PMID- 18622026
OWN - NLM
STAT- MEDLINE
DCOM- 20081014
LR  - 20211020
IS  - 1096-0929 (Electronic)
IS  - 1096-6080 (Print)
IS  - 1096-0929 (Linking)
VI  - 105
IP  - 2
DP  - 2008 Oct
TI  - Ligand activation of peroxisome proliferator-activated receptor beta/delta 
      (PPARbeta/delta) attenuates carbon tetrachloride hepatotoxicity by downregulating 
      proinflammatory gene expression.
PG  - 418-28
LID - 10.1093/toxsci/kfn142 [doi]
AB  - 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.
FAU - Shan, Weiwei
AU  - Shan W
AD  - 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.
FAU - Palkar, Prajakta S
AU  - Palkar PS
FAU - Murray, Iain A
AU  - Murray IA
FAU - McDevitt, Emily I
AU  - McDevitt EI
FAU - Kennett, Mary J
AU  - Kennett MJ
FAU - Kang, Boo Hyon
AU  - Kang BH
FAU - Isom, Harriet C
AU  - Isom HC
FAU - Perdew, Gary H
AU  - Perdew GH
FAU - Gonzalez, Frank J
AU  - Gonzalez FJ
FAU - Peters, Jeffrey M
AU  - Peters JM
LA  - eng
GR  - CA023931/CA/NCI NIH HHS/United States
GR  - CA124533/CA/NCI NIH HHS/United States
GR  - ES04869/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20080712
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 0 (Biomarkers)
RN  - 0 (GW0072)
RN  - 0 (Inflammation Mediators)
RN  - 0 (Ligands)
RN  - 0 (PPAR delta)
RN  - 0 (PPAR-beta)
RN  - 0 (Protective Agents)
RN  - 0 (Thiazolidines)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - CL2T97X0V0 (Carbon Tetrachloride)
SB  - IM
MH  - Animals
MH  - Biomarkers/metabolism
MH  - Carbon Tetrachloride
MH  - Cell Proliferation/drug effects
MH  - Cells, Cultured
MH  - Chemical and Drug Induced Liver Injury
MH  - Disease Models, Animal
MH  - Dose-Response Relationship, Drug
MH  - Down-Regulation
MH  - Inflammation Mediators/*metabolism
MH  - Ligands
MH  - Liver/*drug effects/enzymology/pathology
MH  - Liver Diseases/genetics/metabolism/*prevention & control
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - PPAR delta/*agonists/genetics/metabolism
MH  - PPAR-beta/*agonists/genetics/metabolism
MH  - Protective Agents/*pharmacology
MH  - Thiazolidines/*pharmacology
MH  - Time Factors
MH  - Tumor Necrosis Factor-alpha/genetics/metabolism
PMC - PMC2527639
EDAT- 2008/07/16 09:00
MHDA- 2008/10/15 09:00
PMCR- 2009/10/01
CRDT- 2008/07/16 09:00
PHST- 2008/07/16 09:00 [pubmed]
PHST- 2008/10/15 09:00 [medline]
PHST- 2008/07/16 09:00 [entrez]
PHST- 2009/10/01 00:00 [pmc-release]
AID - kfn142 [pii]
AID - 10.1093/toxsci/kfn142 [doi]
PST - ppublish
SO  - Toxicol Sci. 2008 Oct;105(2):418-28. doi: 10.1093/toxsci/kfn142. Epub 2008 Jul 
      12.