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沙棘熊果酸通过调节线粒体-细胞色素c抑制酒精性肝病大鼠模型肝细胞凋亡的作用分析
DOI: 10.3969/j.issn.1001-5256.2023.07.016
伦理学声明：本研究于2016年12月20日经由包头医学院医学伦理审查委员会审批，审批号：包医伦审2016第(015)号。
利益冲突声明：本文不存在任何利益冲突。
作者贡献声明：戈娜、李楠、李可欣等负责课题设计，资料分析；张文龙、王强、苏军等参与收集数据，修改论文；戈娜、包艳红负责拟定写作思路，撰写文章并最后定稿。
Ursolic acid in Hippophae rhamnoides L. inhibits hepatocyte apoptosis in rats with alcoholic liver disease by regulating mitochondria-cytochrome c
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摘要:
目的 基于线粒体-细胞色素c途径探讨沙棘熊果酸对酒精性肝病大鼠肝细胞凋亡的抑制作用。 方法 根据随机数字表将50只SPF级雄性Wistar大鼠进行完全随机分组，分为正常对照组、酒精模型组、沙棘熊果酸低、中和高剂量组，每组10只。正常对照组给予每日1次生理盐水灌胃8周；酒精模型组用阶梯式浓度酒精灌胃的方法持续灌胃8周；沙棘熊果酸组分别按50 mg/kg、100 mg/kg和150 mg/kg灌胃，1 h后再灌喂模型组同等剂量酒精。测定各组大鼠血清肝功能指标；HE染色观察肝组织病理情况；电镜下观察大鼠肝细胞超微结构；TUNEL法检测大鼠肝细胞凋亡情况；Western Blot法检测肝细胞线粒体和胞浆细胞色素c和活化caspase-3蛋白表达水平。计量资料多组间比较采用单因素方差分析，进一步两两比较采用LSD-t检验。 结果 与酒精模型组相比，沙棘熊果酸中、高剂量组大鼠血清ALT、AST和胆碱酯酶水平均下降(P值均＜0.05)；酒精模型组大鼠肝细胞索排列紊乱，肝细胞水肿、脂肪变性明显，而沙棘熊果酸中、高剂量组大鼠肝细胞索排列逐渐趋于正常、肝脂肪变性明显改善；肝细胞线粒体数目增加、形态明显改善；肝细胞凋亡率、胞浆细胞色素c和活化caspase-3蛋白的表达均低于酒精模型组(P值均＜0.05)。 结论 沙棘熊果酸可改善酒精性肝病大鼠肝功能和肝组织形态，可能与抑制肝细胞线粒体细胞色素c的释放及caspase-3蛋白的活化，通过线粒体-细胞色素c途径抑制肝细胞凋亡有关。 Abstract:Objective To investigate the inhibitory effect of ursolic acid in Hippophae rhamnoides L. on hepatocyte apoptosis in rats with alcoholic liver disease based on the mitochondria-cytochrome c pathway. Methods A total of 50 specific pathogen-free male Wistar rats were divided into normal control group, alcohol model group, and low-, middle-, and high-dose ursolic acid groups using a random number table, with 10 rats in each group. The rats in the normal control group were given normal saline by gavage once a day for 8 weeks; the rats in the alcohol model group were given alcohol at increasing concentrations by gavage for 8 consecutive weeks; the rats in the low-, middle-, and high-dose ursolic acid groups were given ursolic acid at a dose of 50, 100, and 150 mg/kg, respectively, followed by an equal volume of alcohol as the model group 1 hour later. Serum liver function parameters were measured for each group; HE staining was used to observe liver histopathology; an electron microscope was used to observe hepatocyte ultrastructure; the TUNEL method was used to measure hepatocyte apoptosis; Western Blotting was used to measure the protein expression levels of cytochrome c and activated caspase-3 in hepatocyte mitochondria and cytoplasm. A one-way analysis of variance was used for comparison of continuous data between multiple groups, and the least significant difference t-test was used for further comparison between two groups. Results Compared with the alcohol model group, the middle- and high-dose ursolic acid groups had significant reductions in the serum level of alanine