罗格列酮对非酒精性脂肪性肝炎大鼠肝组织Kruppule样因子6信号通路的影响

目的观察罗格列酮对NASH肝纤维化大鼠肝组织kruppule样因子（KLF）6及其下游靶基因TGFβ1信号通路的影响。方法36只雄性Wistar大鼠随机分为对照组、高脂组和罗格列酮组,24周末处死所有大鼠,留取肝组织行HE和Massson染色,检测血清TG、游离脂肪酸、AST、ALT及HA、LN、CⅣ等,RT-PCR检测核转录因子KLF6、TGFβ1以及反映HSC活化的特异性标记α-平滑肌肌动蛋白（α-SMA）mRNA的变化,免疫组织化学检测KLF6、过氧化物酶体增殖物激活受体γ、α-SMA的蛋白表达。结果模型组大鼠24周末出现典型脂肪性肝纤维化,治疗组纤维化程度明显减轻和改善。模型组血清生物化学指标及肝纤维化指标均有不同程度增高,罗格列酮干预16周后上述各指标均见明显改善,两组间差异有统计学意义（P〈0.01）。RT-PCR显示模型组KLF6 mRNA（0.96±0.08）、TGFβ1 mRNA（0.91±0.07）和α-SMA mRNA （1.08±0.19）的相对表达量均明显上升,与对照组比较差异有统计学意义（P〈0.01）;治疗组则显示增高的上述基因呈不同程度的下降,差异有统计学意义（P〈0.01）。免疫组织化学显示罗格列酮组KLF6、α-SMA蛋白的表达较模型组减少,而PPARγ的表达较模型组增加,差异均有统计学意义（P〈0.05）。结论罗格列酮可以激活PPARγ,降低NASH肝纤维化大鼠肝组织核转录因子KLF6及其下游靶基因TGFβ1的表达,抑制HSC的活化,阻止肝纤维化形成,这可能是其发挥抗肝纤维化的作用之一。

Effects of rosiglitazone on Kruppul-like factor 6(KLF6) signaling in the livers of rats with nonalcoholic fatty liver fibrosis

OBJECTIVE: To study the effects of rosiglitazone on Kruppule-like factor 6 (KLF6) and its target gene TGFa1 during the development of nonalcoholic fatty liver fibrosis. METHOD: Thirty-six Wistar rats were divided into three groups: a control group, a high fat model group and an intervention group. Their blood serum TG, FFA, AST, ALT, HA, LN and CIV were measured. Hepatic expressions of KLF6, TGFbeta1 and alpha-SMA were detected by RT-PCR and immunohistochemistry. The pathological features and the degree of liver fibrosis before and after the rosiglitazone intervention were also studied. RESULTS: The contents of TG, FFA, AST, ALT, HA, LN and CIV, the expression of KLF6, TGFbeta1 and alpha-SMA mRNA, and the degree (score) of liver fibrosis at the 24th week in the model group were significantly higher than those in the control group (P<0.01) but they were lower in the rosiglitazone intervention group (P<0.05). The protein expression of a-SMA was also lower in the intervention group compared with that of the model group. CONCLUSION: Rosiglitazone, to a certain extent, can inhibit KLF6-TGFalpha1 signal transduction by inducing expression of PPAR-gamma, and then inhibit the activation of hepatic stellate cells and minimize hepatic fibrosis.