title: Ligand activation of peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) 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.
authors.affiliation: Department of Veterinary and Biomedical Sciences and The Center for Molecular Toxicology and Carcinogenesis, The Huck Institute of Life Sciences, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
authors.forename: Weiwei
authors.initials: W
authors.lastname: Shan
authors.forename: Prajakta S
authors.initials: PS
authors.lastname: Palkar
authors.forename: Iain A
authors.initials: IA
authors.lastname: Murray
authors.forename: Emily I
authors.initials: EI
authors.lastname: McDevitt
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Kennett
authors.forename: Boo Hyon
authors.initials: BH
authors.lastname: Kang
authors.forename: Harriet C
authors.initials: HC
authors.lastname: Isom
authors.forename: Gary H
authors.initials: GH
authors.lastname: Perdew
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Peters
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002251:Carbon Tetrachloride; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D018836:Inflammation Mediators / Q000378:metabolism*; D008024:Ligands; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008107:Liver Diseases / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D047494:PPAR delta / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D048068:PPAR-beta / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D020011:Protective Agents / Q000494:pharmacology*; D053778:Thiazolidines / Q000494:pharmacology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism
chemical_list: D015415:Biomarkers; C119543:GW0072; D018836:Inflammation Mediators; D008024:Ligands; D047494:PPAR delta; D048068:PPAR-beta; D020011:Protective Agents; D053778:Thiazolidines; D014409:Tumor Necrosis Factor-alpha; D002251:Carbon Tetrachloride