Summary of Study ST003595

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 PR002223. The data can be accessed directly via it's Project DOI: 10.21228/M88R7M This work is supported by NIH grant, U2C- DK119886.

See: https://www.metabolomicsworkbench.org/about/howtocite.php

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 IDST003595
Study TitleTrifluoroacetate reduces plasma lipid levels and the development of atherosclerosis in mice
Study SummaryTrifluoroacetate (TFA) has been assumed to be an innocuous counterion (to cationic amino acid side chains) present in countless synthetic bioactive peptides and a few FDA-approved therapeutics. We show here that TFA is in fact bioactive and causes dramatic biological effects in multiple strains of mice and cultured human and rat liver cells. In high-fat diet (HFD)-fed low-density lipoprotein receptor-null (LDLr-/-) mice, TFA reduces the levels of plasma cholesterol, triglycerides, and the development of atherosclerotic lesions following either oral or intraperitoneal administration. These physiological effects were observed with TFA alone, or with TFA present as a counterion of a variety of short, unrelated synthetic peptide sequences. Mechanistic investigations including RNA-seq, confocal microscopy, western blotting, metabolomics, proteomics, pharmacokinetics, and biochemical assays indicated that TFA induces peroxisome proliferation by activating peroxisome proliferator-activated receptor (PPAR)-alpha. We confirmed that TFA also caused peroxisome proliferation and downstream phenotypic effects in cultured human and rat liver cells, wild-type C57/Bl mice, and apolipoprotein E-null (apoE-/-) mice, leading to anti-atherosclerotic effects in the latter strain. Given that TFA is a counterion in many peptides employed in early research and development settings, these findings raise the possibility that TFA may be confounding or contributing to phenotypic changes observed in many studies involving peptides. Although our studies suggest that TFA or its analogues might have therapeutic applications, it should be noted that TFA is also a persistent environmental contaminant that is found at high levels in humans relative to other polyfluoroalkyl substances (PFAS), and is a major metabolite following treatment of patients with common inhaled anesthetics, suggesting that the biological effects reported here could have other implications for human health.
Institute
Scripps Research
Last NameTang
First NameWei
Address10550 North Torrey Pines Road, La Jolla, California, 92037, USA
Emailwtang@scripps.edu
Phone858-784-2711
Submit Date2024-10-26
Raw Data AvailableYes
Raw Data File Type(s)d
Analysis Type DetailLC-MS
Release Date2024-12-18
Release Version1
Wei Tang Wei Tang
https://dx.doi.org/10.21228/M88R7M
ftp://www.metabolomicsworkbench.org/Studies/ application/zip

Select appropriate tab below to view additional metadata details:


Project:

Project ID:PR002223
Project DOI:doi: 10.21228/M88R7M
Project Title:Trifluoroacetate reduces plasma lipid levels and the development of atherosclerosis in mice
Project Summary:Trifluoroacetate (TFA) has been assumed to be an innocuous counterion (to cationic amino acid side chains) present in countless synthetic bioactive peptides and a few FDA-approved therapeutics. We show here that TFA is in fact bioactive and causes dramatic biological effects in multiple strains of mice and cultured human and rat liver cells. In high-fat diet (HFD)-fed low-density lipoprotein receptor-null (LDLr-/-) mice, TFA reduces the levels of plasma cholesterol, triglycerides, and the development of atherosclerotic lesions following either oral or intraperitoneal administration. These physiological effects were observed with TFA alone, or with TFA present as a counterion of a variety of short, unrelated synthetic peptide sequences. Mechanistic investigations including RNA-seq, confocal microscopy, western blotting, metabolomics, proteomics, pharmacokinetics, and biochemical assays indicated that TFA induces peroxisome proliferation by activating peroxisome proliferator-activated receptor (PPAR)-alpha. We confirmed that TFA also caused peroxisome proliferation and downstream phenotypic effects in cultured human and rat liver cells, wild-type C57/Bl mice, and apolipoprotein E-null (apoE-/-) mice, leading to anti-atherosclerotic effects in the latter strain. Given that TFA is a counterion in many peptides employed in early research and development settings, these findings raise the possibility that TFA may be confounding or contributing to phenotypic changes observed in many studies involving peptides. Although our studies suggest that TFA or its analogues might have therapeutic applications, it should be noted that TFA is also a persistent environmental contaminant that is found at high levels in humans relative to other polyfluoroalkyl substances (PFAS), and is a major metabolite following treatment of patients with common inhaled anesthetics, suggesting that the biological effects reported here could have other implications for human health.
Institute:Scripps Research
Last Name:Tang
First Name:Wei
Address:10550 North Torrey Pines Road, La Jolla, California, 92037, USA
Email:wtang@scripps.edu
Phone:858-784-2711

Subject:

Subject ID:SU003724
Subject Type:Mammal
Subject Species:Mus musculus
Taxonomy ID:10090
Species Group:Mammals

