Lack of PPARα exacerbates lipopolysaccharide-induced liver toxicity through STAT1 inflammatory signaling and increased oxidative/nitrosative stress.
Peroxisome proliferator-activated receptor-α (PPARα) has been implicated in a potent anti-inflammatory activity. However, no information is available on whether PPARα can affect signal transducers and activator of transcription proteins (STATs) in acute liver damage. Thus, this study was aimed to investigate the in vivo role of PPARα in elevating STATs as well as oxidative/nitrosative stress in a model of lipopolysaccharide (LPS)-induced acute hepatic inflammatory injury. Using age-matched Ppara-null and wild-type (WT) mice, we demonstrate that the deletion of PPARα aggravates LPS-mediated liver injury through activating STAT1 and NF-κB-p65 accompanied by increased levels of pro-inflammatory cytokines. Furthermore, the activities of key anti-oxidant enzymes and mitochondrial complexes were significantly decreased while lipid peroxidation and protein nitration were elevated in LPS-exposed Ppara-null mice compared to WT. These results indicate that PPARα is important in preventing LPS-induced acute liver damage by regulating STAT1 inflammatory signaling pathways and oxidative/nitrosative stress.
Laboratory of Membrane Biochemistry and Biophysics, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA.
Seong Ho
SH
Yoo
Ogyi
O
Park
Lauren E
LE
Henderson
Mohamed A
MA
Abdelmegeed
Kwan-Hoon
KH
Moon
Byoung-Joon
BJ
Song
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D005260:Female; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D015538:Nitrosation / Q000187:drug effects; D018384:Oxidative Stress / Q000187:drug effects; D047493:PPAR alpha / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D016207:Cytokines; D008070:Lipopolysaccharides; D047493:PPAR alpha; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D008315:Malondialdehyde
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