吡格列酮联合塞来昔布对实验性非酒精性脂肪性肝炎的影响

Combined treatment with pioglitazone and celecoxib for experimental nonalcoholic steatohepatitis

目的探讨吡格列酮联合塞来昔布对非酒精性脂肪性肝炎(NASH)大鼠治疗作用及可能的机制。方法 50只雄性SD大鼠均分为正常组、模型组、吡格列酮组、塞来昔布组和联合治疗组。高脂饮食12周诱导NASH模型,给予吡格列酮(10 mg·kg-1·d-1)和(或)塞来昔布(80 mg·kg-1·d-1)灌胃8周。观察大鼠肝病理、血脂和肝功能改变。荧光定量PCR检测脂联素受体(AdipoR1,Adipo-R2)和环氧合酶-2(COX-2)基因表达变化。多组间比较采用单因素方差分析(S-N-K法)和秩和检验。结果联合治疗组较单药组肝脂肪变、炎症和纤维化明显减轻(均P<0.01)。和单药组比,联合治疗组血清和肝组织总胆固醇(TCH)、总甘油三酯(TG)、丙氨酸转氨酶(ALT)、天冬氨酸转氨酶(AST)明显下降(均P<0.05)。定量PCR显示,联合治疗组Adipo-R基因表达较吡格列酮、塞来昔布单药组明显改善(肝脏Adipo-R1:2.52±0.27,1.27±0.06,2.02±0.06,P<0.01;脂肪Adipo-R1:0.64±0.02,0.21±0.02,0.42±0.03,P<0.01;肌肉Adipo-R1:1.32±0.41,2.68±0.45,4.34±0.47,P<0.01;肝脏Adipo-R2:6.39±0.37,4.81±0.48,5.71±0.22,P<0.01;脂肪Adipo-R2:2.65±0.05,2.17±0.28,1.54±0.05,P<0.01;肌肉Adipo-R2:0.45±0.04,2.58±0.51,2.66±0.57,P<0.01)。联合治疗组更能下调肝COX-2基因表达(0.47±0.06,1.03±0.20,0.98±0.10,P<0.01)。结论吡格列酮联合塞来昔布较单药治疗可更有效治疗实验性NASH,其机制可能和调节Adipo-R在体内的分布有关。

Objective To explore the effects and possible mechanisms of pioglitazone combined with celecoxib on nonalcoholic steatohepatitis （ NASH ） rats.Methods Fifty Sprague-Dawley male rats were randomly divided into the normal group,model group（fed with a high-fat diet for 12 weeks）,pioglitazone group,celecoxib group and combination group.Each group had 10 rats.Pioglitazone（10 mg· kg-1 · d-1 ） and celecoxib（80 mg· kg-1 · d-1 ） were fed from the 12th week for 8 weeks.Hepatic histological changes,blood lipid and liver function were observed.The mRNA expressions of Adipo-R1/2 and COX-2 were disclosed by real-time PCR.One-way analysis of variance（ANOVA） （S-N-K method） and Wilcoxon′s signed-rank test were used for the statistical analysis, respectively.Results Compared with the monotherapy group, histological samples in combination group showed a significant improvement in steatosis, inflammation and fibrosis（all P〈0.01）.The levels of serum and liver tissues in total cholesterol（ TCH）,total triglycerides （TG）,alanine aminotransferase（ALT）and aspartate aminotransferase（AST）in the combination group were significantly ameliorated compared with those indicators in the monotherapy group（all P〈0.05）.Real-time PCR revealed mRNA expressions of Adipo-R1/2 were improved compared with the monotherapy group （Adipo-R1 in liver：2.52 ±0.27,1.27 ±0.06,2.02 ±0.06,P〈0.01;Adipo-R1 in fat：0.64 ±0.02,0.21 ± 0.02,0.42 ±0.03,P〈0.01;Adipo-R1 in muscle：1.32 ±0.41,2.68 ±0.45,4.34 ±0.47,P〈0.01;Adipo-R2 in liver：6.39 ±0.37,4.81 ±0.48,5.71 ±0.22,P 〈0.01;Adipo-R2 in fat：2.65 ±0.05,2.17 ±0.28,1.54 ±0.05,P 〈0.01;Adipo-R2 in muscle：0.45 ±0.04,2.58 ±0.51,2.66 ±0.57,P 〈0.01）.COX-2mRNA expression in combination group exhibited markedly decreased（0.47 ±0.06,1.03 ±0.20,0.98 ±0.10,P 〈0.01）.Conclusions Pioglitazone combined with celecoxib can be more effective thanmonotherapy in NASH rats,which may be associated with normalizing expression of Adipo-R.