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

Abstract

Potential functional roles for the peroxisome proliferator-activated receptor-␤/␦ (PPAR␤/␦) in skeletal muscle fatty acid catabolism and epithelial carcinogenesis have recently been described. Whereas PPAR␤/␦ is expressed in liver, its function in this tissue is less clear. To determine the role of PPAR␤/␦ in chemically induced liver toxicity, wild-type and PPAR␤/␦-null mice were treated with azoxymethane (AOM) and markers of liver toxicity examined. Bile duct hyperplasia, regenerative hyperplasia, and increased serum alanine aminotransferase (ALT) were found in AOM-treated PPAR␤/␦-null mice, and these effects were not observed in similarly treated wild-type mice. Exacerbated carbon tetrachloride (CCl 4 ) hepatoxicity was also observed in PPAR␤/␦-null as compared with wild-type mice. No differences in messenger RNAs (mRNAs) encoding cytochrome2E1 required for the metabolic activation of AOM and CCl 4 were observed between wild-type or PPAR␤/␦-null mice in response to CCl 4 . Significant differences in the expression of genes reflecting enhanced nuclear factor kappa B (NF-B) activity were noted in PPAR␤/␦-null mice. Conclusion:Results from these studies show that PPAR␤/␦ is protective against liver toxicity induced by AOM and CCl 4 , suggesting that this receptor is hepatoprotective against environmental chemicals that are metabolized in this tissue. (HEPATOLOGY 2008;47:225-235.)

Regulation of Cytochrome P450 2B10 (CYP2B10) Expression in Liver by Peroxisome Proliferator-activated Receptor-β/δ Modulation of SP1 Promoter Occupancy

“…Expression of Cyp2b10 is thought to be mediated by CAR activation (18). However, the present study clearly showed that ethanol treatment did not influence the relative expression of CAR as also observed in a previous study (10) or enhance the nuclear translocation of CAR following treatment with ethanol. Because the translocation of CAR to the nucleus is required to initiate target gene expression (19 -21), this illustrates a unique finding from the present study because the results indicate that PPAR␤/␦, rather than CAR, is required for up-regulation of Cyp2b10 in response to ethanol.…”

“…1A). This was of interest because previous studies demonstrated a similar PPAR␤/␦-dependent effect on the hepatic expression of CYP2B10 in mice exposed to carbon tetrachloride (10). Overall, ethanol exposure significantly altered expression of 358 genes or 146 genes, in livers of Ppar␤/␦ ϩ/ϩ or Ppar␤/␦ Ϫ/Ϫ mice, respectively (Fig.…”

“…Variation in the expression of these enzymes influences the sensitivity and the adaption to ethanol consumption (13). PPAR␤/␦ can protect against chemically induced liver injury through multiple mechanisms including inhibition of steatosis, inhibition of NF-kB-dependent signaling, and inhibition of inflammation (10,11,16,17). A previous study revealed that exposure to carbon tetrachloride (CCl 4 ) caused an increase in hepatic Cyp2b10 expression, and this induction was mediated by PPAR␤/␦, which was not due to differences in the relative expression of CAR (10), similar to the results observed in the present study.…”

“…Ethanol-induced Cyp2b10 Expression Is Independent of CAR Signaling-Previous work revealed that ligand activation of CAR caused up-regulation of CYP2B10 in both Ppar␤/␦ ϩ/ϩ and Ppar␤/␦ Ϫ/Ϫ mice (10). This suggested that CAR activity was not influenced by PPAR␤/␦.…”

Effects of a methanolic fraction of soybean seeds on the transcriptional activity of peroxisome proliferator-activated receptors (PPAR)

“…However, little is known about the possibility that isoflavones activate PPARβ/ δ, which plays a critical role in the regulation of metabolic homeostasis, and also in cardiac lipid metabolism (15,16), fetal development (17), inhibition of human cancer cell line growth (18), protection against liver toxicity (19), modulation of inflammation (6,20), and improved skeletal muscle oxidative enzyme activity in obese patients with type 2 diabetes mellitus (21).…”