseases such as diabetes, chronic kidney disease, and atherosclerosis. We used microarray to analyze the genes regulated by TMAO treatment in primary rat hepatocytes to further understand the mechanistic view of TMAO action.

2019-08-22 | GSE135856 | GEO

Feedback regulation of cholesterol metabolism by LeXis, a lipid-responsive non-coding RNA

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Trimethylamine N-oxide impairs β-cell function and glucose tolerance

Project description:β-Cell dysfunction, manifested as impaired glucose-stimulated insulin secretion (GSIS), and β-cell loss, which presents as dedifferentiation, inhibited transcriptional identity and death, are the hallmarks of type 2 diabetes. Trimethylamine N-oxide (TMAO), a gut microbiota metabolite, has been shown to play a role in cardiovascular disease. Here, we found that plasma TMAO levels are elevated in both diabetic mice and human subjects and that TMAO at a similar concentration to that found in diabetes could directly decrease β-cell GSIS in both MIN6 cells and primary islets from mice or humans. Elevation of TMAO levels through choline diet feeding impairs GSIS, the β-cell proportion, and glucose tolerance. TMAO inhibits calcium transients through NLRP3 inflammasome-related inflammatory cytokines and induced Serca2 loss, and a Serca2 agonist reversed the effect of TMAO on β-cell function in vitro and in vivo. Additionally, long-term TMAO exposure promotes β-cell ER stress, dedifferentiation, and apoptosis and inhibits β-cell transcriptional identity. Inhibition of TMAO production through either genetic knockdown or antisense oligomers of Fmo3, the TMAO-producing enzyme, improves β-cell GSIS, the β-cell proportion, and glucose tolerance in both db/db and choline diet-fed mice. These observations elucidate a novel role for TMAO in β-cell dysfunction and maintenance, and inhibition of TMAO could be a new approach for the treatment of type 2 diabetes.

2024-02-23 | GSE243083 | GEO

The murine liver x receptor is selectively modulated by different ligands to differentially alter tumor-associated myeloid cells [scRNA-seq]

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2022-06-01 | GSE186910 | GEO

The murine liver x receptor is selectively modulated by different ligands to differentially alter tumor-associated myeloid cells [bulk RNA-seq]

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RNA-Seq of livers of Gata4LKO and control mouse on LXR agonist GW3965

Project description:GATA4 is a transcription factor known for its crucial role in the development of many tissues, including liver; however, its role in adult liver metabolism is unknown. Here, using high-throughput sequencing technologies, including assay for transposase-accessible chromatin with sequencing (ATAC-Seq), we identified GATA4 as a transcriptional regulator of metabolism in liver. GATA4 expression is elevated in response to refeeding, and its occupancy is increased at enhancers of genes linked to fatty acid and lipoprotein metabolism. Knocking out GATA4 in adult liver (Gata4LKO) decreased transcriptional activity at GATA4 binding sites especially during feeding. Gata4LKO mice have reduced plasma HDL cholesterol and increased liver triglyceride levels. The expression of a panel of genes involved in cholesterol export and triglyceride hydrolysis was downregulated and the expression of those involved in lipid uptake were upregulated in Gata4LKO liver, We further demonstrate that GATA4 collaborates with LXR liver. GATA4 shares a number of binding sites and direct transcriptional targets with LXRs, and loss of GATA4 impairs the hepatic transcriptional response to LXR agonist. Collectively, these results show that hepatic GATA4 contributes to the transcriptional control of hepatic and systemic lipid homeostasis.

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