Summary of Study ST002163

This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001376. The data can be accessed directly via it's Project DOI: 10.21228/M8VH8V This work is supported by NIH grant, U2C- DK119886.

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This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

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Study IDST002163
Study TitleRemote solid cancers rewire hepatic nitrogen metabolism via host nicotinamide-N-methyltransferase
Study SummaryCancers disrupt host homeostasis in various manners but the identity of host factors underlying such disruption remains largely unknown. Here we show that nicotinamide-N-methyltransferase (NNMT) is a novel host factor that mediates metabolic dysfunction in the livers of cancer-bearing mice. Multiple solid cancers distantly increase expression of Nnmt and its product 1-methylnicotinamide (MNAM) in the liver. Multi-omics analyses reveal suppression of the urea cycle accompanied by accumulation of amino acids, and enhancement of uracil biogenesis in the livers of cancer-bearing mice. Importantly, genetic deletion of Nnmt leads to alleviation of these metabolic abnormalities, and buffers cancer-dependent weight loss and reduction of the voluntary wheel-running activity. Our data also demonstrate that MNAM is capable of affecting urea cycle metabolites in the liver. These results suggest that cancers up-regulate the hepatic NNMT pathway to rewire liver metabolism towards uracil biogenesis rather than nitrogen disposal via the urea cycle, thereby disrupting host homeostasis. Anionic polar metabolites (i.e., organic acids, sugar phosphates, nucleotides,etc.) were analyzed via IC/HR/MS/MS. Cationic polar metabolites (i.e., amino acids, bases, nucleosides, NAM, SAM, MNAM, SAH, me2PY, me4PY, etc) were analyzed via PFPP-LC/HR/MS/MS.
Institute
Tohoku University
Last NameKawaoka
First NameShinpei
Address4-1, Seiryou-machi, Aoba-ku, Sendai
Emailkawaokashinpei@gmail.com
Phone0227178443
Submit Date2022-05-11
Raw Data AvailableYes
Raw Data File Type(s)mzXML
Analysis Type DetailLC-MS
Release Date2022-05-27
Release Version1
Shinpei Kawaoka Shinpei Kawaoka
https://dx.doi.org/10.21228/M8VH8V
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

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Project:

Project ID:PR001376
Project DOI:doi: 10.21228/M8VH8V
Project Title:Remote solid cancers rewire hepatic nitrogen metabolism via host nicotinamide-N-methyltransferase
Project Summary:Cancers disrupt host homeostasis in various manners but the identity of host factors underlying such disruption remains largely unknown. Here we show that nicotinamide-N-methyltransferase (NNMT) is a novel host factor that mediates metabolic dysfunction in the livers of cancer-bearing mice. Multiple solid cancers distantly increase expression of Nnmt and its product 1-methylnicotinamide (MNAM) in the liver. Multi-omics analyses reveal suppression of the urea cycle accompanied by accumulation of amino acids, and enhancement of uracil biogenesis in the livers of cancer-bearing mice. Importantly, genetic deletion of Nnmt leads to alleviation of these metabolic abnormalities, and buffers cancer-dependent weight loss and reduction of the voluntary wheel-running activity. Our data also demonstrate that MNAM is capable of affecting urea cycle metabolites in the liver. These results suggest that cancers up-regulate the hepatic NNMT pathway to rewire liver metabolism towards uracil biogenesis rather than nitrogen disposal via the urea cycle, thereby disrupting host homeostasis.
Institute:Tohoku University
Last Name:Kawaoka
First Name:Shinpei
Address:4-1 Seiryo-cho, Sendai, Miyagi, 9808575, Japan
Email:kawaokashinpei@gmail.com
Phone:0227178568

Subject:

Subject ID:SU002249
Subject Type:Mammal
Subject Species:Mus musculus
Taxonomy ID:10090

Factors:

Subject type: Mammal; Subject species: Mus musculus (Factor headings shown in green)