aminotransferase, aspartate aminotransferase, and cholinesterase (all P < 0.05). The rats in the alcohol model group had disordered arrangement of hepatic cords with marked hepatocyte edema and fatty degeneration, while those in the middle- and high- dose ursolic acid groups had basically normal arrangement of hepatic cords and a significant improvement in hepatocyte fatty degeneration, as well as a significant increase in the number of hepatocyte mitochondria and a significant improvement in morphology. Compared with the alcohol model group, the middle- and high-dose ursolic acid groups had significantly lower hepatocyte apoptosis rate and protein expression levels of cytochrome c and caspase-3 in cytoplasm (all P < 0.05). Conclusion Ursolic acid in Hippophae rhamnoides L. can improve the liver function and histomorphology of rats with alcoholic liver disease, possibly by inhibiting the release of cytochrome c in hepatocyte mitochondria, the activation of caspase-3, and the apoptosis of hepatocytes via the mitochondria-cytochrome c pathway. -
Key words:
- Liver Diseases, Alcoholic /
- Hippophae Fructus /
- Apoptosis /
- Mitochondria /
- Cytochromes c
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图 1 沙棘UA对ALD大鼠肝组织病理改变的影响(HE染色，×200)
注：a，正常对照组；b，酒精模型组；c，UA低剂量组；d，UA中剂量组；e，UA高剂量组。
Figure 1. Effect of UA on liver histopathological structure in ALD rats(HE staining, ×200)
图 2 沙棘UA对ALD大鼠肝细胞超微结构的影响
注：a，正常对照组；b，酒精模型组；c，UA低剂量组；d，UA中剂量组；e，UA高剂量组。1，线粒体；2，细胞核；3，内质网；4，胶原纤维；5，脂滴；6，溶酶体；7，脂滴空泡；8，胆小管。
Figure 2. Effect of UA on hepatic cell ultrastructure in ALD rats
图 3 沙棘UA对ALD大鼠肝细胞凋亡的影响(TUNEL法)
Figure 3. Effect of UA on hepatic cell apoptosis in ALD rats(TUNEL method)
图 4 沙棘UA对ALD大鼠肝细胞凋亡率的影响
注: a，正常对照组；b，酒精模型组；c，UA低剂量组；d，UA中剂量组；e，UA高剂量组。
Figure 4. Effect of UA on hepatic cell apoptosis rates in ALD rats
图 5 沙棘UA对ALD大鼠肝脏线粒体和胞浆细胞色素c蛋白表达的影响
注: a，正常对照组；b，酒精模型组；c，UA低剂量组；d，UA中剂量组；e，UA高剂量组。
Figure 5. Effect of UA on the expression of hepatic mitochondrial and cytosolic cytochrome c protein in ALD rats
图 6 沙棘UA对ALD大鼠肝脏活化caspase-3蛋白表达的影响
注: a，正常对照组；b，酒精模型组；c，UA低剂量组；d，UA中剂量组；e，UA高剂量组。
Figure 6. Effect of UA on hepatic activated caspase-3 protein in ALD rats
表 1 沙棘UA对ALD大鼠血清ALT、AST和ChE水平的影响
Table 1. Effects of UA on level of ALT、AST、ChE in ALD rats serum
组别 动物数(只) ALT (U/L) AST (U/L) ChE (U/L) 正常对照组 10 45.88±6.73 88.14±11.89 291.69±65.95 酒精模型组 10 77.75±8.701) 125.14±16.421) 435.44±82.171) UA低剂量组 10 77.88±13.211) 141.00±14.041) 382.85±66.391) UA中剂量组 10 62.75±11.652)3) 102.86±5.872)3) 323.69±63.092) UA高剂量组 10 60.25±8.612)3) 91.28±12.292)3) 319.52±95.582) F值 11.050 10.316 4.095 P值 ＜0.001 ＜0.001 0.009 注：与正常对照组比较，1)P＜0.05；与酒精模型组比较，2)P＜0.05；与UA低剂量组比较，3)P＜0.05。 
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