Metabolic Biomarkers of Ageing in C57BL/6J Wild-Type and Flavin-Containing Monooxygenase 5 (FMO5)-Knockout Mice

Varshavi, Dorsa; Scott, Fiona; Varshavi, Dorna; Veeravalli, Sunil; Phillips, Ian; Veselkov, Kirill; Strittmatter, Nicole; Takáts, Zoltán; Shephard, Elizabeth A.; Everett, Jeremy R.

doi:10.3389/fmolb.2018.00028

Cited by 17 publications

(20 citation statements)

References 59 publications

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“…Pattern recognition analyses were performed as described previously (Varshavi et al 2018). Initially, NMR spectral data were subjected to principal component analysis (PCA) to visualize the general structure of each data set and to identify sub-groups and any potential outliers within the data.…”

Section: Pattern Recognition and Multivariate Data Analysismentioning

confidence: 99%

Metabolic characterization of colorectal cancer cells harbouring different KRAS mutations in codon 12, 13, 61 and 146 using human SW48 isogenic cell lines

Varshavi

McCarthy

et al. 2020

Metabolomics

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Introduction Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) mutations occur in approximately one-third of colorectal (CRC) tumours and have been associated with poor prognosis and resistance to some therapeutics. In addition to the well-documented pro-tumorigenic role of mutant Ras alleles, there is some evidence suggesting that not all KRAS mutations are equal and the position and type of amino acid substitutions regulate biochemical activity and transforming capacity of KRAS mutations. Objectives To investigate the metabolic signatures associated with different KRAS mutations in codons 12, 13, 61 and 146 and to determine what metabolic pathways are affected by different KRAS mutations. Methods We applied an NMR-based metabonomics approach to compare the metabolic profiles of the intracellular extracts and the extracellular media from isogenic human SW48 CRC cell lines with different KRAS mutations in codons 12 (G12D, G12A, G12C, G12S, G12R, G12V), 13 (G13D), 61 (Q61H) and 146 (A146T) with their wild-type counterpart. We used false discovery rate (FDR)-corrected analysis of variance (ANOVA) to determine metabolites that were statistically significantly different in concentration between the different mutants. Results CRC cells carrying distinct KRAS mutations exhibited differential metabolic remodelling, including differences in glycolysis, glutamine utilization and in amino acid, nucleotide and hexosamine metabolism. Conclusions Metabolic differences among different KRAS mutations might play a role in their different responses to anticancer treatments and hence could be exploited as novel metabolic vulnerabilities to develop more effective therapies against oncogenic KRAS.

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Section: Pattern Recognition and Multivariate Data Analysismentioning

confidence: 99%

Metabolic characterization of colorectal cancer cells harbouring different KRAS mutations in codon 12, 13, 61 and 146 using human SW48 isogenic cell lines

Varshavi

McCarthy

et al. 2020

Metabolomics

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“…Flavin-containing monooxygenases (FMOs) catalyze the ingredients of medicine and diet and have a unique catalytic mechanism [ 11 , 12 ]. Flavin-containing monooxygenase 5 (Fmo5) is a member of the FMOs family, and its expression in the liver tissue of aging mice is lower than that in normal mice [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

Alcoholic fatty liver disease inhibited the co-expression of Fmo5 and PPARα to activate the NF-κB signaling pathway, thereby reducing liver injury via inducing gut microbiota disturbance

