奥贝胆酸对高脂喂养的C57BL/6J小鼠糖脂稳态的影响

doi:10.16352/j.issn.1001-6325.2023.05.0755

基础医学与临床 ›› 2023, Vol. 43 ›› Issue (5): 755-761.doi: 10.16352/j.issn.1001-6325.2023.05.0755

奥贝胆酸对高脂喂养的C57BL/6J小鼠糖脂稳态的影响

王星¹, 郭楠^2*

1.川北医学院药学院,四川南充 637100;
2.复旦大学附属闵行医院药剂科,上海 201199

收稿日期:2022-07-27 修回日期:2022-12-27 出版日期:2023-05-05 发布日期:2023-04-26
通讯作者: ^*guon@fudan.edu.cn
基金资助:
川北医学院博士科研启动基金(CBY21-QD16);上海市卫生健康委员会卫生行业临床研究专项(20204Y0106)

Effect of obeticholic acid on glucolipid homeostasis in high-fat fed C57BL/6J mice

WANG Xing¹, GUO Nan^2*

1. Department of Pharmacy, North Sichuan Medical College, Nanchong 637100;
2. Department of Pharmacy, Minhang Hospital, Fudan University, Shanghai 201199, China

Received:2022-07-27 Revised:2022-12-27 Online:2023-05-05 Published:2023-04-26
Contact: ^*guon@fudan.edu.cn

摘要/Abstract

摘要： 目的研究奥贝胆酸(OCA)对高脂喂养C57BL/6J小鼠糖脂代谢的影响。方法给C57BL/6J小鼠喂高脂饮食(HFD)12周后,将其随机分为模型组(model)和OCA干预组(10 mg/kg,连续灌胃6周),每组10只。喂12周正常饲料的C57BL/6J小鼠作为对照组(control),模型组和对照组灌胃给予0.5%羧甲基纤维素钠(CMC-Na)。实验期间开展口服葡萄糖耐量和胰岛素耐量实验。实验结束后,测定血清中肝功能相关指标,记录肝脏质量,测定肝脏中脂质相关指标,并对肝脏进行苏木精-伊红(HE)染色;RT-qPCR检测肝脏中脂质代谢相关基因表达。结果糖负荷和注射胰岛素后,模型组各个时间点血糖和曲线下面积(AUC)明显高于对照组(P＜0.01),OCA干预组能缓解模型组小鼠糖耐量异常(P＜0.05),提高胰岛素敏感性(P＜0.05);模型组血清中三酰甘油(TG)、总胆固醇(TC)、游离脂肪酸(FFA)、低密度脂蛋白总胆固醇(LDL-C)、丙氨酸氨基转移酶(ALT)和天冬氨酸氨基转移酶(AST)水平明显高于对照组(P＜0.01),高密度脂蛋白总胆固醇(HDL-C)水平显著低于对照组(P＜0.01),OCA干预组能显著降低模型组血清中TG、TC、FFA、LDL-C、ALT和AST水平(P＜0.01),增加模型组血清中HDL-C含量(P＜0.01);模型组肝脏中TG、TC、FFA含量明显高于对照组(P＜0.01),OCA干预组能缓解模型组小鼠肝脏脂肪变性(P＜0.05);模型组法尼醇X核受体(FXR)/固醇调节元件结合蛋白(SREBP)途径相关基因与对照组相比表达异常(P＜0.01),OCA干预组逆转模型组FXR/SREBP途径相关基因表达异常(P＜0.05)。结论 OCA可能通过调节FXR/SREBP途径改善HFD小鼠肝脏脂质代谢紊乱,进而改善HFD小鼠糖耐量异常和胰岛素抵抗。

关键词: 奥贝胆酸, 高脂饮食, C57BL/6J小鼠, 糖脂代谢, 肝脏脂肪变性

Abstract: Objective To investigate the effects of obeticholic acid (OCA) on glucolipid metabolism in high-fat fed C57BL/6J mice. Methods After 12 weeks of high-fat diet (HFD) feeding, C57BL/6J mice were randomly divided into two groups: model group (model) and OCA intervention group (10 mg/kg, gavage for six weeks), with 10 in each. The C57BL/6J mice were fed with normal diet for 12 weeks as the control group. The model group and the control group were given 0.5% sodium carboxymethyl cellulose (CMC-Na) by gavage. During the experiment, oral glucose and insulin tolerance tests were conducted. At the end of the experiment, the liver function related indicators were measured in serum, and the liver weight was recorded. The lipid-related indicators were measured in liver, and HE staining microscopy was performed. RT-qPCR was used to detected the expression of genes related to lipid metabolism in liver. Results After glucose loading and insulin injection, the blood glucose at each time point and area under curve (AUC) of the model group were significantly higher than those of the control group (P＜0.01). Abnormal glucose tolerance in OCA intervention group was reversed(P＜0.05) and the insulin sensitivity of the model group mice was improved(P＜0.05). The serum level of triglyceride (TG), total cholesterol (TC), free fatty acid (FFA), low density lipoprotein total cholesterol (LDL-C), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the model group was all significantly higher than those in the control group (P＜0.01), and HDL-C level was evidently lower than that in the control group (P＜0.01). The OCA intervention group could significantly reduce the serum levels of TG, TC, FFA, LDL-C, ALT, AST (P＜0.01) and increase the serum HDL-C content in the model group (P＜0.01). The contents of TG, TC, and FFA in the liver of the model group were significantly higher than those in the control group (P＜0.01), and OCA intervention group did alleviate the hepatic steatosis in the model group (P＜0.05). Compared with the control group, the expression of FXR/SREBP pathway related genes in model group was abnormal (P＜0.01), and OCA intervention reversed abnormal expression of FXR/SREBP pathway related genes in model group (P＜0.05). Conclusions OCA may improve the lipid metabolism disorder in the liver of HFD mice by regulating the FXR/SREBP pathway, thus improve the impaired glucose tolerance and insulin resistance in HFD mice.

Key words: obeticholic acid, high-fat diet, C57BL/6J mice, glycolipid metabolism, hepatic steatosis

中图分类号:

R965

王星, 郭楠. 奥贝胆酸对高脂喂养的C57BL/6J小鼠糖脂稳态的影响[J]. 基础医学与临床, 2023, 43(5): 755-761.

WANG Xing, GUO Nan. Effect of obeticholic acid on glucolipid homeostasis in high-fat fed C57BL/6J mice[J]. Basic & Clinical Medicine, 2023, 43(5): 755-761.

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奥贝胆酸对高脂喂养的C57BL/6J小鼠糖脂稳态的影响

Effect of obeticholic acid on glucolipid homeostasis in high-fat fed C57BL/6J mice

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