阻断肾素-血管紧张素系统对长期高脂喂养大鼠肝脂肪变性的影响

The effects of renin.angiotensin system blockade on the liver steatosis in rats on long-term high-fat diet

目的观察长期高脂喂养诱导胰岛素抵抗状态大鼠肝脏脂肪变性与肝内血管紧张素原（AGT）、解偶联蛋白2（UCP-2）和转化生长因子β1（TGFβ1）表达的关系，并通过阻断肾素-血管紧张素系统（RAS）观察是否改善肝脂肪变性，探讨其作用机制。方法40只大鼠分正常对照组、高脂组、血管紧张素转换酶抑制剂（ACEI）干预高脂组、血管紧张素Ⅱ受体阻滞剂（ARB）干预高脂组。正常血糖高胰岛素钳夹试验评价胰岛素敏感性，免疫组化和RT-PCR检测肝脏内AGT、UCP-2和TGFβ1蛋白及mRNA的表达，并检测血清脂质水平和肝内脂肪含量。结果正常对照组、高脂组、ACEI干预高脂组、ARB干预高脂组稳态第2小时葡萄糖输注率分别为（11．22±1．45）、（6．22±1．02）、（8．08±1．13）、（8．16±1．26）mg·kg^-1·min^-1。高脂组血清学指标和肝内脂肪含量均高于正常对照组（P〈0．05），ACEI干预高脂组、ARB干预高脂组与高脂组比较，肝内脂肪含量降低（P〈0．01），脂肪变和纤维化减轻，肝内UCP-2和TGFβ1表达减少（P〈0．05）。结论阻断RAS可改善胰岛素抵抗，并可能通过下调肝内UCP-2和TGFβ1的表达，对长期高脂喂养大鼠肝脏有保护作用。

Objective To observe the relationship between liver steatosis in rats with long-term high-caloric and high-fat diet and the expression of angiotensinogen （AGT）,uncoupling protein 2（UCP-2） and transforming growth factorβ1 （TGFβ1）. Then angiotensin-converting enzyme inhibitor （ACEI） and angiotensin Ⅱ receptor blocker （ARB） drugs were given to investigate whether rennin-angiotensin system （RAS） blockade can mitigate the liver steatosis and to probe its mechanisms. Methods Forty male Wistar rats were divided into normal control group （ NC group, n = 10 ）, high-calorie and high-fat fed group （ HF group, n = 10）, ARB treated group （AR group, n = 10） and ACEI treated group （AE group, n = 10）. Rats were fed with high-calorie and high-fat diet and given RAS inhibitor drugs （valsartan 40mg/kg to the AR group and perindopril 4 mg/kg to the AE group） for eight weeks. Serum TG, free fatty acids （FFAs） lever and the fat content in liver were then measured with biochemical tests; insulin resistance was evaluated with euglycemic hyperinsulinemia clamp technique, the expression of UCP-2 and TGFβ1 in liver tissue were examind with immunohistochemical staining and AGT mRNA,UCP-2 mRNA and TGFβ1 mRNA were tested with RT-PCR. Results With the administration of RAS inhibitor drugs, following changes were observed. The levels of TG and FFAs and the fat content in liver decreased（ P 〈 0.01 or P 〈 0. 05 ）, insulin resistance in high-fat fed rats was improved（P 〈 0. 05 ） , liver steatosis, inflammation and fibrosis were mitigated. The levels of UCP-2 decreased by 36.5% （P 〈0.05） in AE group and 42.5% （P 〈0. 05） in AR group and TGFβ1 decreased by 37% （P 〈0. 05） in AE group and 41.6% （P 〈0. 05） in AR group as compared with the HF group with immunohistochemical staining. The expression of AGTmRNA decreased by 14.9% （P 〈 0. 05 ） in AE group and 21% （ P 〈 0. 05 ） in AR group, UCP-2 mRNA decreased by 9% （ P 〈 0. 05 ） in AE group and 11% （ P 〈 0. 05 ） in AR group and TGFβ1 mRNA decreased by 17% （ P 〈 0. 05 ） in AE group and 19% （ P 〈 0.05 ） in AR group as compared with the HF group with RT-PCR. Conclusions RAS blockade could improve insulin resistance, mitigate the liver injury of long term high-fat fed rats and have a protective effect on liver. The mechanism may be associated with the effects of improved insulin resistance, the interaction within RAS and the down-regulation of UCP-2 and TGFβ1 in liver tissue.