血府逐瘀汤及其不同提取部位对高脂饮食诱导的非酒精性脂肪性肝病小鼠模型的影响

唐浩; 尹艺晓; 刘伟; 方怡; 王君; 胡义扬; 彭景华

doi:10.3969/j.issn.1001-5256.2022.12.010

血府逐瘀汤及其不同提取部位对高脂饮食诱导的非酒精性脂肪性肝病小鼠模型的影响

DOI: 10.3969/j.issn.1001-5256.2022.12.010

唐浩^{1, 2, 3, 4},
尹艺晓^{1, 2, 3, 4},
刘伟^{1, 2, 3, 4},
方怡^{1, 2, 3, 4},
王君^{1, 2, 3, 4},
胡义扬^{1, 2, 3, 4},
彭景华^{1, 2, 3, 4, , ,}

1.
上海中医药大学附属曙光医院，上海 201203
2.
上海中医药大学肝病研究所，上海 201203
3.
教育部肝肾疾病重点实验室(上海中医药大学)，上海 201203
4.
上海市中医临床重点实验室，上海 201203

基金项目:

国家自然科学基金面上项目 (81673750);

上海中医药大学附属曙光医院四明学者基金 (SGXZ-201911)

伦理学声明：本研究实验一于2020年7月15日经由上海南方模式生物研究中心动物看护与使用委员会审批，批号：IACUC2020-0018；实验二于2021年4月9日经由上海中医药大学实验动物福利与伦理委员会审批，批号：PZSHUTCM2100409023。两项实验均符合实验室动物管理与使用准则。

利益冲突声明：本研究不存在研究者、伦理委员会成员以及与公开研究成果有关的利益冲突。

作者贡献声明：唐浩负责研究数据收集分析，论文初稿撰写；尹艺晓、刘伟、方怡、王君参与研究数据的获取分析解释过程；胡义扬提供指导意见；彭景华负责研究设计，论文修改与定稿，研究资金获取。

详细信息

通信作者:
彭景华，pengjinghua2004@163.com

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出版历程
- 收稿日期: 2022-05-15
- 录用日期: 2022-06-20
- 出版日期: 2022-12-20

Effects of Xuefu Zhuyu decoction and its extracts on a mouse model of nonalcoholic fatty liver disease induced by high-fat diet

Hao TANG^{1, 2, 3, 4},
Yixiao YIN^{1, 2, 3, 4},
Wei LIU^{1, 2, 3, 4},
Yi FANG^{1, 2, 3, 4},
Jun WANG^{1, 2, 3, 4},
Yiyang HU^{1, 2, 3, 4},
Jinghua PENG^{1, 2, 3, 4
, ,
,}

1.
Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
2.
Institute of Liver Diseases, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
3.
Key Laboratory of Liver and Kidney Diseases of the Ministry of Education, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
4.
Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai 201203, China

Research funding:

General Project of National Natural Science Foundation of China (81673750);

Siming Scholar Foundation of Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (SGXZ-201911)

More Information

Corresponding author: PENG Jinghua, pengjinghua2004@163.com (ORCID: 0000-0002-0665-7666)

