替米沙坦调控巨噬细胞极化改善胰岛素抵抗大鼠非酒精性脂肪肝的机制研究

Mechanism of telmisartan regulating macrophage polarization to improve the nonalcoholic fatty liver disease in rats with insulin resistance

目的研究替米沙坦对胰岛素抵抗大鼠的非酒精性脂肪肝(NAFLD)的作用及可能机制。方法雄性大鼠用高糖高脂饲养法构建胰岛素抵抗大鼠模型。按照体重将建模后大鼠随机分为2组:模型组、实验组。另取8只普通饲料喂养的雄性大鼠作为正常组。正常组和模型组均给予等量0.9%NaCl,实验组给予溶于0.9%NaCl(l2 mL)的替米沙坦5 mg·kg^(-1),灌胃均1次/天,连续灌胃12周。测定大鼠胰岛素抵抗指数(HOMA-IR),用蛋白质印迹法分别检测大鼠肝中M1型和M2型巨噬细胞特异标志物、诱导型一氧化氮合酶(iNOS)和精氨酸酶-1(Arg-1)水平(OD值比值),并进行肝脂肪变性评分。结果给药后,正常组、模型组和实验组的HOMA-IR分别为4.54±1.08,10.83±0.82和5.97±0.89;这3组的肝脂肪变性评分分别为(0.67±0.82),(7.50±0.84)和(5.67±1.63)分;这3组的iNOS表达量分别为2.11±0.23,4.59±0.65和3.45±0.46;这3组的Arg-1表达量分别为0.84±0.08,0.43±0.09和0.67±0.10。上述指标:正常组与模型组比较,或实验组与模型组比较,差异均有统计学意义(均P<0.05)。结论替米沙坦可改善胰岛素抵抗大鼠的非酒精性脂肪肝,其作用机制可能与改变巨噬细胞M1/M2型极化状态有关。

Objective To study the effect of telmisartan on nonalcoholic fatty liver disease in insulin-resistant rats and its possible mechanism. Methods The male rats were fed with high-glucose and high-fat to construct insulin resistance rats model. They were randomly divided into two groups according to weight after modeling: model group and experimental group, with 8 rat per group;and another 8 rats were fed routinely as normal group. The normal group and model group were given the same amount of 0.9% NaCl, while the experimental group was given 5 mg·kg^(-1) telmisartan dissolved in 2 mL of 0.9% NaCl. Three groups were given orally once a day for 12 weeks.The insulin resistance(HOMA-IR) in rats was calculated. The level(ratio of OD value)of iNOS and arginase-1(Arg-1)(inducible nitric oxide synthase) which was respectively specific marker of M1 type and M2 type macrophages in the liver of rats were detected by Western blot, and liver steatosis was scored. Results After administration, the HOMA-IR in normal group, model group and experimental group were 4.54±1.08, 10.83±0.82 and 5. 97 ± 0. 89;liver steatosis scores in the three groups were( 0. 67 ± 0. 82),( 7. 50 ± 0. 84) and( 5. 67 ± 1. 63)point;the level of iN OS in the three groups were 2. 11 ± 0. 23,4. 59 ± 0. 65 and 3. 45 ± 0. 46;the level of Arg-1 in the three groups were 0. 84 ± 0. 08,0. 43 ± 0. 09 and 0. 67 ± 0. 10. The above mentioned indexes in the model group were significantly different from those in normal group and experimental group( all P < 0. 05). Conclusion Telmisartan can improve the nonalcoholic fatty liver disease of rats with insulin resistance. And one of the possible mechanisms is to change the polarization state of liver macrophages.