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旋覆花汤对高脂高果糖高胆固醇饮食诱导非酒精性脂肪性肝炎小鼠模型的影响
DOI: 10.3969/j.issn.1001-5256.2023.06.014
伦理学声明：本研究方案于2021年5月7日经由上海中医药大学实验动物伦理委员会审查，伦理编号PZSHUTCM210507006，符合实验室动物管理与使用准则。
利益冲突声明：本文不存在任何利益冲突。
作者贡献声明：辛一敬负责实验实施，资料分析，论文撰写；陈逸云、杨海琳、卓蕴慧参与收集数据，修改论文；张定棋、周峰峰负责课题设计，拟定写作思路，指导撰写文章并最后定稿。
Effect of Xuanfuhua decoction on a mouse model of nonalcoholic steatohepatitis induced by high-fat, high-fructose, and high-cholesterol diet
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摘要:
目的 探讨旋覆花汤对高脂高果糖高胆固醇饮食诱导小鼠非酒精性脂肪性肝炎(NASH)的干预作用。 方法 32只雄性C57/BL6J小鼠随机分为正常组、模型组、旋覆花汤组和奥贝胆酸组，每组8只。高脂高果糖高胆固醇饮食造模第24周开始，各组给予相应药物干预，旋覆花汤组给药剂量为14.19 g/kg灌胃，奥贝胆酸组给药剂量为10 mg/kg灌胃，灌胃体积均为20 mL/kg，每天给药1次，连续6周。HE染色、油红O染色、天狼星红染色及Masson染色观察肝组织病理学变化、脂质沉积及胶原沉积；试剂盒检测血清ALT、AST、TC、TG、LDL-C和葡萄糖水平，肝组织TG及羟脯氨酸(Hyp)含量；实时荧光定量聚合酶链式反应检测肝组织脂质代谢相关、炎症相关以及纤维化相关基因的表达；免疫组化染色观察肝组织F4/80和α-SMA阳性表达。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 与正常组相比，模型组小鼠体质量、肝湿重、血清AST、ALT、TC、TG、LDL-C和葡萄糖水平均显著增高(P值均＜0.01)；HE染色显示，模型组小鼠肝组织可见肝细胞脂肪变，大量脂肪空泡，肝细胞气球样变以及炎症细胞浸润，且非酒精性脂肪性肝病活动度评分(NAS)较正常组显著增加(P＜0.01)；油红O染色显示，模型组小鼠肝细胞内有大量红色脂滴沉积，大小不一，油红O染色面积百分比和肝脏TG含量较正常组均显著增加(P值均＜0.01)；天狼星红染色和Masson染色显示，模型组小鼠窦周、中央静脉以及汇管区胶原纤维增生明显，且肝组织Hyp含量较正常组显著增加(P＜0.05)。与模型组比较，旋覆花汤组小鼠血清AST、ALT、TC、TG、LDL-C及葡萄糖水平均明显降低(P值均＜0.05)；肝组织脂肪变、炎症浸润、脂滴沉积以及胶原纤维增生明显改善，且NAS、油红O染色面积百分比、肝脏TG含量及Hyp含量均显著降低(P值均＜0.05)。与正常组相比，模型组小鼠肝组织脂质代谢相关基因SREBP-1c、FASN、SCD1、PPARγ和CD36，炎症相关基因F4/80、TNFα、CCL2和CD11b，以及纤维化相关基因α-SMA mRNA表达水平均显著增高(P值均＜0.05)；免疫组化染色结果显示，F4/80和α-SMA阳性表达显著增加(P值均＜0.01)。与模型组比较，旋覆花汤组小鼠肝组织SREBP-1c、FASN、SCD1、PPARγ、CD36、F4/80、TNFα、CCL2、CD11b及α-SMA mRNA表达均显著降低(P值均＜0.05)，免疫组化染色F4/80和α-SMA阳性表达明显减少(P值均＜0.01)。 结论 旋覆花汤对高脂高果糖高胆固醇诱导的小鼠NASH具有良好的干预作用，其可显著抑制肝脏脂质沉积、炎症反应及肝纤维化。 -
关键词:
- 非酒精性脂肪性肝炎 /
- 旋覆花汤 /
- 小鼠, 近交C57BL
Abstract:Objective To investigate the intervention effect of Xuanfuhua decoction on mice with nonalcoholic steatohepatitis (NASH) induced by high-fat, high-fructose, and high-cholesterol diet. Methods A total of 32 male C57/BL6J mice were randomly divided into normal group, model group, Xuanfuhua decoction group, and obeticholic acid group, with 8 mice in each group. Since week 24 of modeling using high-fat, high-fructose, and high-cholesterol diet, each group was given the corresponding drug for intervention at a dose of 14.19 g/kg by gavage for the Xuanfuhua decoction group and 10 mg/kg by gavage for the obeticholic acid group and a volume of 20 mL/kg for gavage, once a day for 6 consecutive weeks. HE staining, oil red O staining, Sirius Red staining, and Masson staining were used to observe the pathological changes, lipid deposition, and collagen deposition of liver tissue; related kits were used to measure the serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and glucose, as well as the content of TG and hydroxyproline (Hyp) in liver tissue; quantitative real-time PCR was used to measure the expression of genes associated with lipid metabolism, inflammation, and fibrosis in liver tissue; immunohistochemical staining was used to observe the positive expression of F4/80 and α-SMA in liver tissue. 