Rosuvastatin ameliorates high-fat and high-cholesterol diet-induced nonalcoholic steatohepatitis in rats
Rosuvastatin ameliorates high-fat and high-cholesterol diet-induced nonalcoholic steatohepatitis in rats
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DOI：
10.1111/liv.12033
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发表时间：
2013-02-01
影响因子：
6.7
通讯作者：
Itoh, Yoshito
中科院分区：
文献类型：
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作者：
Okada, Yoshihisa;Yamaguchi, Kanji;Itoh, Yoshito
背景与目的他汀类药物是3-羟基-3-甲基戊二酰辅酶A还原酶的抑制剂，具有抗炎、抗氧化、抗纤维化等多种作用，可抑制内源性胆固醇的合成。在这里，我们研究了他汀类药物是否改善脂肪性肝炎使用高脂肪和高胆固醇（HFHC）饮食诱导的大鼠模型。方法8周龄雄性Sprague-Dawley大鼠，分别饲喂对照饲料和HFHC饲料。半数HFHC饲料喂养大鼠经口给予2 mg/kg/天瑞舒伐他汀，持续12周。评价肝损伤、脂肪变性、纤维化和脂质过氧化/氧化应激标志物。结果如前所述，HFHC饮食诱导大鼠脂肪性肝炎伴高胆固醇血症。瑞舒伐他汀降低HFHC饲料喂养大鼠的油红O染色阳性面积、肝/体重比、血清总胆固醇水平和肝脏游离脂肪酸含量。进一步研究显示，瑞舒伐他汀显著降低了肿瘤坏死因子-a和白细胞介素-6的肝脏mRNA表达、血清丙氨酸氨基转移酶水平和肝小叶炎症分级。瑞舒伐他汀还可改善肝纤维化，降低转化生长因子β、结缔组织生长因子和1型前胶原的肝脏mRNA表达。同样，肝脏天狼星红染色或α-平滑肌肌动蛋白染色阳性区域和脂质过氧化/氧化应激标志物[肝脏8-羟基-氧鸟苷和肝脏4-羟基-2-壬烯醛]的表达减少。有趣的是，而肉毒碱棕榈酰转移酶-1和长链酰基辅酶A脱氢酶的表达没有受到影响，过氧化氢酶和酰基辅酶A氧化酶恢复。结论这些数据表明，瑞舒伐他汀不仅改善了肝脂肪变性，而且通过改善大鼠HFHC模型中过氧化物酶体β-氧化改善了肝损伤和肝纤维化。
Background/Aims Statins, which are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase and inhibit endogenous cholesterol synthesis, possess pleiotropic activities, such as anti-inflammatory, anti-oxidative and antifibrotic effects. Here, we investigated whether statins ameliorate steatohepatitis using a high-fat and high-cholesterol (HFHC) diet-induced rat model. Methods Eight-week-old male SpragueDawley rats were fed control chow or HFHC diet. Half of the HFHC diet-fed rats were orally administered 2 mg/kg/day rosuvastatin for 12 weeks. Hepatic injury, steatosis, fibrosis and markers of lipid peroxidation/oxidant stress were evaluated. Results As previously reported, HFHC diet induced steatohepatitis in rat livers with hypercholesterolaemia. Rosuvastatin decreased Oil Red O stained-positive areas, liver/body weight ratio, serum total cholesterol levels and hepatic free fatty acid contents in HFHC diet-fed rats. Further study revealed that rosuvastatin significantly decreased hepatic mRNA expression of tumour necrosis factor-a and interleukin-6, serum alanine aminotransferase levels and hepatic lobular inflammation grade. Hepatic fibrosis was also ameliorated by rosuvastatin with decreases in hepatic mRNA expression of transforming growth factor-beta, connective tissue growth factor and type-1 procollagen. Similarly, hepatic Sirius red stained or a-smooth muscle actin stained-positive areas and expression of markers of lipid peroxidation/oxidant stress [hepatic 8-hydroxy-oxyguanosine and hepatic 4-hydroxy-2-nonenal] were decreased. Interestingly, whereas the expression of carnitine palmitoyltransferase-1 and long-chain acyl-CoA dehydrogenase was not affected, that of catalase and acyl-coA oxidase was restored. Conclusions These data suggest that rosuvastatin improved not only hepatic steatosis but also hepatic injury and fibrosis via improved peroxisomal beta-oxidation in this rat HFHC model.