Trifluoroacetate reduces plasma lipid levels and the development of atherosclerosis in mice

ABSTRACT: Here we show that trifluoroacetate (TFA), previously assumed to be an innocuous counterion to cationic amino acid side chains (Lys, Arg, His, N-terminal amines) found in countless synthetic bioactive peptides and a few FDA-approved therapeutics, is in fact bioactive– TFA 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 induces reductions in plasma cholesterol and triglycerides levels, 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. Furthermore, 10-wk daily oral administration of TFA reduced the development of atherosclerotic lesions in the LDLr-/- mice. 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 present as 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. Moreover, TFA is 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 be relevant to human health.

INSTRUMENT(S): Orbitrap Fusion Lumos, Orbitrap Fusion

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Liver

SUBMITTER: Louis Conway  

LAB HEAD: Christopher G Parker

PROVIDER: PXD057035 | Pride | 2025-03-12

REPOSITORIES: Pride