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 normal group, the model group had significant increases in body weight, liver wet weight, and serum levels of AST, ALT, TC, TG, LDL-C and glucose (all P < 0.01). HE staining showed hepatocyte steatosis, a large number of fat vacuoles, hepatocyte ballooning degeneration, and inflammatory cell infiltration in liver tissue of the mice in the model group, and the model group had a significant increase in NAFLD activity score (NAS) compared with the normal group (P < 0.01). Oil red O staining showed the deposition of a large number of red lipid droplets with different sizes in hepatocytes of the mice in the model group, and compared with the normal group, the model group had significant increases in the area percentage of oil red O staining and the content of TG in the liver (P < 0.01). Sirius Red staining and Masson staining showed significant collagen fiber hyperplasia in the perisinusoidal area, the central vein, and the portal area in the model group, and the model group had a significant increase in the content of Hyp in liver tissue compared with the normal group (P < 0.05). Compared with the model group, the Xuanfuhua decoction group had significant reductions in the serum levels of AST, ALT, TC, TG, LDL-C, and glucose (all P < 0.05), significant improvements in hepatic steatosis, inflammatory infiltration, lipid droplet deposition, and collagen fiber hyperplasia, and significant reductions in NAS score, area percentage of oil red O staining, and content of TG and Hyp in the liver (all P < 0.05). Compared with the normal group, the model group had significant increases in the mRNA expression levels of lipid metabolism-related genes (SREBP-1c, FASN, SCD-1, PPAR-γ, and CD36), inflammation-related genes (F4/80, TNF-α, CCL2, and CD11b), and the fibrosis-related gene α-SMA (all P < 0.05), and immunohistochemical staining showed significant increases in the positive expression of F4/80 and α-SMA (P < 0.01). Compared with the model group, the Xuanfuhua decoction group had significant reductions in the mRNA expression levels of SREBP-1c, FASN, SCD-1, PPAR-γ, CD36, F4/80, TNF-α, CCL2, CD11b, and α-SMA in liver tissue (all P < 0.05), and immunohistochemical staining showed significant reductions in the positive expression of F4/80 and α-SMA (P < 0.01). Conclusion Xuanfuhua decoction has a good intervention effect on mice with NASH induced by high fat, high fructose, and high-cholesterol diet and can significantly inhibit hepatic lipid deposition, inflammatory response, and liver fibrosis. -