Factors:

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

mb_sample_id local_sample_id Sample source Treatment
SA391885PBS8plasma Control
SA391886PBS2plasma Control
SA391887PBS10plasma Control
SA391888PBS9plasma Control
SA391889PBS1plasma Control
SA391890PBS7plasma Control
SA391891PBS6plasma Control
SA391892PBS5plasma Control
SA391893PBS4plasma Control
SA391894PBS3plasma Control
SA391895TFA2plasma TFA
SA391896TFA3plasma TFA
SA391897TFA4plasma TFA
SA391898TFA5plasma TFA
SA391899TFA6plasma TFA
SA391900TFA7plasma TFA
SA391901TFA8plasma TFA
SA391902TFA9plasma TFA
SA391903TFA10plasma TFA
SA391904TFA1plasma TFA
Showing results 1 to 20 of 20

Collection:

Collection ID:CO003717
Collection Summary:Blood was collected from female LDLr-/- mice treated by daily oral gavage for two weeks with a 200 µmol/kg TFA daily dose (n=10) or PBS vehicle (n=10). Samples were obtained by retro-orbital puncture using a heparinized capillary tube and then transferred to a K2EDTA collection tube. Plasma was immediately separated by centrifuging the blood at 5000 rpm for 10 minutes at 4°C.
Sample Type:Blood (plasma)

Treatment:

Treatment ID:TR003733
Treatment Summary:Female LDLr-/- mice were treated for two weeks with daily oral gavage of either 200 µmol/kg TFA (n=10) or a PBS vehicle (n=10).

Sample Preparation:

Sampleprep ID:SP003731
Sampleprep Summary:Plasma samples (100 µL) from female LDLr-/- mice treated by daily oral gavage for two weeks with a 200 µmol/kg TFA daily dose (n=10) or PBS vehicle (n=10) were extracted with cold MeOH (400 µL) and analyzed individually by reversed phase LC-MS, in both positive and negative mode.

Combined analysis:

Analysis ID AN005903 AN005904
Analysis type MS MS
Chromatography type Reversed phase Reversed phase
Chromatography system Agilent 1290 Infinity II Agilent 1290 Infinity II
Column Waters ACQUITY UPLC BEH C18 (100 x 1 mm , 1.7 um, 130A) Waters ACQUITY UPLC BEH C18 (100 x 1 mm , 1.7 um, 130A)
MS Type ESI ESI
MS instrument type QTOF QTOF
MS instrument name Bruker Impact II Bruker Impact II
Ion Mode POSITIVE NEGATIVE
Units intensity intensity

Chromatography:

Chromatography ID:CH004482
Instrument Name:Agilent 1290 Infinity II
Column Name:Waters ACQUITY UPLC BEH C18 (100 x 1 mm , 1.7 um, 130A)
Column Temperature:25
Flow Gradient:0-2min, 1%B; 2-12min, 1%-99%B; 12-15min, 99%B; 15-15.1min, 99%-1%B; 15.1-18min, 1%B
Flow Rate:0.15 mL/min
Solvent A:100% water; 0.1% formic acid
Solvent B:100% Acetonitrile; 0.1% formic acid
Chromatography Type:Reversed phase

MS:

MS ID:MS005621
Analysis ID:AN005903
Instrument Name:Bruker Impact II
Instrument Type:QTOF
MS Type:ESI
MS Comments:Untargeted metabolomics were performed on an Agilent Technologies 1290 Infinity II system with an Waters ACQUITY UPLC BEH C18 Column, 130A, 1.7 um, 1 mm X 100 mm, coupled online to a Bruker Impact II QTOF mass spectrometer with electrospray ionization (ESI) source. The source dry gas temperature was set to 200°C at a flow of 8 L/min. The capillary voltage was set to 4000 V for positive mode and 5000 V for negative mode and the nebulizer operated at 29 psi.
Ion Mode:POSITIVE
Capillary Voltage:4000 V
Dry Gas Flow:8 l/min
Dry Gas Temp:200
Nebulizer:29 psi
  
MS ID:MS005622
Analysis ID:AN005904
Instrument Name:Bruker Impact II
Instrument Type:QTOF
MS Type:ESI
MS Comments:Untargeted metabolomics were performed on an Agilent Technologies 1290 Infinity II system with an Waters ACQUITY UPLC BEH C18 Column, 130A, 1.7 um, 1 mm X 100 mm, coupled online to a Bruker Impact II QTOF mass spectrometer with electrospray ionization (ESI) source. The source dry gas temperature was set to 200°C at a flow of 8 L/min. The capillary voltage was set to 4000 V for positive mode and 5000 V for negative mode and the nebulizer operated at 29 psi.
Ion Mode:NEGATIVE
Capillary Voltage:4000 V
Dry Gas Flow:8 l/min
Dry Gas Temp:200
Nebulizer:29 psi
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