血管生成抑制剂ZM 306416对高脂饮食诱导的非酒精性脂肪性肝病小鼠的保护作用  

Protective effects of angiogenesis inhibitor ZM 306416 on non-alcoholic fatty liver disease induced by high-fat diet in mice

作　　者：赵维良 王治霞 喇登海 姚元滨 Zhao Weiliang;Wang Zhixia;La Denghai;Yao Yuanbin(Department of Gastroenterology,Qinghai Recreation Hospital,Xining 810000,China;Department of Internal Medicine,Qinghai Integrated Traditional Chinese and Western Medicine Hospital,Xining 810001,China;Department of Internal Medicine,Qinghai People’s Hospital,Xining 810007,China)

机构地区：[1]青海省康乐医院消化内科,西宁810000 [2]青海省中西医结合医院内科,西宁810001 [3]青海省人民医院内科,西宁810007

出　　处：《中国肝脏病杂志（电子版）》2023年第2期36-46,共11页Chinese Journal of Liver Diseases：Electronic Version

基　　金：青海省重点研发与转化计划(2020-0202-SFC-0014)。

摘　　要：目的探讨血管生成抑制剂ZM 306316调节内脏脂肪的功能,分析其对高脂饮食诱导的非酒精性脂肪性肝病(non-alcohol fatty liver disease,NAFLD)小鼠的保护作用及可能机制。方法将32只C57BL/6J小鼠按照随机数字表法分为3组:高脂饮食组(含130 kcal l%的脂肪饲料,11只,HFD组)、低脂饮食组(含45 kcal l%的脂肪饲料,11只、LFD组)和高脂饮食-ZM组(添加0.8%ZM 306416,10只,HFD-ZM组),饲养15周,定时检测小鼠体质量。处死小鼠后,检测小鼠血清生物化学指标,包括丙氨酸氨基转移酶(alanine aminotransferase,ALT)、天门冬氨酸氨基转移酶(aspartate aminotransferase,AST)、总胆固醇(total cholesterol,TC)、甘油三酯(triglyceride,TG)和游离脂肪酸(free fatty acids,FFA)水平。采用免疫组织化学分析附睾脂肪组织中血管性假血友病因子(von Willebrand factor,vWF)阳性细胞数;采用实时荧光定量聚合酶链反应检测各组织中相关基因的表达。结果与HFD组相比,HFD-ZM组小鼠体质量[(37.53±3.64)g vs(45.17±3.22)g]、VAT质量[(2.25±0.85)g vs(3.34±0.54)g]、内脏脂肪细胞大小[(7854.9±60.4)mm2 vs(10800.6±52.7)mm2]、vWF阳性细胞[(47.32±6.2)个vs(31.2±5.4)个]、血管密度[(320.47±10.66)%vs(184.26±14.94)%]及附睾组织中血管生成因子VEGF-A mRNA相对表达量(0.54±0.16 vs 0.24±0.12)均显著降低(P均<0.05),而抗血管生成因子TSP-1的mRNA相对表达量(0.32±0.07 vs 0.42±0.14)显著升高(P<0.05);HFD-ZM组小鼠ALT[(122.47±4.11)U/L vs(95.28±2.21)U/L]、AST[(172.17±5.20)U/L vs(124.39±2.54)U/L]、TG[(4.91±1.13)mmol/L vs(3.56±1.07)mmol/L]、FFA[(1640.55±22.51)μEq/L vs(1131.62±18.33)uEq/L]和TC[(8.10±2.11)mmol/L vs(6.11±2.19)mmol/L]水平均显著降低,差异均有统计学意义(P均<0.05),小鼠肝小叶及门管区可见少量胶原纤维增生,主要位于小叶中央静脉周围,α-SMA阳性细胞数目显著减少。与HFD组相比,HFD-ZM组脂肪酸氧化基因mRNA相对表达量(CPT-1:1.64±0.17 vs 0.97±0.24;MCAD:1.23�Objective To investigate the angiogenesis inhibitor ZM 306316 in regulating visceral fat function and analyze the protective effect on non-alcoholic fatty liver disease(NAFLD)induced by high-fat diet in mice and its possible mechanism.Methods Total of thirty-two C57BL/6J mice were randomly divided into high fat diet group(130 kcal l%fat diet,11 cases,HFD group),low fat diet group(45 kcal l%fat diet,11 cases,LFD group)and high fat diet-ZM group(0.8%ZM 306416 was added,10 cases,HFD-ZM group),the mice were fed on different diets for 15 weeks.The body weight of the mice were measured regularly.The serum biochemistry index of the mice were detected,including alanine aminotransferase(ALT),aspartate aminotransferase(AST),total cholesterol(TC),triglyceride(TG)and free fatty acids(FFA).The number of vascular pseudophlebrand factor(von Willebrand factor,vWF)positive cells in epididymal adipose tissue was analyzed by immunohistochemistry.Real-time fluorescent quantitative polymerase chain reaction(FQ-PCR)was used to detect the expression of relevant genes in each tissue.Results The body mass[(37.53±3.64)g vs(45.17±3.22)g],VAT mass[(2.25±0.85)g vs(3.34±0.54)g],visceral adipocyte size[(7854.9±60.4)mm2 vs(10800.6±52.7)mm2],vWF positive cells(47.32±6.2 vs 31.2±5.4),vascular density[(320.47±10.66)%vs(184.26±14.94)%]and angiogenic factor VEGF-A mRNA relative expression(0.54±0.16 vs 0.24±0.12)of mice in HFD-ZM group were significantly lower than those in HFD group,and the relative mRNA expression of the anti-angiogenic factor TSP-1 was significantly higher(0.32±0.07 vs 0.42±0.14),the differences were statistically significant(all P<0.05).The level of ALT[(122.47±4.11)U/L vs(95.28±2.21)U/L],AST[(172.17±5.20)U/L vs(124.39±2.54)U/L],TG[(4.91±1.13)mmol/L vs(3.56±1.07)mmol/L],FFA[(1640.55±22.51)μEq/L vs(1131.62±18.33)μEq/L]and TC[(8.10±2.11)mmol/L vs(6.11±2.19)mmol/L]of mice in HFD-ZM group were significantly lower than those in HFP group,the differences were statistically significant(all P<0.05).A small amoun

关 键 词：脂肪性肝病 非酒精性 炎症 纤维化 脂肪组织 血管生成抑制剂 

分 类 号：R575.5[医药卫生—消化系统]