摘要

摘要: 目的评价血府逐瘀汤对非酒精性脂肪性肝病(NAFLD)的药效，解析血府逐瘀汤发挥效应的物质基础。方法实验一探究血府逐瘀汤对高脂饮食诱导的小鼠NAFLD的作用，将50只C57BL/6J健康雄性小鼠随机分为正常组、模型组、血府逐瘀汤高剂量和低剂量组、奥贝胆酸对照组，每组10只。正常组小鼠予对照饮食，其余各组高脂饮食，造模第13周开始灌胃给药，16周末取材。记录进食量、体质量，酶联免疫法测定空腹血清胰岛素水平，检测空腹血糖并计算胰岛素抵抗指数。HE染色和NAFLD活动评分(NAS)观察小鼠肝组织病理；油红O染色观察脂质沉积；检测肝组织TG和血清ALT水平。实验二分析血府逐瘀汤各提取部位对高脂饮食诱导的小鼠NAFLD的作用，利用水煎、水提醇沉、石油醚萃取技术，获得血府逐瘀汤提取部位1、2、3。将54只C57BL/6J健康雄性小鼠随机分为正常组、模型组、血府逐瘀汤提取部位1、2、3和血府逐瘀汤对照组，每组9只。正常组予对照饮食，其余各组高脂饮食，造模第13周开始灌胃给药，16周末取材。记录进食量、体质量，酶联免疫法测定空腹血清胰岛素含量，检测空腹血糖并计算胰岛素抵抗指数。HE染色和NAS评分观察小鼠肝组织病理；油红O染色观察脂质沉积；检测肝组织TG、GGT、血清ALT水平。正态分布的计量资料两组间比较采用t检验；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。非正态分布的计量资料多组间比较及进一步两两比较均采用Kruskal-Wallis H检验。结果实验一，血府逐瘀汤高、低剂量组和奥贝胆酸对照组均较模型组降低小鼠体质量和胰岛素抵抗指数(P值均＜0.05)，肝组织空泡状脂滴分布、小叶内炎症减少，肝细胞气球样变减轻，NAS评分下降(P值均＜0.05)，降低肝脏TG、血清ALT水平(P值均＜0.05)。血府逐瘀汤高、低剂量降低体质量、胰岛素抵抗指数和NAS总分的作用均优于奥贝胆酸(P值均＜0.05)。血府逐瘀汤低剂量改善血清ALT的作用优于奥贝胆酸(P＜0.05)。实验二，与模型组比较，血府逐瘀汤提取部位1、2、3组均显著降低小鼠空腹血糖及胰岛素抵抗指数(P值均＜0.05)，减少肝组织脂滴分布、小叶内炎症灶和肝细胞气球样变，降低NAS总分和肝脏TG水平(P值均＜0.05)。血府逐瘀汤提取部位1较模型组降低NAFLD小鼠体质量(P＜0.05)；提取部位2、3较模型组降低血清ALT水平(P值均＜0.05)；提取部位2较模型组降低肝组织GGT水平(P＜0.05)。提取部位2的作用最接近血府逐瘀汤复方。结论血府逐瘀汤及其各提取部位均可不同程度改善高脂饮食诱导的小鼠NAFLD，其中提取部位2很可能是血府逐瘀汤发挥效应的主要物质基础。
- 非酒精性脂肪性肝病 /
- 血府逐瘀汤 /
- 小鼠, 近交C57BL
Abstract: Objective To investigate the effect of Xuefu Zhuyu decoction on nonalcoholic fatty liver disease (NAFLD) and its material basis. Methods In experiment 1 for exploring the effect of Xuefu Zhuyu decoction on mice with NAFLD induced by high-fat diet, 50 healthy male C57BL/6J mice were randomly divided into normal group, model group, high- and low-dose Xuefu Zhuyu decoction groups, and obeticholic acid control group, with 10 mice in each group. The mice in the normal group were given control diet, and those in the other groups were given high-fat diet. Gastric administration was started at week 13, and related samples were collected at the end of week 16. Food intake and body weight were recorded, enzyme-linked immunosorbent assay was used to measure the serum level of fasting insulin, fasting blood glucose was measured, and insulin resistance index was calculated. HE staining and NAFLD activity score (NAS) were used to observe liver histopathology in mice, oil red O staining was used to observe lipid deposition, and triglyceride (TG) level in liver tissue and serum alanine aminotransferase (ALT) level were measured. In experiment 2 for exploring the effect of different extracts of Xuefu Zhuyu decoction on mice with NAFLD induced by high-fat diet, the methods of water decocting, water extraction and alcohol precipitation, and petroleum ether extraction were used to obtain the extracts 1, 2, and 3 of Xuefu Zhuyu decoction, and 54 healthy male C57BL/6J mice were randomly divided into normal group, model group, Xuefu Zhuyu decoction extract 1, 2, and 3 groups, and Xuefu Zhuyu decoction control group, with 9 mice in each group. The mice in the normal group were given control diet, and those in the other groups were given high-fat diet. Gastric administration was started at week 13, and related samples were collected at the end of week 16. Food intake and body weight were recorded, and enzyme-linked immunosorbent assay was used to measure the serum level of fasting insulin, fasting blood glucose was measured, and insulin resistance index was calculated. HE and NAS were used to observe liver histopathology in mice, oil red O staining was used to observe lipid deposition, and the levels of TG and gamma-glutamyl transpeptidase (GGT) in liver tissue and the serum level of ALT were measured. The t-test was used for comparison of normally distributed continuous data between two groups; a one-way analysis of variance was used for comparison between multiple groups, and the least significant difference t-test was used for further comparison between two groups. The Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data between multiple groups and further comparison between two groups. Results In experiment 1, compared with the model group, the high- and low-dose Xuefu Zhuyu decoction groups and the obeticholic acid control group had significant reductions in body weight, insulin resistance index, the distribution of vacuolar lipid droplets in liver tissue, intralobular inflammation, the ballooning degeneration of hepatocytes, NAS score, the level of TG in liver tissue, and the serum level of ALT (all P < 0.05). Compared with obeticholic acid, high- and low-dose Xuefu Zhuyu decoction had a significantly better effect in reducing body weight, insulin resistance index, and total NAS score (all P < 0.05), and low-dose Xuefu Zhuyu decoction had a significantly better effect in improving serum ALT (P < 0.05). In experiment 2, compared with the model group, the Xuefu Zhuyu decoction extract 1, 2, and 3 groups had significant reductions in fasting blood glucose, insulin resistance index, the distribution of lipid droplets in liver tissue, intralobular inflammation lesions, the ballooning degeneration of hepatocytes, total NAS score, and the level of TG in the liver (all P < 0.05). Compared with the model group, the extract 1 group had a significant reduction in body weight (P < 0.05); the extract 2 and 3 groups had a significant reduction in the serum level of ALT (P < 0.05); the extract 2 group had a significant reduction in the level of GGT in liver tissue (P < 0.05). The extract 2 of Xuefu Zhuyu decoction had the closest effect to compound Xuefu Zhuyu decoction. Conclusion Xuefu Zhuyu decoction and its extracts can help to achieve varying degrees of improvement in NAFLD induced by high-fat diet in mice, and the extract 2 of Xuefu Zhuyu decoction might be the main material basis for Xuefu Zhuyu decoction.
- Non-alcoholic Fatty Liver Disease /
- XuefuZhuyu Decoction /
- Mice, Inbred C57BL

