Regulation of flavin-containing mono-oxygenase (<i>Fmo3</i>) gene expression by steroids in mice and humans

Esposito, Teresa; Varriale, Bruno; D’Angelo, Rosalia; Amato, Aldo; Sidoti, Antonina

doi:10.1515/hmbci-2014-0012

Cited by 31 publications

(25 citation statements)

References 47 publications

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“…Comparing male mice with intact testes to male mice that have been gonadectomized demonstrates that both hepatic FMO3 expression and TMAO generation are repressed by testosterone, while parallel studies in female mice demonstrate a positive correlation between estrogen and FMO3 gene expression. Furthermore, an estrogen receptor α binding site has been identified in the promoter region of FMO3 in both mouse and human samples [35]. Of note, the incidence of trimethylaminuria reported is higher among females, with patients reporting a worsening of symptoms occurring during menstruation [36].…”

Section: Flavin Monooxygenasesmentioning

confidence: 99%

Emerging roles of flavin monooxygenase 3 in cholesterol metabolism and atherosclerosis

Schugar

Brown

2015

Current Opinion in Lipidology

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Purpose of Review Atherosclerosis and associated cardiovascular disease (CVD) still remain the largest cause of mortality worldwide. Several recent studies have discovered that metabolism of common nutrients by gut microbes can produce a proatherogenic metabolite called trimethylamine-N-oxide (TMAO). The goal of this review is to discuss emerging evidence that the hepatic enzyme that generates TMAO, flavin monooxygenase 3 (FMO3), plays a regulatory role in maintaining whole body cholesterol balance and atherosclerosis development. Recent Findings Several independent studies have recently uncovered a link between either FMO3 itself or its enzymatic product TMAO with atherosclerosis and hepatic insulin resistance. These recent studies show that inhibition of FMO3 stimulates macrophage reverse cholesterol transport (RCT) and protects against atherosclerosis in mice. Summary A growing body of work demonstrates that nutrients present in high fat foods (phosphatidylcholine, choline, and L-carnitine) can be metabolized by the gut microbial enzymes to generate trimethylamine (TMA), which is then further metabolized by the host enzyme FMO3 to produce proatherogenic TMAO. Here we discuss emerging evidence that the TMAO producing enzyme FMO3 is centrally involved in the pathogenesis of atherosclerosis by regulating cholesterol metabolism and insulin resistance, and how these new insights provide exciting new avenues for CVD therapies.

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Section: Flavin Monooxygenasesmentioning

confidence: 99%

Emerging roles of flavin monooxygenase 3 in cholesterol metabolism and atherosclerosis

Schugar

Brown

2015

Current Opinion in Lipidology

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“…TMA metabolism is regulated by a combination of genetic, dietary and hormonal factors, the complexity of which may obscure the interpretation of the precise roles of this pathway 14,15. For example, in humans, more than 30 FMO3 genetic variants have been reported to impair N -oxygenation of TMA and contribute to the fish odor syndrome phenotype 16.…”

Section: Introductionmentioning

confidence: 99%

Genetic Variant in Flavin-Containing Monooxygenase 3 Alters Lipid Metabolism in Laying Hens in a Diet-Specific Manner

Wang¹,

Lü²,

Zhang³

et al. 2016

Int. J. Biol. Sci.

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Genetic variant T329S in flavin-containing monooxygenase 3 (FMO3) impairs trimethylamine (TMA) metabolism in birds. The TMA metabolism that under complex genetic and dietary regulation, closely linked to cardiovascular disease risk. We determined whether the genetic defects in TMA metabolism may change other metabolic traits in birds, determined whether the genetic effects depend on diets, and to identify genes or gene pathways that underlie the metabolic alteration induced by genetic and diet factors. We used hens genotyped as FMO3 c.984 A>T as well as those with the homozygous normal genotype. For each genotype, hens were provided with either a corn-soybean meal basal diets (SM), which contains lower levels of TMA precursor, or the basal diets supplemented with 21% of rapeseed meal (RM), which contains higher levels of TMA precursor. An integrative analysis of metabolomic and transcriptomic was used to explore the metabolic patterns of FMO3 genetic variant in hens that were fed the two defined diets. In birds that consumed SM diets, the T329S mutation increased levels of plasma TMA and lipids, FMO3 mRNA levels, and the expression of genes involved in long chain polyunsaturated fatty acid biosynthesis. In birds that consumed RM diets, the T329S mutation induced fishy odor syndrome, a repression in LXR pathway and a reciprocal change in lipid metabolism. Variations in TMA and lipid metabolism were linked to the genetic variant in FMO3 in a diet-specific manner, which suggest FMO3 functions in TMA metabolism and lipid homeostasis. LXR pathway and polyunsaturated fatty acid metabolism are two possible mechanisms of FMO3 action in response to dietary TMA precursor.

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“…Koukouritaki and others () determined that different haplotypes upstream of FMO3 significantly alter the promoter activity. In addition, FMO3 expression is regulated by steroids in humans and mice (Esposito and others ).…”

Section: Resultsmentioning

confidence: 99%

Fishy Odor and TMA Content Levels in Duck Egg Yolks

Yuan

Xia

et al. 2017

Journal of Food Science

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The differences between the trimethylamine (TMA) content levels in duck and chicken egg yolks under normal dietary conditions were compared. Moreover, the association between the polymorphisms of the duck FMO3 gene and TMA content levels in duck egg yolks was analyzed. Then, to detect the mutations associated with the fish-flavor trait, duck populations were selected for a high-choline diet experiment, which was followed by full-length sequencing of the FMO3 exons. The results showed that the TMA content levels in duck eggs (3.60 μg/g) were significantly higher than those in chicken eggs (2.35 μg/g) under normal dietary conditions (P < 0.01). With regard to the high-choline diet, the average TMA content levels in duck egg yolks (9.21 μg/g; P < 0.01) increased significantly. Furthermore, 5 SNPs reported in Ensembl database were detected in duck FMO3 exons. However, no mutation loci were found to be significantly associated with the TMA content levels in duck egg yolks. Besides, duck liver FMO3 mRNA expression levels were not associated with the TMA content levels. The results indicated that excessive TMA deposition in duck eggs is one of main factors causing the fishy odor in duck eggs, and the addition of choline in the ducks' diets was responsible for inducing an increase in the TMA content levels in duck eggs.

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Regulation of flavin-containing mono-oxygenase (Fmo3) gene expression by steroids in mice and humans

Cited by 31 publications

References 47 publications

Emerging roles of flavin monooxygenase 3 in cholesterol metabolism and atherosclerosis

Emerging roles of flavin monooxygenase 3 in cholesterol metabolism and atherosclerosis

Genetic Variant in Flavin-Containing Monooxygenase 3 Alters Lipid Metabolism in Laying Hens in a Diet-Specific Manner

Fishy Odor and TMA Content Levels in Duck Egg Yolks

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