Flavin containing monooxygenase 3 exerts broad effects on glucose and lipid metabolism and atherosclerosis

Shih, Diana M.; Wang, Zeneng; Lee, Richard; Meng, Yan; Che, Nam; Charugundla, Sarada; Qi, Hannah; Wu, Junzhou; Pan, Calvin; Brown, J. Mark; Vallim, Thomas Q. de Aguiar; Bennett, Brian J.; Graham, Mark; Hazen, Stanley L.; Lusis, Aldons J.

doi:10.1194/jlr.m051680

Cited by 278 publications

(246 citation statements)

References 46 publications

(48 reference statements)

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“…However, their prognostic values were restricted only to those with concomitant increased levels of TMAO, consistent with this gut microbe metabolite being the proximate and mechanistically linked metabolite in the pathway 4. In several recent studies genetically repressing hepatic flavin monooxygenase 3 expression, the host enzyme primarily responsible for converting gut microbe–generated TMA into TMAO, choline diet–enhanced atherosclerosis was inhibited, further implicating the TMAO pathway in atherosclerosis development 18, 19. These and other studies have also implicated FMO3 as an important regulator of body cholesterol and bile acid metabolism, suggesting mechanistic links between the gut microbe–TMAO pathway and atherosclerosis pathogenesis 18, 19, 20.…”

Section: Discussionmentioning

confidence: 82%

“…In several recent studies genetically repressing hepatic flavin monooxygenase 3 expression, the host enzyme primarily responsible for converting gut microbe–generated TMA into TMAO, choline diet–enhanced atherosclerosis was inhibited, further implicating the TMAO pathway in atherosclerosis development 18, 19. These and other studies have also implicated FMO3 as an important regulator of body cholesterol and bile acid metabolism, suggesting mechanistic links between the gut microbe–TMAO pathway and atherosclerosis pathogenesis 18, 19, 20. Interestingly, TMAO can promote atherosclerosis by inhibiting reverse cholesterol transport and enhanced macrophage foam cell formation in both the artery wall and peritoneal cavity, as well as promoting aortic root atherosclerotic plaque development 1, 2.…”

Section: Discussionmentioning

confidence: 95%

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Trimethylamine N ‐Oxide and Mortality Risk in Patients With Peripheral Artery Disease

Senthong

Wang

Fan

et al. 2016

JAHA

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144

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BackgroundProduction of the proatherogenic metabolite, trimethylamine N‐oxide (TMAO), from dietary nutrients by intestinal microbiota enhances atherosclerosis development in animal models and is associated with atherosclerotic coronary artery disease in humans. The utility of studying plasma levels of TMAO to risk stratify in patients with peripheral artery disease (PAD) has not been reported.Methods and ResultsWe examined the relationship between fasting plasma TMAO and all‐cause mortality (5‐year), stratified by subtypes of PAD and presence of coronary artery disease in 935 patients with PAD who underwent elective angiography for cardiac evaluation at a tertiary care hospital. Median plasma TMAO was 4.8 μmol/L (interquartile range, 2.9–8.0 μmol/L). Elevated TMAO levels were associated with 2.7‐fold increased mortality risk (fourth versus first quartiles, hazard ratio 2.86, 95% CI 1.82–3.97, P<0.001). Following adjustments for traditional risk factors, inflammatory biomarkers, and history of coronary artery disease, the highest TMAO quartile remained predictive of 5‐year mortality (adjusted hazard ratio 2.06, 95% CI 1.36–3.11, P<0.001). Similar prognostic value for elevated TMAO was seen for subjects with carotid artery, non–carotid artery, or lower extremity PAD. TMAO provided incremental prognostic value for all‐cause mortality (net reclassification index, 40.22%; P<0.001) and improvement in area under receiver operator characteristic curve (65.7% versus 69.4%; P=0.013).Conclusions TMAO, a pro‐atherogenic metabolite formed by gut microbes, predicts long‐term adverse event risk and incremental prognostic value in patients with PAD. These findings point to the potential for TMAO to help improve selection of high‐risk PAD patients with or without significant coronary artery disease, who likely need more aggressive and specific dietary and pharmacologic therapy.

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Section: Discussionmentioning

confidence: 82%

Section: Discussionmentioning

confidence: 95%

Trimethylamine N ‐Oxide and Mortality Risk in Patients With Peripheral Artery Disease

Senthong

Wang

Fan

et al. 2016

JAHA

Self Cite

144

110

View full text Add to dashboard Cite

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“…However, beginning in 2011, investigators in the Cleveland Clinic and other venues published a series of groundbreaking papers suggesting TMAO formed from dietary TMA-containing nutrients, especially animal products, might, in fact, be the "toxic" metabolite, a prime cause of atherosclerosis (Wang et al, 2011;Koeth et al, 2013;Tang et al, 2013;Jonsson and Bäckhed, 2015;Shih et al, 2015;Troseid et al, 2015;Wang et al, 2015;Warrier et al, 2015). Basically, what these investigators have shown is that the TMA covalently incorporated in lecithin, choline, betaine, or carnitine can be metabolized in gut by bacterial lyases to release TMA, a gas.…”

