Ligand Activation of Peroxisome Proliferator-Activated Receptor / (PPAR / ) Attenuates Carbon Tetrachloride Hepatotoxicity by Downregulating Proinflammatory Gene Expression

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.
Toxicological Sciences (Impact Factor: 3.85). 08/2008; 105(2):418-28. DOI: 10.1093/toxsci/kfn142
Source: PubMed


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.

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Available from: Gary H Perdew, Dec 06, 2014
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    • "In addition to regulating glucose and lipid metabolism, PPARβ displays an anti-inflammatory activity, which could be important in the modulation of liver regeneration [14]. Ligand activation of PPARβ protects against CCl4-induced hepatotoxicity by repression of pro-inflammatory genes [15]. Compared with its anti-inflammatory role, the function of PPARβ in regulating cell fate is more complicated. "
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    ABSTRACT: The current study tests the hypothesis that peroxisome proliferator-activated receptor β (PPARβ) has a role in liver regeneration due to its effect in regulating energy homeostasis and cell proliferation. The role of PPARβ in liver regeneration was studied using two-third partial hepatectomy (PH) in Wild-type (WT) and PPARβ-null (KO) mice. In KO mice, liver regeneration was delayed and the number of Ki-67 positive cells reached the peak at 60 hr rather than at 36-48 hr after PH shown in WT mice. RNA-sequencing uncovered 1344 transcriptomes that were differentially expressed in regenerating WT and KO livers. About 70% of those differentially expressed genes involved in glycolysis and fatty acid synthesis pathways failed to induce during liver regeneration due to PPARβ deficiency. The delayed liver regeneration in KO mice was accompanied by lack of activation of phosphoinositide-dependent kinase 1 (PDK1)/Akt. In addition, cell proliferation-associated increase of genes encoding E2f transcription factor (E2f) 1-2 and E2f7-8 as well as their downstream target genes were not noted in KO livers 36-48 hr after PH. E2fs have dual roles in regulating metabolism and proliferation. Moreover, transient steatosis was only found in WT, but not in KO mice 36 hr after PH. These data suggested that PPARβ-regulated PDK1/Akt and E2f signaling that controls metabolism and proliferation is involved in the normal progression of liver regeneration.
    PLoS ONE 06/2013; 8(6):e65644. DOI:10.1371/journal.pone.0065644 · 3.23 Impact Factor
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    • "In rats, acute treatment with L165041 and CCl4 increased the expression of fibrotic markers [10]. In contrast, PPARβ/δ was protective against azoxymethane and CCl4-induced hepatotoxicity and, when activated with the synthetic ligand GW0742, down-regulated proinflammatory gene expression in CCl4-treated mice [12,13]. In a model of chronic ethanol-fed rats, L165041 reduced hepatic injury, oxidative stress and DNA damage, and improved the regenerative response in livers [14]. "
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    ABSTRACT: Background After liver injury, the repair process comprises activation and proliferation of hepatic stellate cells (HSCs), which produce extracellular matrix (ECM) proteins. Peroxisome proliferator-activated receptor beta/delta (PPARβ/δ) is highly expressed in these cells, but its function in liver repair remains incompletely understood. This study investigated whether activation of PPARβ/δ with the ligand GW501516 influenced the fibrotic response to injury from chronic carbon tetrachloride (CCl4) treatment in mice. Wild type and PPARβ/δ-null mice were treated with CCl4 alone or CCl4 co-administered with GW501516. To unveil mechanisms underlying the PPARβ/δ-dependent effects, we analyzed the proliferative response of human LX-2 HSCs to GW501516 in the presence or absence of PPARβ/δ. Results We found that GW501516 treatment enhanced the fibrotic response. Compared to the other experimental groups, CCl4/GW501516-treated wild type mice exhibited increased expression of various profibrotic and pro-inflammatory genes, such as those involved in extracellular matrix deposition and macrophage recruitment. Importantly, compared to healthy liver, hepatic fibrotic tissues from alcoholic patients showed increased expression of several PPAR target genes, including phosphoinositide-dependent kinase-1, transforming growth factor beta-1, and monocyte chemoattractant protein-1. GW501516 stimulated HSC proliferation that caused enhanced fibrotic and inflammatory responses, by increasing the phosphorylation of p38 and c-Jun N-terminal kinases through the phosphoinositide-3 kinase/protein kinase-C alpha/beta mixed lineage kinase-3 pathway. Conclusions This study clarified the mechanism underlying GW501516-dependent promotion of hepatic repair by stimulating proliferation of HSCs via the p38 and JNK MAPK pathways.
    Cell and Bioscience 10/2012; 2(1):34. DOI:10.1186/2045-3701-2-34 · 3.63 Impact Factor
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    ABSTRACT: Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that respond to endogenous and exogenous signaling molecules and modulate cellular functions. PPARs regulate many target genes that in turn influence cell growth, differentiation, and inflammatory signaling. These changes can occur through direct transcriptional up-regulation of target genes, through secondary changes subsequent to direct transcriptional up-regulation of target genes, and through protein-protein interactions. The focus of this chapter is to summarize PPAR-dependent regulation of cellular signaling in squamous epithelium, and how these changes influence cancer.
    01/1970: pages 223-240;
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