Peroxisome Proliferator-Activated Receptor Alpha-Null Mice Lack Resistance to Acetaminophen Hepatotoxicity following Clofibrate Exposure

Abstract

The purpose of this study was to investigate whether activation of the nuclear receptor PPARalpha is needed for protection from acetaminophen (APAP) hepatotoxicity produced by repeated administration of the peroxisome proliferator clofibrate (CFB). Female wild-type and PPARalpha-null mice received corn oil vehicle or 500 mg CFB/kg, ip, daily for 10 days. They were then fasted overnight (18 h) and either killed at 4 or 24 h after challenge with 400 mg APAP/kg. Controls received 50% propylene glycol vehicle only. In this model of CFB hepatoprotection, liver injury was assessed by measuring plasma sorbitol dehydrogenase activity and by histopathology at 24 h after APAP challenge. Significant hepatocellular necrosis was evident in both corn oil-pretreated PPARalpha-null and wild-type mice at 24 h after APAP challenge. In agreement with previous studies, CFB-pretreated wild-type mice showed marked protection against APAP toxicity. In contrast, CFB did not provide protection against APAP hepatotoxicity in the PPARalpha-null mice. Similarly, at 4 h after APAP challenge, hepatic glutathione depletion and selective arylation of cytosolic proteins were reduced significantly in CFB-pretreated wild-type mice, but not in PPARalpha-null mice. The lack of changes in APAP binding and NPSH depletion in CFB-pretreated, PPARalpha-null mice is consistent with the presence of significant liver injury at 24 h in this treatment group. These findings demonstrate that the protection against APAP hepatotoxicity by peroxisome proliferator treatment is mediated by the activation of PPARalpha.

Delayed liver regeneration in peroxisome proliferator-activated receptor-α-null mice

“…For example, they are more sensitive to the liver toxicants acetaminophen, 37 trichloroethylene (Laughter et al, unpublished data), and carbon tetrachloride (Xiao et al, manuscript in preparation). Moreover, wild-type mice pretreated with a PP are resistant to several other hepatotoxicants (summarized in Chen et al 38 ). Because toxic liver damage is determined by both the extent of cellular injury and also the degree of repair by regenerating hepatocytes, 39 the molecular basis for the differences in sensitivity could be due to defects in signals initiating hepatocyte regeneration.…”

Peroxisome proliferator-activated receptor-β/δ protects against chemically induced liver toxicity in mice

“…Pretreatment of mice with the PPAR␣ ligand clofibrate protects against carbon tetrachloride-induced hepatotoxicity 16,17 and attenuates acetaminophen-induced hepatotoxicity in wildtype mice but not in PPAR␣-null mice. 18 This indicates that the protective effects of clofibrate are PPAR␣ dependent. The PPAR␥ ligand pioglitazone also inhibits hepatic fibrosis caused by carbon tetrachloride through inhibition of hepatic stellate cell proliferation and inflammation, suggesting that PPAR␥ has a protective role against hepatotoxicity as well.…”

From hepatoprotection models to new therapeutic modalities for treating liver diseases: a personal perspective

“…A subsequent study showed that a single dose of CFB prior to intoxication with APAP also protects against APAP hepatotoxicity, but neither produces changes in reactive intermediate covalent binding nor GSH depletion 22 . Additionally, PPARα activation is a requirement for this response, since the PPARα knockout mice are not afforded protection by CFB 23 .…”