Section: New Informationmentioning

confidence: 99%

New Insight into the Dietary Cause of Atherosclerosis: Implications for Pharmacology

Spector¹

2016

Journal of Pharmacology and Experimental Therapeutics

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At present, the guideline approach to the medical treatment and prevention of atherosclerotic cardiovascular disease (ASCVD) is to classify patients by risk and treat the known risk factors (contributory causes), e.g., hypertension, diabetes, obesity, smoking, and poor diet, as appropriate. All high-risk patients should receive statins. This approach has had substantial success but ASCVD still remains the number one cause of death in the United States. Until recently, the underlying cause of ASCVD remained unknown, although a potential dietary cause was suggested by the fact that vegetarians, especially vegans, have a much lower incidence of ASCVD than animal flesh eaters. Recently, consistent with the vegetarian data, substantial evidence for a cause of ASCVD in animals and humans has been discovered. Trimethylamine (TMA)-containing dietary compounds in meat, milk, and other animal foods (e.g., lecithin, choline, and carnitine) are converted by closely related gut bacterial TMA lyases to TMA, which is absorbed and converted predominantly by flavin mono-oxygenase 3 to the toxic trimethylamine N-oxide (TMAO). TMAO causes atherosclerosis in animals and is elevated in patients with coronary heart disease. Inhibition of bacterial lyases in mice prevents TMA and secondarily TMAO formation and atherosclerosis, strong evidence for the TMAO hypothesis. At present, the challenge for the pharmaceutical industry is to discover and develop a potent "broad spectrum" bacterial lyase inhibitor that, along with diet and exercise, could, if the TMAO hypothesis is correct, revolutionize the preventive treatment of ASCVD.

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“…257 TMAO is formed from trimethylamine via hepatic flavin mono-oxygenase 3. 258 Mechanistic studies in mice have identified that modulation of flavin mono-oxygenase 3 levels affect TMAO levels and glucose and lipid metabolism, 259,260 further complicating the identification of the precise mechanism by which TMAO affects CVD. The microbiome plays an obligate role in the formation of trimethylamine (from the trimethylamine-containing nutrients choline and carnitine), and antibiotic knockdown studies clearly show that TMAO is not formed in the absence of the microbiome.…”

Section: Effect Of Dietmentioning

confidence: 99%

Nutrigenomics, the Microbiome, and Gene-Environment Interactions: New Directions in Cardiovascular Disease Research, Prevention, and Treatment

Ferguson¹,

Allayee²,

Gerszten³

et al. 2016

Circ Cardiovasc Genet

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101

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Abstract-Cardiometabolic diseases are the leading cause of death worldwide and are strongly linked to both genetic and nutritional factors. The field of nutrigenomics encompasses multiple approaches aimed at understanding the effects of diet on health or disease development, including nutrigenetic studies investigating the relationship between genetic variants and diet in modulating cardiometabolic risk, as well as the effects of dietary components on multiple "omic" measures, including transcriptomics, metabolomics, proteomics, lipidomics, epigenetic modifications, and the microbiome. Here, we describe the current state of the field of nutrigenomics with respect to cardiometabolic disease research and outline a direction for the integration of multiple omics techniques in future nutrigenomic studies aimed at understanding mechanisms and developing new therapeutic options for cardiometabolic disease treatment and prevention. The interpretation and scope of nutrigenomics may vary, but it can be thought to encompass the spectrum of nutritional genomics research, including classic nutrigenetics studies of gene-diet interactions and molecular nutrition, in vitro and in vivo models, human nutrition studies, and the application of largescale, unbiased studies using high-throughput "omics" techniques to study the effects of nutrients on the body. 6 As the Figure shows, diet and the genome may influence cardiometabolic health through a variety of interconnected intermediates, perturbations in which can be measured through omics technologies, including RNA expression (transcriptome), epigenetic modifications (epigenome), metabolites (metabolome), lipids (lipidome), proteins (proteome), and resident microbial communities (microbiome). Although it is clear that both nutrients and genes play a distinct role in determining health, the complex interactions among genes, diet, and downstream networks are not well understood. The application of nutrigenomics approaches to questions of human health and disease is an important component in understanding the complexities of the interplay between basic metabolic processes and externalThe American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on January 22, 2016, and the American Heart Association Executive Committee on February 23, 2016. A copy of the document is available at http://professional.heart.org/statements by using either "Search for Guidelines & Statements" or the "Browse by Topic" area. To purchase additional reprints, call 843-216-2533 or e-mail kelle.ramsay@ wolterskluwer.com.The...

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Flavin containing monooxygenase 3 exerts broad effects on glucose and lipid metabolism and atherosclerosis

Cited by 278 publications

References 46 publications

Trimethylamine N ‐Oxide and Mortality Risk in Patients With Peripheral Artery Disease

Trimethylamine N ‐Oxide and Mortality Risk in Patients With Peripheral Artery Disease

New Insight into the Dietary Cause of Atherosclerosis: Implications for Pharmacology

Nutrigenomics, the Microbiome, and Gene-Environment Interactions: New Directions in Cardiovascular Disease Research, Prevention, and Treatment

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