Ligand Activation of Peroxisome Proliferator–Activated Receptor β/δ (PPARβ/δ) Attenuates Carbon Tetrachloride Hepatotoxicity by Downregulating Proinflammatory Gene Expression

Abstract

Peroxisome proliferator-activated receptor (PPAR) beta/delta-null mice exhibit exacerbated hepatotoxicity in response to administration of carbon tetrachloride (CCl(4)). To determine whether ligand activation of the receptor protects against chemical toxicity in the liver, wild-type and PPARbeta/delta-null mice were administered CCl(4) with or without coadministration of the highly specific PPARbeta/delta ligand GW0742. Biomarkers of liver toxicity, including serum alanine aminotransferase (ALT) and hepatic tumor necrosis factor (TNF) alpha mRNA, were significantly higher in CCl(4)-treated PPARbeta/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 CCl(4)-treated PPARbeta/delta-null mice compared to wild-type mice. GW0742 treatment resulted in reduced serum ALT concentration and lower expression of CCl(4)-induced TNF-alpha, S100A6, monocyte chemoattractant protein-1 (MCP1), and TWEAKr in wild-type mice, and these effects were not observed in PPARbeta/delta-null mice. Expression of TNF-alpha was higher in PPARbeta/delta-null primary hepatocytes in response to interleukin-1beta treatment compared to wild-type hepatocytes, but GW0742 did not significantly modulate TNF-alpha expression in hepatocytes from either genotype. While PPARbeta/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 PPARbeta/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 PPARbeta/delta in liver, suggesting the involvement of paracrine and autocrine events mediated by hepatic cells.

Transcriptional profiling reveals divergent roles of PPARα and PPARβ/δ in regulation of gene expression in mouse liver

“…It was shown that the PPAR␤/␦ agonist GW501516 reduced histopathological changes in the MCD model of steatohepatitis and reduced expression of inflammatory cytokines and chemokines (32). Also, recent data suggest that PPAR␤/␦ protects against liver toxicity induced by environmental chemicals, likely by suppressing proinflammatory genes (42,43). Importantly, Odegaard et al (35) recently showed that PPAR␤/␦ is required for the acquisition of the metabolic and immune phenotypes of alternatively activated macrophages in liver.…”

“…Recent studies indicate that PPAR␤/␦ may influence the inflammatory properties of Kupffer cells (35). Furthermore, recent data suggest that PPAR␤/␦ is protective against liver toxicity induced by environmental chemicals, possibly by downregulating expression of proinflammatory genes (42,43). Other studies have linked PPAR␤/␦ to proliferation of stellate cells and vitamin A metabolism (16,17).…”

Hepatic PPARs: Their Role in Liver Physiology, Fibrosis and Treatment

“…PPAR / is expressed in quiescent HSCs, and especially in activated HSCs in vitro and in vivo but its role is not completely clear yet; indeed PPAR / favors HSCs proliferation but also counterbalances this effect expressing genes involved in esterification of vitamin A (2) and downregulating proinflammatory gene expression, thus working to maintain HSCs in a quiescent phase [69][70][71].…”

“…Finally, it has been shown that PPAR / has hepatoprotective effects being able to modulate NF-kB signaling thus attenuating carbon tetrachloride hepatotoxicity [78].…”

PPARδ agonist-mediated ROS stimulates mouse embryonic stem cell proliferation through cooperation of p38 MAPK and Wnt/β-catenin

“…3 Additionally, PPARδ agonist may be involved in stem cell and progenitor cell proliferation and protection against apoptosis. [4][5][6] The effects of PPARδ on ES cells are relatively unknown, although a recent study revealed that high glucose-mediated mouse ES cells proliferation levels are required for PPARδ activation. 5 Therefore, PPARδ in ES cells may have an essential role in self-renewal.…”