mb_sample_id local_sample_id Genotype Sample group Sex Treatment
SA207523L14NNMT KO 4T1 female No treatment
SA207524L15NNMT KO 4T1 female No treatment
SA207525L51NNMT KO 4T1 female No treatment
SA207526L13NNMT KO 4T1 female No treatment
SA207527L16NNMT KO 4T1 female No treatment
SA207528L11NNMT KO Sham female No treatment
SA207529L12NNMT KO Sham female No treatment
SA207530L52NNMT KO Sham female No treatment
SA207531L10NNMT KO Sham female No treatment
SA207532L9NNMT KO Sham female No treatment
SA207533L13_MNAMWT 4T1 female MNAM treatment
SA207534L14_MNAMWT 4T1 female MNAM treatment
SA207535L15_MNAMWT 4T1 female MNAM treatment
SA207536L16_MNAMWT 4T1 female MNAM treatment
SA207537L17_MNAMWT 4T1 female MNAM treatment
SA207538L12_MNAMWT 4T1 female No treatment
SA207539L9_MNAMWT 4T1 female No treatment
SA207540L10_MNAMWT 4T1 female No treatment
SA207541L6WT 4T1 female No treatment
SA207542L7WT 4T1 female No treatment
SA207543L8WT 4T1 female No treatment
SA207544L5WT 4T1 female No treatment
SA207545L50WT 4T1 female No treatment
SA207546L11_MNAMWT 4T1 female No treatment
SA207547L8_MNAMWT Sham female MNAM treatment
SA207548L6_MNAMWT Sham female MNAM treatment
SA207549L7_MNAMWT Sham female MNAM treatment
SA207550L5_MNAMWT Sham female MNAM treatment
SA207551L2WT Sham female No treatment
SA207552L2_MNAMWT Sham female No treatment
SA207553L4WT Sham female No treatment
SA207554L49WT Sham female No treatment
SA207555L1WT Sham female No treatment
SA207556L3WT Sham female No treatment
SA207557L3_MNAMWT Sham female No treatment
SA207558L1_MNAMWT Sham female No treatment
SA207559L4_MNAMWT Sham female No treatment
Showing results 1 to 37 of 37

Collection:

Collection ID:CO002242
Collection Summary:Mouse livers were crushed in liquid-nitrogen and homogenized.
Sample Type:Liver

Treatment:

Treatment ID:TR002261
Treatment Summary:Daily 250 mg/kg MNAM injection for 12 days in the absence (sham) and presence (4T1cancers).

Sample Preparation:

Sampleprep ID:SP002255
Sampleprep Summary:Metabolites were extracted from the frozen livers (approximately 5 mg) using the Bligh and Dyer’s method with some modifications. Briefly, each sample was mixed with 1 mL of cold methanol containing 10-camphorsulfonic acid (1.5 nmol) and piperazine-1,4-bis (2-ethanesulfonic acid) (PIPES, 1.5 nmol) as internal standards for mass spectrometry-based metabolomic analysis. The samples were vigorously mixed by vortexing for 1 min followed by 5 min of sonication. The extracts were then centrifuged at 16,000 × g for 5 min at 4 °C, and the resultant supernatant (400 uL) was collected. After mixing 400 uL of supernatant with 400 uL of chloroform and 320 uL of water, the aqueous and organic layers were separated by vortexing and subsequent centrifugation at 16,000 × g and 4 °C for 5 min. The aqueous (upper) layer (500 uL) was transferred into a clean tube. After the aqueous layer extracts were evaporated under vacuum, the dried extracts were stored at −80 °C until the analysis of hydrophilic metabolites. Prior to analysis, the dried aqueous layer was reconstituted in 50 uL of water.

Combined analysis:

Analysis ID AN003544 AN003545
Analysis type MS MS
Chromatography type Ion exchange Reversed phase
Chromatography system Dionex ICS-5000+ HPIC system Shimadzu Nexera X2
Column Dionex IonPac AS11-HC (2 um i.d. × 250 mm, 4 um particle size) Discovery HS (2.1 mm i.d. × 150 mm, 3 um particle size, Merck)
MS Type ESI ESI
MS instrument type Orbitrap Orbitrap
MS instrument name Thermo Q Exactive Orbitrap Thermo Q Exactive Orbitrap
Ion Mode NEGATIVE POSITIVE
Units peak area peak area

Chromatography:

Chromatography ID:CH002618
Chromatography Summary:Anionic polar metabolites (i.e., organic acids, sugar phosphates, nucleotides, etc.) were analyzed via IC/HRMS/MS.
Instrument Name:Dionex ICS-5000+ HPIC system
Column Name:Dionex IonPac AS11-HC (2 um i.d. × 250 mm, 4 um particle size)
Chromatography Type:Ion exchange
  
Chromatography ID:CH002619
Chromatography Summary:Cationic polar metabolites (i.e., amino acids, bases, nucleosides, NAM, SAM, MNAM, SAH, me2PY, me4PY, etc) were analyzed via PFPP-LC/HRMS/MS.
Instrument Name:Shimadzu Nexera X2
Column Name:Discovery HS (2.1 mm i.d. × 150 mm, 3 um particle size, Merck)
Chromatography Type:Reversed phase

MS:

MS ID:MS003302
Analysis ID:AN003544
Instrument Name:Thermo Q Exactive Orbitrap
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:-
Ion Mode:NEGATIVE
  
MS ID:MS003303
Analysis ID:AN003545
Instrument Name:Thermo Q Exactive Orbitrap
Instrument Type:Orbitrap
MS Type:ESI
MS Comments:-
Ion Mode:POSITIVE
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