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血红素加氧酶-1调控核转录因子-κB表达抑制非酒精性脂肪性肝纤维化的机制
Role and molecular mechanism of HO-1-mediated NF-κB modulation in fibrosis progression of nonalcoholic steatohepatitis
文章发布日期:2013年05月04日  来源:  作者:南月敏,米红梅,杜静华,等  点击次数:2423次  下载次数:450次

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【摘要】:目的探讨在非酒精性脂肪性肝纤维化进展中血红素加氧酶-1(HO-1)靶向激活对核转录因子-κB(NF-κB)、细胞间黏附分子-1(ICAM-1)及血小板源性生长因子(PDGF)表达的影响,以明确HO-1基因调控阻止该病发生发展的分子机制。方法选用清洁级7~8周龄健康雄性C57BL/6J小鼠,蛋氨酸-胆碱缺乏(MCD)饮食喂养8周建立非酒精性脂肪性肝纤维化模型,分别采用HO-1激动剂血晶素、抑制剂锌原卟啉进行干预实验,以蛋氨酸-胆碱充足饮食设立对照组。实时荧光定量PCR检测肝组织HO-1、NF-κB、ICAM-1和PDGF mRNA表达;Western Blot检测肝组织HO-1、PDGF蛋白表达。结果模型组伴随肝脂肪变、炎症及纤维化的形成,肝组织HO-1、NF-κB、ICAM-1和PDGF mRNA表达显著增强,HO-1、PDGF蛋白表达与mRNA表达趋势一致;应用血晶素组肝损伤明显改善,肝组织NF-κB、ICAM-1和PDGF表达显著下调,而应用锌原卟啉组则呈相反趋势。结论HO-1靶向激活可通过抑制NF-κB、及其下游ICAM-1、及PDGF表达阻止非酒精性脂肪性肝纤维化的发生与进展。
【Abstract】:ObjectiveTo investigate the potential effects and molecular mechanisms of heme oxygenase-1 (HO-1)-mediated modulation of nuclear factor-kappa B (NF-κB), and its downstream activation of intercellular adhesion molecule 1 (ICAM-1) and platelet derived growth factor (PDGF), in fibrosis progression of non-alcoholic steatohepatitis (NASH) using the methionine and choline deficient (MCD) mouse model of NASH. Methods Forty C57BL/6J male mice (18-20 g) were randomly divided into four groups (n=10 each): NASH model group, administered the MCD diet; HO-1 agonist group, administered the MCD diet with intraperitoneal (ip) injections of hemin (30 μmol/kg every other day); HO-1 inhibitor group, administered the MCD diet with ip injections of zinc protoporphyrin (ZnPP-IX; 20 μmol/kg every other day); and control group, administered a methionine and choline sufficient (MCS) diet, without agonist nor inhibitor injections. After eight weeks, the mice were sacrificed and resected liver tissues used to assess successful model establishment by histological analysis (hematoxylin-eosin and Masson staining) and the differential mRNA expression of HO-1, NF-κB, ICAM-1, and PDGF by real-time quantitative PCR (GAPDH normalized) and protein expression of HO-1 and PDGF by western blotting ( β-actin normalized). Significance of an intergroup difference was assessed by single-factor analysis of variance test, and the Student-Newman-Keuls test was used for pairwise comparisons. ResultsThe NASH model group showed the appropriate histologic features of hepatic steatosis, necroinflammation and fibrogenesis, while the control group showed normal lobular architecture. In addition, the NASH model group showed significantly higher expression of HO-1, NF-κB, ICAM-1 and PDGF mRNA (all P<0.05), and concomitant increases in HO-1 and PDGF protein. The group treated with HO-1 agonist showed significant down-regulation of the NASH-induced NF-κB, ICAM-1 and PDGF expressions, while the opposite effect (accompanied by severe liver injury) was observed in the group treated with HO-1 inhibitor. Conclusion Inhibiting HO-1 activation in NASH could attenuate NF-κB signaling and expression of its downstream effectors ICAM-1 and PDGF to protect against fibrosis- and inflammation-related liver injury.
【关键字】:肝硬化; 血红素加氧酶-1; NF-κB;胞间黏附分子 1;血小板源性生长因子
【Key words】:liver cirrhosis; heme oxygenase-1; NF-kappaB; intercellular adhesion molecule-1; platelet-derived growth factor
【引证本文】:

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