Differential hepatic effects of perfluorobutyrate mediated by mouse and human PPAR-alpha.
Perfluorobutyrate (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-alpha (PPAR-alpha). In this study, the role of PPAR-alpha in mediating the effects of PFBA was examined using PPAR-alpha null mice and a mouse line expressing the human PPAR-alpha in the absence of mouse PPAR-alpha (PPAR-alpha humanized mice). PFBA caused upregulation of known PPAR-alpha target genes that modulate lipid metabolism in wild-type and PPAR-alpha humanized mice, and this effect was not found in PPAR-alpha null mice. Increased liver weight and hepatocyte hypertrophy were also found in wild-type and humanized PPAR-alpha mice treated with PFBA, but not in PPAR-alpha 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-alpha null and PPAR-alpha 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-alpha and that these effects do not exhibit a species difference. In contrast, the PPAR-alpha-dependent increase in PFBA-induced hepatocyte focal necrosis with inflammatory cell infiltrate was mediated by the mouse PPAR-alpha but not the human PPAR-alpha. Collectively, these findings demonstrate that PFBA can activate both the mouse and human PPAR-alpha, but there is a species difference in the hepatotoxic response to this chemical.
Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
Jennifer E
JE
Foreman
Shu-Ching
SC
Chang
David J
DJ
Ehresman
John L
JL
Butenhoff
Cherie R
CR
Anderson
Prajakta S
PS
Palkar
Boo-Hyon
BH
Kang
Frank J
FJ
Gonzalez
Jeffrey M
JM
Peters
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology*; D005466:Fluorocarbons / Q000493:pharmacokinetics / Q000633:toxicity*; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009929:Organ Size / Q000187:drug effects; D047493:PPAR alpha / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D005466:Fluorocarbons; D047493:PPAR alpha; D011743:Pyrimidines; D012333:RNA, Messenger; C033094:perfluorobutyric acid; C006253:pirinixic acid; D000410:Alanine Transaminase