Key words:
- Non-alcoholic Steatohepatitis /
- Xuanfuhua Decoction /
- Mice, Inbred C57BL
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图 1 各组小鼠肝组织HE染色(×100)
注：a，正常组；b，模型组；c，旋覆花汤组；d，奥贝胆酸组。
Figure 1. HE staining of liver tissue in mice of each group (×100)
图 2 各组小鼠肝组织油红O染色(×50)
注：a，正常组；b，模型组；c，旋覆花汤组；d，奥贝胆酸组。
Figure 2. Oil red O staining of liver tissue in mice of each group (×50)
图 3 各组小鼠肝组织F4/80免疫组化染色(×100)
注：a，正常组；b，模型组；c，旋覆花汤组；d，奥贝胆酸组。
Figure 3. F4/80 immunohistochemical staining of liver tissue in mice of each group (×100)
图 4 各组小鼠肝组织天狼星红染色、Masson染色及α-SMA免疫组化染色结果(×100)
Figure 4. Sirius red staining, Masson staining and α-SMA immunohistochemical staining in mice of each group (×100)
表 1 PCR引物序列
Table 1. PCR Primer sequence
基因 引物序列 GAPDH 上游 5′-CATCACTGCCACCCAGAAGACTG-3′ 下游 5′-ATGCCAGTGAGCTTCCCGTTCAG-3′ CD36 上游 5′-GGACATTGAGATTCTTTTCCTCTG-3′ 下游 5′-GCAAAGGCATTGGCTGGAAGAAC-3′ SREBP-1c 上游 5′-CGACTACATCCGCTTCTTGCAG-3′ 下游 5′-CCTCCATAGACACATCTGTGCC-3′ FASN 上游 5′-CACAGTGCTCAAAGGACATGCC-3′ 下游 5′-CACCAGGTGTAGTGCCTTCCTC-3′ SCD1 上游 5′-GCAAGCTCTACACCTGCCTCTT-3′ 下游 5′-CGTGCCTTGTAAGTTCTGTGGC-3′ PPARγ 上游 5′-GTACTGTCGGTTTCAGAAGTGCC-3′ 下游 5′-ATCTCCGCCAACAGCTTCTCCT-3′ F4/80 上游 5′-CGTGTTGTTGGTGGCACTGTGA-3′ 下游 5′-CCACATCAGTGTTCCAGGAGAC-3′ CD11b 上游 5′-TACTTCGGGCAGTCTCTGAGTG-3′ 下游 5′-ATGGTTGCCTCCAGTCTCAGCA-3′ TNFα 上游 5′-GGTGCCTATGTCTCAGCCTCTT-3′ 下游 5′-GCCATAGAACTGATGAGAGGGAG-3′ CCL2 上游 5′-GCTACAAGAGGATCACCAGCAG-3′ 下游 5′-GTCTGGACCCATTCCTTCTTGG-3′ α-SMA 上游 5′-TGCTGACAGAGGCACCACTGAA-3′ 下游 5′-CAGTTGTACGTCCAGAGGCATAG-3′ 注：GAPDH，甘油醛-3-磷酸脱氢酶；CD36，脂肪酸转运蛋白；SREBP-1c，固醇调节元件结合蛋白-1c；FASN，脂肪酸合酶；SCD1，正硬脂酰辅酶A去饱和酶1；PPARγ，过氧化物酶体增殖物激活受体γ；F4/80，小鼠含生长因子样模体黏液样激素样受体；CD11b，分化抗原簇分子11b；TNFα，肿瘤坏死因子α；CCL2，趋化因子配体2；α-SMA，α-平滑肌肌动蛋白。 
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表 2 各组小鼠体质量和肝湿重结果比较
Table 2. Comparison of body weight and liver wet weight of mice in each group
组别 动物数(只) 体质量(g) 肝湿重(g) 正常组 8 33.90±1.60 1.26±0.07 模型组 8 43.78±3.321) 3.33±0.591) 旋覆花汤组 8 41.30±2.83 2.74±0.58 奥贝胆酸组 8 41.95±3.72 2.81±0.59 F值 12.825 18.230 P值 ＜0.001 ＜0.001 注：与正常组比较，1)P＜0.01。
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表 3 各组小鼠血清ALT、AST、TG、TC、LDL-C及葡萄糖水平变化
Table 3. Changes of serum ALT, AST, TC, TG and glucose levels in mice of each group
组别 动物数(只) ALT (U/L) AST (U/L) 葡萄糖(mmol/L) TC (mmol/L) TG (mmol/L) LDL-C (mmol/L) 正常组 8 32.83±6.82 139.67±16.88 5.45±1.27 3.61±0.39 0.85±0.07 0.21±0.02 模型组 8 348.67±89.131) 392.83±66.621) 8.22±0.831) 9.83±1.221) 1.28±0.121) 1.28±0.051) 旋覆花汤组 8 191.50±67.293) 279.67±62.733) 6.32±1.482) 6.96±0.993) 1.03±0.183) 1.03±0.072) 奥贝胆酸组 8 239.67±67.753) 282.33±80.343) 6.53±0.882) 6.73±0.873) 1.08±0.172) 0.87±0.072) F值 24.153 17.082 6.095 45.951 9.021 78.603 P值 ＜0.001 ＜0.001 0.004 ＜0.001 0.001 ＜0.001 注：与正常组比较，1)P＜0.01；与模型组比较，2)P＜0.05，3)P＜0.01。
