长期给予辛伐他汀对实验性高胆固醇血症小鼠胆汁酸代谢及相关基因的影响

发布时间：2018-02-06 07:49

本文关键词： 辛伐他汀调脂药胆汁酸类和盐类胆固醇　出处：《中国新药与临床杂志》2017年09期 　论文类型：期刊论文

【摘要】：目的研究辛伐他汀对高胆固醇血症小鼠胆汁酸代谢通路的调控。方法 C57/BL小鼠随机分为正常对照组、模型组和辛伐他汀(20 mg·kg~(-1)·d~(-1))组。采用高脂饮食喂养16周制备高胆固醇血症模型,造模成功后给药22周,取肝脏组织HE染色,化学法测定血清总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)、丙氨酸转氨酶(ALT)及天冬氨酸转氨酶(AST)水平,实时定量PCR检测肝脏或肠组织中Cyp7a1、Cyp8b1、Fxr、Shp、Lrh1、Hnf4α、Fgf15、Fgfr4、Jnk1/2及Erk1/2的基因表达,液质联用技术分析肝脏中胆汁酸的含量。结果辛伐他汀显著降低了高胆固醇血症小鼠的TC及LDL-C水平(P0.05),改善了肝细胞内的脂肪蓄积,但是同时引起了ALT的异常升高,出现了肝损伤征兆。在胆汁酸通路的基因表达水平上,辛伐他汀可显著改善高脂饮食造成的胆汁酸通路相关基因的抑制,尤其是回调了胆汁酸合成关键酶Cyp7a1的基因表达(P0.05),对Fxr、Fgf15、Jnk1/2及Erk1/2等相关基因也有显著上调作用(P0.05)。辛伐他汀对胆汁酸调控肠肝循环通路基因Fgf15等有显著的回调作用(P0.05),但是对胆汁酸合成的关键酶Cyp8b1的抑制没有回调作用。肝脏胆汁酸含量在高脂饮食压力下显著抑制(P0.05),辛伐他汀对部分胆汁酸的肝脏丰度抑制程度加剧(P0.01)。结论辛伐他汀对胆汁酸通路中关键基因有显著的调控作用。
[Abstract]:Objective to study the regulation of simvastatin on bile acid metabolism pathway in hypercholesterolemia mice. Methods C57 / BL mice were randomly divided into normal control group. Model group and simvastatin 20 mg 路kg ~ (-1) 路d ~ (-1) group were fed with high-fat diet for 16 weeks to establish hypercholesterolemia model. The liver tissues were stained with HE and the levels of serum total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), alanine aminotransferase (alt) and aspartate aminotransferase (AST) were determined by chemical method. Real time quantitative PCR was used to detect the Fgfr4 伪 of Cyp7a1Cyp8b1Cyp8b1FxrHnf4 伪 and Fgf15 Fgfr4 in liver or intestine. Gene expression of Jnk1/2 and Erk1/2. Results Simvastatin significantly decreased TC and LDL-C levels in hypercholesterolemia mice and improved lipid accumulation in liver cells. At the same time, simvastatin can significantly improve the inhibition of genes associated with bile acid pathway caused by high fat diet in the level of gene expression of bile acid pathway. In particular, the gene expression of Cyp7a1, a key enzyme of bile acid synthesis, was corrected by P0.05, and Fxr-Fgf15. Jnk1/2, Erk1/2 and other related genes were also significantly up-regulated. Simvastatin had a significant callback effect on bile acid regulation of intestinal and hepatic circulation pathway gene Fgf15 (. P0.05). However, the inhibition of Cyp8b1, a key enzyme of bile acid synthesis, was not reversed. Liver bile acid content was significantly inhibited under high fat diet stress (P 0.05). The inhibition degree of simvastatin on the hepatic abundance of some bile acids was aggravated by P0.01.Conclusion Simvastatin plays a significant role in regulating the key genes in bile acid pathway.
【作者单位】：遵义医学院药学院国家级药学实验教学示范中心药学实验室;上海中医药大学上海市复方中药重点实验室;遵义医学院基础药理教育部重点实验室暨特色民族药教育部国际合作联合实验室;遵义医学院附属医院药剂科;
【基金】：国家自然科学基金(81402985,81560673,81660685) 贵州省科技重大专项(黔科合重大专项字[2015]6010) 贵州省科学技术基金(黔科合J字[2015]2158号,黔科合JZ字[2015]2010号) 贵州省出国留学人员择优资助计划(黔人项目资助合同(2015)03号) 上海市复方中药重点实验室开放基金(14DZ2271000) 国家级/省级大学生创新创业项目(201510661002) 遵义医学院大学生创新创业项目(遵医[2015]5046) 贵州省药剂学研究生卓越人才培养计划(黔教研合ZYRC字[2014]019)
【分类号】：R965

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