Kong

Chen

et al. 2021

J Exp Clin Cancer Res

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Background Alcohol-induced intestinal dysbiosis disrupts and inflammatory responses are essential in the development of alcoholic fatty liver disease (AFLD). Here, we investigated the effects of Fmo5 on changes in enteric microbiome composition in a model of AFLD and dissected the pathogenic role of Fmo5 in AFLD-induced liver pathology. Methods The expression profile data of GSE8006 and GSE40334 datasets were downloaded from the GEO database. The WGCNA approach allowed us to investigate the AFLD-correlated module. DEGs were used to perform KEGG pathway enrichment analyses. Four PPI networks were constructed using the STRING database and visualized using Cytoscape software. The Cytohubba plug-in was used to identify the hub genes. Western blot and immunohistochemistry assays were used to detect protein expression. ELISA assay was used to detect the levels of serum inflammatory cytokines. Lipid droplets in the cytoplasm were observed using Oil Red O staining. Apoptosis was detected using a TUNEL assay and flow cytometry analysis. ROS levels were detected using flow cytometry analysis. Nuclear translocation of NF-κB p65 was observed using immunofluorescence staining. Co-immunoprecipitation was used to detect the co-expression of PPARα and Fmo5 in L02 cells. 16S rDNA sequencing defined the bacterial communities in mice with AFLD. Results Fmo5 is a key DEG and is closely associated with the gut microbiota and PPAR signaling pathway. Gut microbiome function in AFLD was significantly related to the PPAR signaling pathway. AFLD induced shifts in various bacterial phyla in the cecum, including a reduction in Bacteroidetes and increased Firmicutes. Fmo5 and PPARα co-expression in cell and animal models with AFLD, which decreased significantly. Silencing of Fmo5 and PPARα aggravated the functions of AFLD inducing apoptosis and inflammatory response, promoting liver injury, and activating the NF-κB signaling pathway in vivo and in vitro. The NF-κB inhibitor abolished the functions of silencing of Fmo5 and PPARα promoting AFLD-induced apoptosis, inflammatory response, and liver injury. Conclusion Our data indicated that the co-expression of Fmo5 and PPARα was involved in AFLD-related gut microbiota composition and alleviated AFLD-induced liver injury, apoptosis, and inflammatory response by inhibiting the nuclear translocation of NF-κB p65 to inhibit the NF-κB signaling pathway.

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“…Mice were genotyped as described (37). Mice were given free access to food (a standard Sample preparation for NMR spectroscopy: Urine samples (50 µl) were prepared for NMR spectroscopy as described previously (39). Enzyme assay samples were thawed, vortexed, then 160 µl of sample was mixed with 80 µl of 0.6 M phosphate buffer, as described previously (39).…”

Section: Methodsmentioning

confidence: 99%

“…Mice were given free access to food (a standard Sample preparation for NMR spectroscopy: Urine samples (50 µl) were prepared for NMR spectroscopy as described previously (39). Enzyme assay samples were thawed, vortexed, then 160 µl of sample was mixed with 80 µl of 0.6 M phosphate buffer, as described previously (39). The samples were re-vortexed and centrifuged at 13 000 g for 5 min at 4 0 C. Supernatant (200 µl) was then pipetted into 3.0-mm outer diameter (o.d.)…”

Section: Methodsmentioning

confidence: 99%

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FMO1 catalyzes the production of taurine from hypotaurine

Shephard

Veeravalli

Phillips

et al. 2019

Preprint

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Taurine is one of the most abundant amino acids in mammalian tissues. It is obtained from the diet and by de novo synthesis, from cysteic acid or hypotaurine. Despite the discovery in 1954 that the oxygenation of hypotaurine produces taurine, the identification of an enzyme catalyzing this reaction has remained elusive. In large part this is due to the incorrect assignment, in 1962, of the enzyme as a NAD-dependent hypotaurine dehydrogenase. For more than 55 years the literature has continued to refer to this enzyme as such. Here we show, both in vivo and in vitro, that the enzyme that oxygenates hypotaurine to produce taurine is flavin-containing monooxygenase 1 (FMO1). Metabolite analysis of the urine of Fmo1-null mice by 1 H NMR spectroscopy revealed a build-up of hypotaurine and a deficit of taurine in comparison with the concentrations of these compounds in the urine of wild-type mice. In vitro assays confirmed that FMO1 of human catalyzes the conversion of hypotaurine to taurine utilizing either NADPH or NADH as co-factor. FMO1 has a wide substrate range and is best known as a xenobiotic-or drug-metabolizing enzyme. The identification that the endogenous molecule hypotaurine is a substrate for the FMO1catalyzed production of taurine resolves a long-standing mystery. This finding should help establish the role FMO1 plays in a range of biological processes in which taurine or its deficiency is implicated, including conjugation of bile acids, neurotransmitter, anti-oxidant and anti-inflammatory functions, the pathogenesis of obesity and skeletal muscle disorders.

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Metabolic Biomarkers of Ageing in C57BL/6J Wild-Type and Flavin-Containing Monooxygenase 5 (FMO5)-Knockout Mice

Cited by 17 publications

References 59 publications

Metabolic characterization of colorectal cancer cells harbouring different KRAS mutations in codon 12, 13, 61 and 146 using human SW48 isogenic cell lines

Metabolic characterization of colorectal cancer cells harbouring different KRAS mutations in codon 12, 13, 61 and 146 using human SW48 isogenic cell lines

Alcoholic fatty liver disease inhibited the co-expression of Fmo5 and PPARα to activate the NF-κB signaling pathway, thereby reducing liver injury via inducing gut microbiota disturbance

FMO1 catalyzes the production of taurine from hypotaurine

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