Ligand activation of peroxisome proliferator - Activated receptor β/ δ (PPARβ/δ) attenuates carbon tetrachloride hepatotoxicity by downregulating proinflammatory gene expression

Peroxisome proliferator-activated receptor (PPAR) β/δ-null mice exhibit exacerbated hepatotoxicity in response to administration of carbon tetrachloride (CCl₄). To determine whether ligand activation of the receptor protects against chemical toxicity in the liver, wild-type and PPARβ/δ-null mice were administered CCl₄ with or without coadministration of the highly specific PPARβ/δ ligand GW0742. Biomarkers of liver toxicity, including serum alanine aminotransferase (ALT) and hepatic tumor necrosis factor (TNF) α mRNA, were significantly higher in CCl₄-treated PPARβ/δ-null mice compared to wild-type mice. Hepatic expression of TNF-like weak inducer of apoptosis receptor (TWEAKr) and S100 calcium-binding protein A6 (S100A6/ calcyclin), genes involved in nuclear factor kappa B signaling, was higher in the CCl₄-treated PPARβ/δ-null mice compared to wild-type mice. GW0742 treatment resulted in reduced serum ALT concentration and lower expression of CCl₄-induced TNF-α, S100A6, monocyte chemoattractant protein-1 (MCP1), and TWEAKr in wild-type mice, and these effects were not observed in PPARβ/δ-null mice. Expression of TNF-α was higher in PPARβ/δ-null primary hepatocytes in response to interleukin-1β treatment compared to wild-type hepatocytes, but GW0742 did not significantly modulate TNF-α expression in hepatocytes from either genotype. While PPARβ/δ-null hepatic stellate exhibited higher rates of proliferation compared to wild-type cells, GW0742 did not affect α-smooth muscle actin expression in these cells. Combined, these findings demonstrate that ligand activation of PPARβ/δ protects against chemically induced hepatotoxicity by downregulating expression of proinflammatory genes. Hepatocytes and hepatic stellate cells do not appear to directly mediate the inhibitory effects of ligand activation of PPARβ/δ in liver, suggesting the involvement of paracrine and autocrine events mediated by hepatic cells.