Differential hepatic effects of perfluorobutyrate mediated by mouse and human PPAR-α

Perfluorobutryate (PFBA) is a short chain perfluoroalkyl carboxylate that is structurally similar to perfluorooctanoate. Administration of PFBA can cause peroxisome proliferation, induction of peroxisomal fatty acid oxidation and hepatomegaly, suggesting that PFBA activates the nuclear receptor, peroxisome proliferator-activated receptor-α (PPAR-α). In this study, the role of PPAR-α in mediating the effects of PFBA was examined using PPAR-α null mice and a mouse line expressing the human PPAR-α in the absence of mouse PPAR-α (PPAR-α humanized mice). PFBA caused upregulation of known PPAR-α target genes that modulate lipid metabolism in wild-type and PPAR-α humanized mice, and this effect was not found in PPAR-α null mice. Increased liver weight and hepatocyte hypertrophy were also found in wild-type and humanized PPAR-α mice treated with PFBA, but not in PPAR-α null mice. Interestingly, hepatocyte focal necrosis with inflammatory cell infiltrate was only found in wild-type mice administered PFBA; this effect was markedly diminished in both PPAR-α null and PPAR-α humanized mice. Results from these studies demonstrate that PFBA can modulate gene expression and cause mild hepatomegaly and hepatocyte hypertrophy through a mechanism that requires PPAR-α and that these effects do not exhibit a species difference. In contrast, the PPAR-α-dependent increase in PFBA-induced hepatocyte focal necrosis with inflammatory cell infiltrate was mediated by the mouse PPAR-α but not the human PPAR-α. Collectively, these findings demonstrate that PFBA can activate both the mouse and human PPAR-α, but there is a species difference in the hepatotoxic response to this chemical.