6种精准脂肪肝小鼠模型病理表型与免疫特征的比较分析OA
Comparison of pathological phenotypes and immune characteristics in six precision mouse models of fatty liver disease
目的 比较 6 种常用的饮食造模方式对小鼠脂肪肝模型的影响,期望通过精准建模,更深入地研究脂肪肝的病理机制.方法 4 周龄雄性 C57BL/6J 小鼠随机分为 7 组(n=6～8):正常(ND)组、高脂(HFD)组、高脂高糖(HFHSD)组、胆碱缺乏(CDAA)组、高脂高果糖高胆固醇(AMLN)组、四氯化碳(CCl4)组及酒精(AFLD)组(后 6 组为造模组),进行为期 16 周的建模.通过血清生化、肝组织学及免疫学等多维度分析,评估各实验模型的病理表型及免疫特征.结果 与ND 组相比:(1)HFD 组、HFHSD 组、CDAA 组和AMLN组小鼠的体质量、肝质量及肝指数显著增加(P＜0.001);除 CCl4 组外,各组小鼠的肝 TG 含量和附睾脂肪质量显著升高(P＜0.05);(2)所有造模组小鼠血清 TG、TC 水平显著升高(P＜0.001);(3)所有造模组小鼠血清中 IL-1、IL-6、IL-8、TNF-α 的水平显著升高(P＜0.05);(4)病理学分析显示除 CCl4 组外,各组小鼠肝中均有大量脂滴形成,其中 AMLN 组、AFLD 组和 CCl4 组小鼠肝中有炎症细胞浸润,CCl4 组小鼠肝出现明显纤维化;(5)免疫组化显示除 CCl4 组外,各组小鼠肝中 CD4、CD8 阳性细胞均有增加;CD19 阳性细胞集中在HFHSD 组和 AMLN 组小鼠肝中;F4/80 阳性细胞集中在 AMLN 组和 CCl4 组小鼠肝中.结论 HFD、HFHSD与 CDAA 饮食适用于常规代谢功能障碍相关的脂肪性肝病(MASLD)研究;AMLN 饮食侧重于代谢功能障碍相关性脂肪性肝炎(MASH)进展、免疫调控及肝纤维化机制探索;CCl4 模型专用于肝纤维化及相关研究;Lieber-DeCarli 酒精液体饮食是研究 AFLD 的经典选择.
Objective To compare the effects of six common diet-induced modeling method on mouse models of fatty liver disease,and to further explore the pathological mechanisms through precision modeling.Methods Four-week-old male C57BL/6J mice were randomly divided into 7 groups:normal diet(ND),high-fat diet(HFD),high-fat and high-sugar diet(HFHSD),choline-deficient amino acid diet(CDAA),amylin liver NASH diet(AMLN),carbon tetrachloride(CCl4)treatment,and alcoholic liquid diet(AFLD)groups(n=6～8),among which the latter six were designated as modeling groups.The modeling period lasted for 16 weeks.Multi-dimensional analyses,including serum biochemistry,liver histology,and immunology,were performed to evaluate the pathological phenotypes and immune characteristics of each experimental model.Results Compared with the ND group,(1)The body mass,liver mass,and liver index of mice in the HFD,HFHSD,CDAA and AMLN groups increased significantly(P＜0.001);except for the CCl4 group,the hepatic triglyceride(TG)content and epididymal fat mass of mice in other groups increased significantly(P＜0.05).(2)The serum TG and total cholesterol levels of mice in all modeling groups increased significantly(P＜0.001).(3)Serum levels of interleukin-1(IL-1),IL-6,IL-8 and TNF-α in all modeling groups increased significantly(P＜0.05).(4)Pathological analysis showed that a large number of lipid droplets formed in the livers of mice in all groups except the CCl4 group;inflammatory cell infiltration was observed in the livers of mice in the AMLN,AFLD,and CCl4 groups,with obvious liver fibrosis observed in the CCl4 group.(5)The number of CD4 and CD8-positive cells in the livers of mice in all groups except the CCl4 group increased;CD19-positive cells were concentrated in the HFHSD and AMLN groups,while F4/80-positive cells were concentrated in the AMLN and CCl4 groups.Conclusions HFD,HFHSD and CDAA diets were deemed suitable for metabolic dysfunction-associated steatotic liver disease,while the AMLN diet was focused on the exploration of metabolic dysfunction-associated steatohepatitis,and liver fibrosis mechanisms.The CCl4 model can be used for liver fibrosis and related research,while the Lieber-DeCarli alcoholic liquid diet is ideal for studying alcoholic fatty liver disease.
栗宏伟;章慕宬;高静;许涛;周燕蓉;陈侃
浙江理工大学生命科学与医药学院,杭州 310018浙江理工大学生命科学与医药学院,杭州 310018浙江理工大学生命科学与医药学院,杭州 310018||东南大学生命科学与技术学院,南京 210096浙江理工大学生命科学与医药学院,杭州 310018浙江理工大学生命科学与医药学院,杭州 310018浙江理工大学生命科学与医药学院,杭州 310018
生物科学
脂肪肝C57BL/6J小鼠精准建模病理表型免疫特征
fatty liver diseaseC57BL/6J miceprecision modelingpathological phenotypeimmune characteristic
《中国实验动物学报》 2026 (7)
937-948,12
国家自然科学基金项目(81972281),国家级大学生创新创业训练计划(202410338074). Funded by National Natural Science Foundation of China(81972281),National College Students'Innovation and Entrepreneurship Training Program(202410338074).
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