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图 1 血府逐瘀汤对NAFLD小鼠肝组织病理及脂质沉积的影响

注：绿色箭头指示空泡状脂肪变性；黄色箭头指示炎症灶；蓝色箭头指示肝细胞气球样变。

Figure 1. Effects of XuefuZhuyu Decoction on liver histopathology and lipid deposition in NAFLD mice

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图 2 血府逐瘀汤各提取部位对NAFLD小鼠肝组织病理及脂质沉积的影响

注：绿色箭头指示空泡状脂肪变性；黄色箭头指示炎症灶；蓝色箭头指示肝细胞气球样变。

Figure 2. Effects of each extract of XuefuZhuyu Decoction on liver histopathology and lipid deposition in NAFLD mice

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表 1 肝组织NAS评分标准

Table 1. NAS scoring criteria for liver tissue

项目	标准	评分
肝细胞脂肪变	＜5%	0
	5%~33%	1
	34%~66%	2
	＞67%	3
小叶内炎症(200倍镜计数坏死灶)	无	0
	＜2个	1
	2~4个	2
	＞4个	3
肝细胞气球样变	无	0
	少见	1
	多见	2

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表 2 血府逐瘀汤对进食量、体质量、空腹血糖和胰岛素、胰岛素抵抗指数、肝脏TG、血清ALT的作用

Table 2. Effects of XuefuZhuyu Decoction on food intake, body weight, fasting blood glucose and insulin, insulin resistance index, liver TG, serum ALT

组别	动物数(只)	进食量(g/d)	体质量(g)	空腹血糖(mg/dL)	空腹血清胰岛素(ng/mL)	胰岛素抵抗指数	肝脏TG (mg/g)	血清ALT (U/L)
正常组	10	2.18±0.12	29.40±1.71	15.38±11.26	0.39±0.10	0.33±0.28	55.33±11.09	16.76±6.29
模型组	10	2.07±0.14	41.01±4.36¹⁾	52.08±19.79¹⁾	1.47±0.46¹⁾	4.16±2.31¹⁾	84.69±17.65¹⁾	77.03±42.46¹⁾
血府逐瘀汤高剂量组	7	1.96±0.31	30.46±1.30²⁾³⁾	35.05±15.89²⁾	0.39±0.14²⁾	0.75±0.48²⁾³⁾	37.19±19.03²⁾	4.54±2.91²⁾
血府逐瘀汤低剂量组	10	1.92±0.25	33.90±4.06²⁾³⁾	39.92±16.78	0.56±0.19²⁾	1.21±0.81²⁾³⁾	48.20±18.78²⁾	3.14±1.15²⁾³⁾
奥贝胆酸对照组	10	1.96±0.14	37.38±4.90²⁾	42.38±7.07	1.26±0.61	2.79±1.46²⁾	52.13±13.21²⁾	27.55±22.80²⁾
F值		1.37	16.24	8.42	17.98	13.59	11.10	16.07
P值		0.260	＜0.001	＜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；与奥贝胆酸对照组比较，3)P＜0.05。

