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小檗碱改善2型糖尿病合并代谢相关脂肪性肝病的机制研究
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| 篇名： | 小檗碱改善2型糖尿病合并代谢相关脂肪性肝病的机制研究 |
| TITLE： | Study on the mechanism of berberine in improving diabetes mellitus type 2 combined with metabolic-associated fatty liver disease |
| 摘要： | 目的 探讨小檗碱通过调节神经酰胺改善2型糖尿病（T2DM）合并代谢相关脂肪性肝病（MAFLD）的潜在机制。方法取血糖水平＞11.1mmol/L的db/db小鼠（即T2DM模型小鼠）32只，分为模型组，小檗碱低、高剂量组[100、200mg/（kg·d）]和二甲双胍组[300mg/（kg·d）]，每组8只；另取wt/wt小鼠8只，作为正常对照组。各组小鼠灌胃相应药液或水，每天1次，持续6周。观察小鼠实验期间的体重变化，并分析其末周体重差异；末次给药后，观察各组小鼠的体型，检测其空腹血糖（FBG）水平和血脂指标[总胆固醇（TC）、甘油三酯（TG）、低密度脂蛋白胆固醇（LDL-C）、高密度脂蛋白胆固醇（HDL-C）]含量；检测其空腹胰岛素（FINS）水平并计算胰岛素抵抗指数（HOMA-IR）和胰岛素敏感性指数（ISI）；检测其肝脏质量、肝脏指数和血清肝功能指标[丙氨酸转氨酶（AST）、天冬氨酸转氨酶（ALT）]水平，观察肝组织病理学变化，检测其肝组织中脂肪酸合成相关蛋白[固醇调节元件结合蛋白1（SREBP1）、脂肪酸合酶（FASN）、乙酰辅酶A羧化酶1（ACC1）]的表达。收集正常对照组、模型组、小檗碱高剂量组小鼠血清样本，进行非靶向脂质组学分析并验证。结果与模型组比较，小檗碱低、高剂量组小鼠肝组织细胞排列紊乱、脂质空泡等病理改变均得以改善；其末周体重，FBG水平，TC、TG、LDL-C含量，HOMA-IR（小檗碱低剂量组除外），肝脏质量和肝脏指数，AST、ALT水平，以及SREBP1、FASN、ACC1蛋白的表达均显著降低或下调，而HDL-C含量、FINS水平（小檗碱高剂量组除外）、ISI（小檗碱低剂量组除外）均显著升高（P＜0.05）。共鉴定出21个潜在差异代谢物，含多种神经酰胺；上述代谢物主要富集于鞘脂代谢、甘油磷脂代谢等通路；验证实验结果显示，高剂量小檗碱可显著降低模型小鼠血清神经酰胺含量（P＜0.05）。结论小檗碱可减轻T2DM合并MAFLD小鼠的胰岛素抵抗，改善其肝脏受损和脂质沉积，上述作用可能与降低神经酰胺含量有关。 |
| ABSTRACT： | OBJECTIVE To investigate the potential mechanism of berberine improving diabetes mellitus type 2 （T2DM） combined with metabolic-associated fatty liver disease （MAFLD） by regulating ceramide. METHODS Thirty-two db/db mice with blood glucose levels＞11.1 mmol/L （T2DM model） were divided into four groups： model group， berberine low- and high-dose groups [100， 200 mg/（kg·d）] and metformin group [300 mg/（kg·d）]， with 8 mice in each group. Additionally， 8 wt/wt mice were selected as the normal control group. Mice in each group were administered the corresponding drug solution or water by gavage once daily for a continuous period of 6 weeks. During the experiment， the body weight of the mice was monitored， and the differences in final body weight were analyzed. After the last administration， the body shape of the mice in each group was observed， and their fasting blood glucose （FBG） and the lipid indicators [total cholesterol （TC）， triglyceride （TG）， low-density lipoprotein cholesterol （LDL-C）， high-density lipoprotein cholesterol （HDL-C）] were measured. Fasting serum insulin （FINS） levels were also measured， and the insulin resistance index HOMA-IR） and insulin sensitivity index （ISI） were calculated. Liver weight， liver index and serum liver function indicators [alanine transaminase （ALT）， aspartate transaminase（AST）] were assessed， and hepatic histopathological changes were observed. Additionally， the expression of fatty acid synthesis-related proteins [sterol regulatory element-binding protein 1 （SREBP1）， fatty acid synthase （FASN）， acetyl-CoA carboxylase 1 （ACC1）] in liver tissue was examined. Serum samples from the normal control group， model group， and berberine high-dose group were collected for non-targeted lipidomics analysis and validation. RESULTS Compared with the model group， the pathological changes， including disordered liver tissue cell arrangement and lipid vacuoles， were significantly improved in the berberine low- and high-dose groups. The significant decreases or down-regulations were observed in body weight in the last week， as well as FBG， TC， TG， and LDL-C levels， HOMA-IR （except for the berberine low-dose group）， liver weight， liver index， AST and ALT levels， and protein expressions of SREBP1， FASN and ACC1. Additionally， HDL-C levels， FINS （except for the berberine high-dose group）， and ISI （except for the berberine low-dose group） were significantly increased （P＜0.05）. A total of 21 potential differential metabolites， including multiple types of ceramides， were identified； these metabolites were primarily enriched in sphingolipid metabolism and glycerophospholipid metabolism pathways. Verification experiments confirmed that high-dose berberine significantly reduced the serum content of ceramide in model mice （P＜0.05）. CONCLUSIONS Berberine reduces insulin resistance， improves liver damage and lipid accumulation in the T2DM combined with MAFLD mice， and these effects may be related to the reduction of ceramide content. |
| 期刊： | 2025年第36卷第16期 |
| 作者： | 李怡；康舒羽；王琪文；黄曼婷；曾聪彦；童隽；董更婷 |
| AUTHORS： | LI Yi，KANG Shuyu，WANG Qiwen，HUANG Manting，ZENG Congyan，TONG Jun，DONG Gengting |
| 关键字： | 小檗碱；2型糖尿病；代谢相关脂肪性肝病；非靶向脂质组学分析；鞘脂代谢；神经酰胺 |
| KEYWORDS： | berberine； diabetes mellitus type 2； metabolic-associated fatty liver disease； non-targeted lipidomics analysis； |
| 阅读数： | 4 次 |
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