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.
Study ID | ST003595 |
Study Title | Trifluoroacetate reduces plasma lipid levels and the development of atherosclerosis in mice |
Study 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 |
wtang@scripps.edu | |
Phone | 858-784-2711 |
Submit Date | 2024-10-26 |
Raw Data Available | Yes |
Raw Data File Type(s) | d |
Analysis Type Detail | LC-MS |
Release Date | 2024-12-18 |
Release Version | 1 |
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 |
---|---|---|---|
SA391885 | PBS8 | plasma | Control |
SA391886 | PBS2 | plasma | Control |
SA391887 | PBS10 | plasma | Control |
SA391888 | PBS9 | plasma | Control |
SA391889 | PBS1 | plasma | Control |
SA391890 | PBS7 | plasma | Control |
SA391891 | PBS6 | plasma | Control |
SA391892 | PBS5 | plasma | Control |
SA391893 | PBS4 | plasma | Control |
SA391894 | PBS3 | plasma | Control |
SA391895 | TFA2 | plasma | TFA |
SA391896 | TFA3 | plasma | TFA |
SA391897 | TFA4 | plasma | TFA |
SA391898 | TFA5 | plasma | TFA |
SA391899 | TFA6 | plasma | TFA |
SA391900 | TFA7 | plasma | TFA |
SA391901 | TFA8 | plasma | TFA |
SA391902 | TFA9 | plasma | TFA |
SA391903 | TFA10 | plasma | TFA |
SA391904 | TFA1 | plasma | 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 |