Trifluoroacetate mediated reduction of atherosclerosis in mice

Trifluoroacetate (TFA) has been assumed to be an innocuous counterion in countless synthetic bioactive peptides and a few FDA-approved therapeutics. Here we show that TFA is in fact bioactive, inducing peroxisome proliferation and causing significant metabolic effects in three strains of mice (wild-type C57BL/6 J, Ldlr−/−, and Apoe−/−) and cultured liver cells. In a high-fat diet induced Ldlr−/− mouse model of atherosclerosis, TFA reduced the levels of plasma LDL cholesterol, triglycerides, and the development of atherosclerotic lesions. These physiological effects were observed with TFA alone, or with TFA present as a counterion of a variety of short, unrelated synthetic peptide sequences. Multiple lines of mechanistic evidence supported that TFA acts by binding to peroxisome proliferator activated receptor (PPAR)-α to induce peroxisome proliferation. These findings indicate the need to assess the contribution of TFA to phenotypic effects observed in some studies using synthetic peptides and, if these effects extend to humans, suggest potential therapeutic applications as well as broader health implications of widespread environmental TFA exposure. Trifluoroacetate (TFA), long assumed to be an inert peptide counterion, is a bioactive modulator of PPARα signaling that induces peroxisome proliferation, alters lipid metabolism, and attenuates atherosclerosis in mice.