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) beta/delta-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 PPAR beta/delta-null mice were administered CCl4 with or without coadministration of the highly specific PPAR beta/delta ligand GW0742. Biomarkers of liver toxicity, including serum alanine aminotransferase (ALT) and hepatic tumor necrosis factor (TNF) alpha mRNA, were significantly higher in CCl4-treated PPAR beta/delta-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 PPAR beta/delta-null mice compared to wild-type mice. GW0742 treatment resulted in reduced serum ALT concentration and lower expression of CCl4-induced TNF-alpha, S100A6, monocyte chemoattractant protein-1 (MCP1), and TWEAKr in wild-type mice, and these effects were not observed in PPAR beta/delta-null mice. Expression of TNF-alpha was higher in PPAR beta/delta-null primary hepatocytes in response to interleukin-1 beta treatment compared to wild-type hepatocytes, but GW0742 did not significantly modulate TNF-alpha expression in hepatocytes from either genotype. While PPAR beta/delta-null hepatic stellate exhibited higher rates of proliferation compared to wild-type cells, GW0742 did not affect alpha-smooth muscle actin expression in these cells. Combined, these findings demonstrate that ligand activation of PPAR beta/delta 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 PPAR beta/delta in liver, suggesting the involvement of paracrine and autocrine events mediated by hepatic cells.