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Lack of PPAR? exacerbates lipopolysaccharide-induced liver toxicity through STAT1 inflammatory signaling and increased oxidative/nitrosative stress.

ABSTRACT: Peroxisome proliferator-activated receptor-? (PPAR?) has been implicated in a potent anti-inflammatory activity. However, no information is available on whether PPAR? can affect signal transducers and activator of transcription proteins (STATs) in acute liver damage. Thus, this study was aimed to investigate the in vivo role of PPAR? in elevating STATs as well as oxidative/nitrosative stress in a model of lipopolysaccharide (LPS)-induced acute hepatic inflammatory injury. Using age-matched Ppara-null and wild-type (WT) mice, we demonstrate that the deletion of PPAR? aggravates LPS-mediated liver injury through activating STAT1 and NF-?B-p65 accompanied by increased levels of pro-inflammatory cytokines. Furthermore, the activities of key anti-oxidant enzymes and mitochondrial complexes were significantly decreased while lipid peroxidation and protein nitration were elevated in LPS-exposed Ppara-null mice compared to WT. These results indicate that PPAR? is important in preventing LPS-induced acute liver damage by regulating STAT1 inflammatory signaling pathways and oxidative/nitrosative stress.

SUBMITTER: Yoo SH

PROVIDER: S-EPMC3056153 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Lack of PPARα exacerbates lipopolysaccharide-induced liver toxicity through STAT1 inflammatory signaling and increased oxidative/nitrosative stress.

Yoo Seong Ho SH Park Ogyi O Henderson Lauren E LE Abdelmegeed Mohamed A MA Moon Kwan-Hoon KH Song Byoung-Joon BJ

Toxicology letters 20110122 1

Peroxisome proliferator-activated receptor-α (PPARα) has been implicated in a potent anti-inflammatory activity. However, no information is available on whether PPARα can affect signal transducers and activator of transcription proteins (STATs) in acute liver damage. Thus, this study was aimed to investigate the in vivo role of PPARα in elevating STATs as well as oxidative/nitrosative stress in a model of lipopolysaccharide (LPS)-induced acute hepatic inflammatory injury. Using age-matched Ppara ...[more]

PMID: 21262334

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Project description:Diabetic retinopathy is a leading cause of visual loss and blindness, characterized by microvascular dysfunction. Hyperglycemia is considered the major pathogenic factor for the development of diabetic retinopathy and is associated with increased oxidative/nitrosative stress in the retina. Since heme oxygenase-1 (HO-1) is an enzyme with antioxidant and protective properties, we investigated the potential protective role of HO-1 in retinal endothelial cells exposed to high glucose and oxidative/nitrosative stress conditions. Retinal endothelial cells were exposed to elevated glucose, nitric oxide (NO) and hydrogen peroxide (H(2)O(2)). Cell viability and apoptosis were assessed by MTT assay, Hoechst staining, TUNEL assay and Annexin V labeling. The production of reactive oxygen species (ROS) was detected by the oxidation of 2',7'-dichlorodihydrofluorescein diacetate. The content of HO-1 was assessed by immunobloting and immunofluorescence. HO activity was determined by bilirubin production. Long-term exposure (7 days) of retinal endothelial cells to elevated glucose decreased cell viability and had no effect on HO-1 content. However, a short-time exposure (24 h) to elevated glucose did not alter cell viability, but increased both the levels of intracellular ROS and HO-1 content. Moreover, the inhibition of HO with SnPPIX unmasked the toxic effect of high glucose and revealed the protection conferred by HO-1. Oxidative/nitrosative stress conditions increased cell death and HO-1 protein levels. These effects of elevated glucose and HO inhibition on cell death were confirmed in primary endothelial cells (HUVECs). When cells were exposed to oxidative/nitrosative stress conditions there was also an increase in retinal endothelial cell death and HO-1 content. The inhibition of HO enhanced ROS production and the toxic effect induced by exposure to H(2)O(2) and NOC-18 (NO donor). Overexpression of HO-1 prevented the toxic effect induced by H(2)O(2) and NOC-18. In conclusion, HO-1 exerts a protective effect in retinal endothelial cells exposed to hyperglycemic and oxidative/nitrosative stress conditions.

Dataset Information

Lack of PPAR? exacerbates lipopolysaccharide-induced liver toxicity through STAT1 inflammatory signaling and increased oxidative/nitrosative stress.

Publications

Lack of PPARα exacerbates lipopolysaccharide-induced liver toxicity through STAT1 inflammatory signaling and increased oxidative/nitrosative stress.

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