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表 3 血府逐瘀汤对小鼠肝组织NAS评分的影响

Table 3. Effects of XuefuZhuyu Decoction on NAS score of mouse liver tissue

组别	动物数(只)	脂肪变	炎症浸润	气球样变	NAS总分
正常组	10	0	0	0	0
模型组	10	3.00(2.75~3.00)¹⁾	3.00(3.00~3.00)¹⁾	2.00(2.00~2.00)¹⁾	8.00(7.75~8.00)¹⁾
血府逐瘀汤高剂量组	7	0²⁾⁴⁾	0(0~1.00)²⁾	0(0~1.00)²⁾	0(0~1.00)²⁾⁴⁾
血府逐瘀汤低剂量组	10	0.50(0~1.00)²⁾³⁾	0(0~1.00)²⁾	0²⁾	1.00(0~1.25)²⁾⁴⁾
奥贝胆酸对照组	10	1.00(0.75~1.25)²⁾	1.00(0~1.00)²⁾	0(0~1.00)²⁾	1.50(1.00~4.00)²⁾
H值		35.76	32.49	37.64	36.70
P值		＜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；与血府逐瘀汤高剂量组比较，3)P＜0.05；与奥贝胆酸对照组比较，4)P＜0.05。

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表 4 血府逐瘀汤各提取部位对进食量、体质量、空腹血糖和胰岛素、胰岛素抵抗指数、肝脏TG、血清ALT、肝脏GGT的作用

Table 4. Effects of each extract of XuefuZhuyu Decoction on food intake, body weight, fasting blood glucose and insulin, insulin resistance index, liver TG, serum ALT

组别	动物数(只)	进食量(g/d/)	体质量(g)	空腹血糖(mg/dL)	空腹血清胰岛素(ng/mL)	胰岛素抵抗指数	肝脏TG (mg/g)	血清ALT (U/L)	肝脏GGT (μmol/g)
正常组	9	2.49±0.09	28.74±2.15	59.26±5.86	1.14±0.54	3.74±1.94	27.12±15.60	17.35±3.51	4.22±1.72
模型组	9	2.51±0.18	44.61±3.61¹⁾	93.09±18.59¹⁾	4.58±1.46¹⁾	22.12±8.10¹⁾	68.57±26.47¹⁾	45.25±8.06¹⁾	7.58±2.78¹⁾
血府逐瘀汤提取部位1组	9	2.52±0.29	39.26±7.12²⁾	38.37±5.40²⁾³⁾	3.68±2.29	7.43±3.57²⁾	38.81±15.26²⁾⁴⁾	48.87±31.21	5.78±3.51
血府逐瘀汤提取部位2组	9	2.44±0.30	39.99±6.12	51.99±10.33²⁾	3.74±2.29	8.32±3.43²⁾	29.58±13.79²⁾	34.32±6.31²⁾	4.89±2.13²⁾
血府逐瘀汤提取部位3组	9	2.50±0.36	41.27±4.39	38.00±3.19²⁾³⁾	4.98±1.61	9.82±2.98²⁾⁴⁾	28.61±10.58²⁾	31.45±9.79²⁾	5.92±2.25
血府逐瘀汤对照组	8	2.40±0.29	34.83±4.28²⁾	38.81±5.41²⁾³⁾	2.64±1.40²⁾	5.33±2.72²⁾	20.45±8.86²⁾	31.41±5.78²⁾	3.42±0.58²⁾
F值		0.47	11.56	42.06	5.92	18.45	9.96	5.51	3.31
P值		0.798	＜0.001	＜0.001	＜0.001	＜0.001	＜0.001	＜0.001	0.012
注：与正常组比较，1)P＜0.05；与模型组比较，2)P＜0.05；与血府逐瘀汤提取部位2组比较，3)P＜0.05；与血府逐瘀汤对照组比较，4)P＜0.05。

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表 5 血府逐瘀汤各提取部位对小鼠肝组织NAS评分的影响

Table 5. Effects of each extract of XuefuZhuyu Decoction on NAS score of mouse liver tissue

组别	动物数(只)	脂肪变	炎症浸润	气球样变	NAS总分
正常组	9	0	0	0	0
模型组	9	3.00(2.00~3.00)¹⁾	2.00(1.00~3.00)¹⁾	2.00(1.50~2.00)¹⁾	7.00(4.50~7.50)¹⁾
血府逐瘀汤提取部位1组	9	1.00(0.50~2.00)²⁾³⁾	0(0~1.00)²⁾	0²⁾	2.00(0.50~2.50)²⁾³⁾
血府逐瘀汤提取部位2组	9	0(0~1.00)²⁾	0(0~1.00)²⁾	0²⁾	1.00(0~2.00)²⁾
血府逐瘀汤提取部位3组	9	1.00(0~2.00)²⁾	0(0~1.00)²⁾	0²⁾	1.00(0~2.50)²⁾³⁾
血府逐瘀汤对照组	8	0²⁾	0²⁾	0²⁾	0²⁾
H值		31.56	29.84	51.69	34.97
P值		＜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；与血府逐瘀汤对照组比较，3)P＜0.05。

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