灯盏花素通过调控LKB1/AMPK和Notch1/Jagged1通路改善高脂血症大鼠血脂水平及肝肾功能的作用机制研究＊

目的 基于LKB1/AMPK和Notch1/Jagged1通路探讨灯盏花素改善高脂血症大鼠血脂水平及肝肾功能的作用机制。方法 60只雄性SD大鼠随机为正常组、模型组、辛伐他汀组（20 mg·kg^-1）和灯盏花素低、中、高剂量组（6、12、24 mg·kg^-1）,每组10只。采用先腹腔注射75%蛋黄乳液后饲喂高脂饲料的方式建立高脂血症模型,同时给药干预,1次/天,连续28d。采用ELISA法检测大鼠血清中T-CHO、TG、LDL-C、HDL-C、AST、ALT、Cr、BUN水平;测定大鼠肝脏、肾脏系数;采用HE染色法观察肝肾组织病理学变化;采用免疫组化法检测肝组织p-AMPK、LKB1、HMGCR水平及肾组织Notch1、Jagged1、Hes1水平;采用RT-PCR法检测肝组织p-AMPK、LKB1、HMGCR水平mRNA水平及肾组织Notch1、Jagged1、Hes1 mRNA水平。结果 与正常组比较,模型组大鼠血清TG、T-CHO、LDL-C、ALT、AST、Cr、BUN水平明显升高（P<0.05）,HDL-C水平明显降低（P<0.05）;肝脏、肾脏系数明显增加（P<0.05）且出现病理变化;肝组织中p-AMPK、LKB1水平明显降低（P<0.05）,HMGCR水平明显升高（P<0.05）;肾组织Notch1、Jagged1、Hes1水平明显升高（P<0.05）。与模型组比较,辛伐他汀组和灯盏花素低、中、高剂量组大鼠血清TG、T-CHO、LDL-C、ALT、AST、Cr、BUN水平明显降低（P<0.05）,HDL-C水平明显升高（P<0.05）;肝脏、肾脏系数明显减小（P<0.05）且病变程度减轻;肝组织中p-AMPK、LKB1水平明显升高（P<0.05）,HMGCR水平明显降低（P<0.05）;肾组织Notch1、Jagged1、Hes1水平明显降低（P<0.05）。结论 灯盏花素能够改善高脂血症大鼠血脂水平及肝肾功能,其机制与激活LKB1/AMPK通路及抑制Notch/Jagged1通路和HMGCR水平有关。

Restoring the Blood Lipid Levels and Liver and Renal Functions of Breviscapine on Hyperlipidemia Rats by Regulating LKB1/AMPK and Notch1/Jagged1 Signal Pathway

Objective To study the protective effect and mechanism of breviscapine on blood lipids level and hepatic and renal functions in hyperlipidemia model rats.Methods Totally 60 healthy rats were randomly divided into normal, model (simvastatin 20 mg·kg^-1), and breviscapine 6, 12, 24 mg·kg^-1 groups, with 10 rats in each group. Hyperlipidemic rat model was induced by intraperitoneal injection of 75% solution of egg yolk and feeding high fat feed. The rats in each group were given the corresponding dose of drugs daily by gavage, and the intervention was continued for 4 weeks. ELISA method was used to detect total cholesterol (T-CHO), triglyceride (TG), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), aspartate aminotransferase (AST), alanine aminotransferase (ALT), creatinine (Cr) and urea nitrogen (BUN); Liver and renal weight was measured and liver and renal index was calculated; hematoxylin-eosin (HE) staining method was used to observe the histopathological characteristics of liver and renal tissues; Immunohistochemistry was used to determine the levels of p-AMPK, LKB1, HMGCR, Notch1, Jagged, and Hes1; RT-PCR was used to determine the mRNA levels of p-AMPK, LKB1, HMGCR, Notch1, Jagged, and Hes1.Results Compared with normal group, there was pathological changes in the liver and renal tissues of the model group; the liver and renal index and the level of TG, T-CHO, LDL-C, ALT, AST, Cr and BUN were significantly higher (P<0.05), and the level of HMGCR were significantly lower (P<0.05) in the model group; the level of p-AMPK and LKB1 were significantly lower (P<0.05), and HMGCR, Notch1, Jagged1 and Hes1 were significantly higher (P<0.05) in the model group. Compared with the model group, simvastatin and breviscapine (6, 12, 24 mg·kg^-1) decreased the renal index and the content of TG, T-CHO, LDL-C, ALT, AST, Cr, BUN and the level of HMGCR, Notch1, Jagged1 and Hes1 (P<0.05); improved the content of HDL-C and the level of p-AMPK and LKB1 (P<0.05); improved the histopathological changes of the hyperlipidemia rats.Conclusion Breviscapine have the liver and renal protective effect on hyperlipidemia rats, and its mechanism is related to activation LKB1/AMPK signal pathway and inhibition Notch1/Jagged1 signal pathway and the level of HMGCR.