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表 4 各组小鼠肝脏病理学NAS
Table 4. NAS of liver pathology in mice of each group
组别 动物数(只) 肝细胞脂肪变(分) 小叶内炎症(分) 肝细胞气球样变(分) 总分 正常组 8 0.00±0.00 0.00±0.00 0.00±0.00 0.00±0.00 模型组 8 3.00±0.001) 1.83±0.751) 2.00±0.001) 6.83±0.751) 旋覆花汤组 8 1.83±0.753) 0.83±0.413) 1.00±0.632) 3.67±1.212) 奥贝胆酸组 8 2.00±0.893) 1.00±0.632) 1.17±0.752) 4.17±1.472) F值 27.439 11.961 14.314 45.951 P值 ＜0.001 ＜0.001 ＜0.001 ＜0.001 注：与正常组比较，1)P＜0.01；与模型组比较，2)P＜0.05，3)P＜0.01。
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表 5 各组小鼠肝组织油红O染色面积百分比和肝脏TG含量
Table 5. Oil red O staining area ratio and hepatic TG content of mice in each group
组别 动物数(只) 油红O染色面积百分比(%) 肝组织TG (μg/g) 正常组 8 0.70±0.31 47.94±17.33 模型组 8 41.48±4.321) 172.34±22.501) 旋覆花汤组 8 24.76±6.562) 115.98±24.813) 奥贝胆酸组 8 27.75±7.392) 127.22±24.913) F值 59.233 31.058 P值 ＜0.001 ＜0.001 注：与正常组比较，1)P＜0.01；与模型组比较，2)P＜0.05，3)P＜0.01。
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表 6 各组小鼠脂质代谢相关基因表达
Table 6. The expressions of lipid metabolism related genes in mice of each group
组别 动物数(只) PPARγ mRNA相对表达量 CD36 mRNA相对表达量 SCD1 mRNA相对表达量 FASN mRNA相对表达量 SREBP-1c mRNA相对表达量 正常组 8 1.00±0.06 1.00±0.05 1.00±0.16 1.00±0.19 1.00±0.10 模型组 8 2.44±0.372) 2.70±0.252) 2.93±0.102) 2.64±1.692) 2.63±0.411) 旋覆花汤组 8 1.62±0.213) 1.96±0.084) 2.00±0.094) 1.20±0.453) 1.35±0.353) 奥贝胆酸组 8 1.78±0.31 1.87±0.134) 2.10±0.194) 1.40±0.543) 1.76±0.16 F值 29.605 21.404 31.045 3.878 6.034 P值 ＜0.001 ＜0.001 ＜0.001 0.025 0.004 注：与正常组比较，1)P＜0.05，2)P＜0.01；与模型组比较，3)P＜0.05，4)P＜0.01。
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表 7 各组小鼠肝脏炎症相关基因和蛋白表达
Table 7. The expressions of hepatic inflammation related genes and protein in each group
组别 动物数(只) mRNA相对表达量 F4/80蛋白阳性面积百分比(%) TNFα CD11b CCL2 F4/80 正常组 8 1.00±0.18 1.00±0.38 1.00±0.16 1.00±0.19 2.11±0.62 模型组 8 3.78±0.671) 3.33±0.231) 2.93±0.101) 2.64±1.691) 6.38±0.451) 旋覆花汤组 8 2.28±0.433) 2.22±0.743) 2.00±0.093) 1.20±0.453) 3.40±0.673) 奥贝胆酸组 8 2.49±0.613) 2.54±0.472) 2.10±0.19 1.40±0.543) 3.97±0.543) F值 30.138 23.167 14.449 12.761 28.787 P值 ＜0.001 ＜0.001 ＜0.001 ＜0.001 ＜0.001 注：与正常组比较，1)P＜0.05；与模型组比较，2)P＜0.05，3)P＜0.01。
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表 8 各组小鼠肝组织Hyp含量、α-SMA免疫组化染色阳性面积百分比和基因表达
Table 8. Hepatic Hyp content, percentage of positive area of α-SMA immunohistochemical staining and gene expression in mice of each group
组别 动物数(只) 肝组织Hyp (μg/g) α-SMA阳性面积百分比(%) α-SMA mRNA相对表达量 正常组 8 244.74±36.72 1.21±0.16 1.00±0.27 模型组 8 574.01±54.401) 4.88±0.651) 2.75±0.721) 旋覆花汤组 8 446.15±57.732) 2.23±0.102) 1.69±0.442) 奥贝胆酸组 8 464.48±79.082) 2.87±0.312) 1.92±0.262) F值 32.530 51.894 14.650 P值 ＜0.001 ＜0.001 ＜0.001 注：与正常组比较，1)P＜0.05；与模型组比较，2)P＜0.01。
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