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第44卷第10期 马 君,王 敏,陶梦圆,等. GLP⁃1/GIP双受体激动剂替西帕肽改善db/db小鼠代谢相关脂
2024年10月 肪性肝病[J]. 南京医科大学学报(自然科学版),2024,44(10):1344-1352 ·1345 ·
haemoglobin A1c(HbA1c)and body weight of mice in each group were compared. The levels of serum total cholesterol(TC),
triglyceride(TG),low⁃density lipoprotein⁃cholesterol(LDL⁃C),high⁃density lipoprotein⁃cholesterol(HDL⁃C),alanine aminotransferase
(ALT)and aspartate aminotransferase(AST)in each group were compared. HE staining and oil red O staining were used to compare
the liver pathological changes and lipid deposition in each group. Western blot and RT⁃PCR were used to detect the expressions of
inflammatory factors and fibrosis mediators in the liver tissues of mice in each group. Western blot was used to detect the insulin
signaling pathway and glucose metabolism related protein expression differences. Results:Compared with the model group,the levels
of FBG,HbA1c,body weight,TC,TG,LDL⁃C,ALT and AST in the Liraglutide group decreased by 56%,32%,20%,19%,22%,39%,
26% and 28%,respectively,while HDL⁃C increased by 25%. In Tirzepatide group,FBG,HbA1c,body weight,TC,TG,LDL⁃C,ALT,
and AST decreased by 69%,40%,30%,31%,35%,57%,46% and 38%,respectively,while HDL⁃C increased by 61%. HE staining
and oil red O staining showed that the liver of the model group showed obvious hepatocyte steatosis,balloon⁃like degeneration and
vacuolization,and a large number of lipid droplets were accumulated in hepatocytes. The hepatocyte steatosis and liver fat deposition of
the two intervention groups were improved,and the effect of Tirzepatide was better than that of Liraglutide. Western blot and RT⁃PCR
results showed that two drug intervention groups markedly reduced the expressions of inflammatory factors and fibrosis mediators,at
the same time,the two drugs increased insulin metabolic pathways related protein expression and decreased the glucose metabolism
related protein expression,and Tirzepatide was more effective than Liraglutide in improving the above indicators. Conclusion:
Tirzepatide can improve glucose and lipid metabolism disorders,reduce body weight,improve liver injury,reduce liver fat deposition,
and delay liver inflammation and fibrosis in MAFLD mice by activating insulin ⁃ related signaling pathway and reducing
gluconogenemia,and its comprehensive efficacy is better than that of Liraglutide,which may provide a new treatment for MAFLD.
[Key words] Tirzepatide;Liraglutide;metabolic associated fatty liver disease
[J Nanjing Med Univ,2024,44(10):1344⁃1352]
代谢相关性脂肪性肝病(metabolic associated 糖依赖性促胰岛素多肽(glucose⁃dependent insulino⁃
fatty liver disease,MAFLD),又称非酒精性脂肪性肝 tropic polypeptide,GIP)和 GLP⁃1 双受体激动剂替西
病(non⁃alcoholic fatty liver disease,NAFLD),影响了 帕肽(Tirzepatide)相比GLP⁃1受体激动剂,能更好地
[1]
全球1/3以上的人口 。MAFLD的特征是肝脂肪变 改善血糖和降低体重,并且其安全性与GLP⁃1受体激
[2]
性、胰岛素抵抗、氧化应激和慢性炎症 。它的病理 动剂一致 。2022 年 5 月替西帕肽已被美国食品和
[14]
进展始于肝脂肪变性,并可经历不同阶段,如非酒 药 物 管 理 局 批 准 为 治 疗 T2DM 的 药 物 ,但 其 对
精性脂肪性肝炎、肝纤维化、肝硬化,严重时可发展 MAFLD的改善作用是否优于利拉鲁肽仍未可知。
[3]
为肝细胞癌 。它的发病与胰岛素抵抗和代谢综合 本研究选择 db/db 小鼠作为研究对象,该类小
征等多种疾病密切相关,包括 2 型糖尿病(type 2 鼠因瘦素受体缺乏而导致肥胖、胰岛素抵抗、高血
diabetes mellitus,T2DM)、肥胖、高脂血症和高血压 。 糖、脂质代谢紊乱和肝脂肪变性,可用作MAFLD 研
[4]
迄今为止,美国食品和药物管理局尚未批准能够治 究的模型 [15] ,比较替西帕肽及利拉鲁肽对db/db小鼠
疗MAFLD的药物。由于MAFLD的致病因素之一是 MAFLD的影响,以期为MAFLD提供新的治疗方法。
胰岛素抵抗,因此正在MAFLD患者中评估T2DM药
1 材料和方法
物的疗效。
胰高血糖素样肽⁃1(glucagon⁃like peptide⁃1, 1.1 材料
GLP⁃1)受体激动剂利拉鲁肽(Liraglutide)目前已经广 1.1.1 动物
泛应用于 T2DM 的临床治疗,它已被证明具有降低血 7 周龄 SPF 级雄性 BKS db/db 小鼠和同窝对照
糖、血压、血脂,减重,改善胰岛素抵抗等作用 [5-8] 。最 db/m 小鼠购自江苏省集萃药康生物科技股份有限
近研究表明,利拉鲁肽对MAFLD 患者,尤其对合并 公司。将所有小鼠饲养在南京医科大学附属淮安
T2DM 的 MAFLD 患者有益 [9-13] 。在这些研究中,利 第一人民医院实验动物中心,环境温度为(21±2)℃,
拉鲁肽可改善血清转氨酶、减轻体重、降低血糖血 湿度为(45±10)%,每天进行12 h的光照/黑暗循环,
脂、减少肝脂肪变性和改善MAFLD 炎症反应,在有 实验期间各组小鼠可以自由获取灭菌的食物(含
些研究中甚至有减少肝纤维化的能力。新型葡萄 20%蛋白质、12%脂肪、68%碳水化合物)和水。所