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Title: [The protective role of peroxisome proliferator activated receptors-α and pathomechanism in D-galactosamine/lipopolysaccharide- induced acute liver failure in rats].
Author: Jiao M, Ren F, Zhou L, Duan Z, Zhao C.
Journal: Zhonghua Nei Ke Za Zhi; 2014 Sep; 53(9):730-4. PubMed ID: 25511408.
Abstract:
OBJECTIVE: To determine the role and mechanism of peroxisome proliferator activated receptors (PPAR) α in a mouse model of D-galactosamine/lipopolysaccharide (D-GalN/LPS)-induced acute liver failure (ALF). METHODS: Firstly, C57BL/6 mice were randomly divided into control group (n = 8), ALF 2h group (n = 8), ALF 4h group (n = 8), ALF 6h group (n = 8). Secondly C57BL/6 mice were randomly divided into control group (n = 8), ALF group (n = 8), WY14643 group (n = 8). To induce ALF, the mice were injected intraperitoneally with D-GalN (700 mg/kg) and LPS (10 µg/kg). WY14643 (6 mg/kg), the selective agonist of PPAR α, was administered via tail vein two hours prior to D-GalN/LPS exposure. Two, four, and six hours after D-GalN/LPS treatment in the first study, mice were anesthetized and blood was collected, 6h after D-GalN/LPS treatment in the second study, blood was collected. The liver tissue was harvested for histology and mRNA extraction. Serum levels of ALT and AST were measured to evaluate the hepatic damage. Inflammatory cytokines (TNFα, IL-1β, IL-6) and chemokines (CXCL-1, CXCL-10) were detected by real-time quantitative PCR. Differential protein expression of p-NF-κBp65, p-JNK, p-ERK, p-p38 in inflammatory pathways was detected by Western blotting. Significance of inter-group differences was assessed by one-way ANOVA, and pairwise comparison was performed by the least significant difference test. RESULTS: The gene and protein expression of PPAR α were gradually reduced during the development of ALF. Compared with the model group, the liver architecture was better preserved almost with normal morphology in WY14643-treated mice. Serum ALT and AST levels in WY14643-treated group were significantly lower [ALT: (555 ± 62)U/L vs (2 898 ± 822) U/L, P < 0.05; AST: (791 ± 58) U/L vs (3 013 ± 997) U/L, P < 0.05]. The expression of proinflammatory cytokines and chemokines was significantly suppressed during the activation of PPAR α. In the second study, the levels of gene expression of proinflammatory cytokines and chemokines were detected in control group, ALF group and WY14643 group respectively as followings: TNFα (0.161 ± 0.085, 7.996 ± 1.068, 3.346 ± 0.94, P < 0.05), IL-1β (0.041 ± 0.002, 3.657 ± 0.904, 0.176 ± 0.089, P < 0.01), IL-6 (0.018 ± 0.008, 1.762 ± 0.589, 0.163 ± 0.0487, P < 0.05), CXCL-1 (0.063 ± 0.008, 7.881 ± 0.966, 2.737 ± 0.864, P < 0.01), CXCL-10 (0.054 ± 0.005, 5.671 ± 0.948, 2.578 ± 0.804, P < 0.05). CONCLUSION: Our findings first demonstrate that PPARα protects liver from injury in an ALF mouse model by suppressing inflammatory response, indicating PPARα as a potential new therapeutic target for ALF.

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