CN116712440A - 脱氧胆酸在制备促进脂滴裂解药物中的应用 - Google Patents
脱氧胆酸在制备促进脂滴裂解药物中的应用 Download PDFInfo
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Abstract
本发明公开了脱氧胆酸在制备促进脂滴裂解药物中的应用。具体地,脱氧胆酸能够应用在制备促进脂滴裂解药物中,以及应用在制备血管生成素样蛋白8Angptl8表达抑制药物中。本发明可为脱氧胆酸的应用提供新的方向。
Description
技术领域
本发明属于生物医药技术领域,涉及脱氧胆酸的新应用,尤其涉及脱氧胆酸在制备促进脂滴裂解的药物中的应用。
背景技术
肥胖是一种由遗传和环境因素引起的以过量体脂积累为特征的代谢性疾病。肥胖是二型糖尿病、高血脂、非酒精性脂肪肝、动脉粥样硬化、心衰、心梗、中风的高风险因子,严重威胁国民身体素质的提高,也给我国的医疗卫生支出造成了巨大负担。
近年来,肥胖已成为全球重要的公共健康问题。在过去的10-20年间,全球范围的成年人肥胖患病率大幅提升,预计到2030年,全球成年人肥胖和超重人数将达到33亿。而在我国,截至2019年,中国肥胖人数约有2.3亿,超重人数约有4.8亿。此外,我国儿童青少年肥胖患病率也持续明显升高,预计到2030年,中国6-17岁儿童青少年以及6岁以下儿童超重肥胖率将分别上升至31.8%和15.6%,预示未来中国成年人肥胖相关疾病负担将继续加重。
据最新估计,到2030年我国居民心脑血管疾病治疗费用可能高达2.9万亿元,占全部医疗花费的33%,如果有效控制肥胖可节省4300亿元。目前主要有5种消除脂肪的原理:①部分切胃,如胃旁路切除手术;②物理去除过量的脂肪组织,如抽脂手术;③抑制食欲,如食欲抑制药物奥利司他;④控制脂肪摄入,如采用低碳水低脂饮食和轻断食;⑤促进脂滴裂解,如增加运动。然而,有效预防和治疗肥胖的措施和药物仍然很少,尤其是靶向促进脂滴裂解的药物几乎没有。因此,有必要对靶向促进脂滴裂解的药物进行开发研究。
血管生成素样蛋白8(Angptl8)基因是人体细胞,尤其是脂肪细胞内调控脂滴裂解的关键基因。在细胞内高表达的Angptl8能抑制脂滴裂解,低表达和敲除Angptl8能促进脂滴裂解。目前,还没有靶向Angptl8促进脂滴裂解的药物。本发明针对靶向Angptl8促进脂滴裂解的药物进行了开发研究。
发明内容
本发明的目的在于提供脱氧胆酸的新用途,具体为在制备治疗或减轻肥胖症状的药物,以及促进脂滴裂解的药物的新用途,以及在制备血管生成素样蛋白8Angptl8表达抑制药物中的新用途。
具体技术方案如下:
本发明提供了脱氧胆酸在制备治疗或减轻肥胖症状的药物中的应用。所述脱氧胆酸的化学式为C24H40O4,结构式为:
本发明通过低频核磁共振观察发现口服脱氧胆酸的试验组能够显著性改善肥胖症状。进一步地,所述药物通过减少体重和体脂含量治疗或减轻肥胖症状。其中,所述体脂含量为全身总脂肪的含量,和/或甘油三脂的含量。
进一步地,所述药物通过促进肝脏和脂肪组织中脂滴裂解来治疗或减轻肥胖症状。
进一步地,所述药物通过至少以下方式中的一种来治疗或减轻肥胖症状;
(1)降低脂肪细胞中抑制脂滴裂解的关键基因血管生成素样蛋白8(Angptl8)的转录表达含量;
(2)降低肝脏中抑制脂滴裂解的关键蛋白血管生成素样蛋白8的转录表达含量。
本发明还提供了脱氧胆酸在制备促进脂滴裂解的药物中的应用。
进一步地,所述药物通过至少以下方式中的一种来诱导脂肪细胞胞内脂滴裂解;
(a)降低脂肪细胞中抑制脂滴裂解的关键基因Angptl8的转录表达含量。
(b)升高脂肪细胞中促进脂肪利用的关键基因ATGL和促进脂肪酸β氧化的关键基因Acad10的表达。
本发明还提供一种血管生成素样蛋白8Angptl8表达抑制药物。
本发明还提供一种促进肝脏细胞或脂肪细胞中脂滴裂解的药物。
本发明所述的药物包括脱氧胆酸、脱氧胆酸盐中的一种或多种,还可包括可药用载体,可以片剂、粉剂、胶囊、口服液体等形式存在。所述的药物为口服,活性成分给药量可以为:每天10ng/kg体重到33.3mg/kg体重。
进一步地,所述脱氧胆酸盐为脱氧胆酸钠、脱氧胆酸钾中的一种或多种。
与现有技术相比,本发明具有以下有益效果:
本发明提供了脱氧胆酸在制备血管生成素样蛋白8Angptl8表达抑制药物中的新用途,以及在制备促进脂滴裂解的药物中的新用途,为脱氧胆酸的应用提供了新的方向。
附图说明
图1为小鼠体重情况对比;
图2为小鼠体脂比例情况对比;
图3为脂肪细胞中Angptl8、ATGL、Acad10的表达情况对比(a)及肝脏中Angptl8的表达情况对比(b)。
图4为肝脏中甘油三脂含量对比;
图5为肝脏中(a)以及脂肪细胞中(b)Angptl8的表达情况对比;
图6为不同浓度脱氧胆酸直接处理原代肝细胞后Angptl8的表达情况对比;
具体实施方式
下面结合具体实施例对本发明作进一步描述,以下列举的仅是本发明的具体实施例,但本发明的保护范围不仅限于此。
实施例1
一、动物实验设计
脱氧胆酸口服长期干预试验
脱氧胆酸(Deoxycholic acid),是广泛使用的商业化化合物,为公众可获取的资源。高脂饲料高脂含量60%。
试验设置3组分别为:
①正常组(阴性对照,CON,n=5/组):基础饲料+8周自由饮水;
②高脂组(简称HFD,n=5/组):高脂饲料+8周自由饮水;
③高脂+脱氧胆酸组(简称HFD+DCA,n=5/组):高脂饲料++8周自由饮含脱氧胆酸水。
每组5只,进行8周的脱氧胆酸口服干预试验。脱氧胆酸采用饮水补充,饮水DCA浓度为100μg/mL。试验过程中每周准确测定小鼠生长指标(体重、采食量)。试验结束后,经CO2安乐死,收集血样和组织器官待测。
二、指标测定方法
(1)体脂比例的测定
体脂比采用核磁共振法(核磁身体组成分析仪MesoQMR06-100H,苏州纽迈)测定。
(2)肝脏和脂肪组织脂滴分解关键基因分析
转录组测序技术:液氮分别碾磨肝脏和脂肪组织,提取组织中总RNA,采用相应的关键基因的引物序列和建库试剂盒,测定肝脏中脂滴裂解的关键基因(Angptl8)和脂肪组织中脂滴裂解的关键基因(Angptl8/ATGL/Acad10)的转录表达情况。
三、实验结果
结果如图1-4所示。
由图1和图2可知,由于8周高脂饲料饲喂,HFD组体重和体脂含量均显著升高,表明在高脂饲料作用下导致了肥胖和体脂积累很明显,而脱氧胆酸饮水干预后,能显著降低体重和体脂含量,表明脱氧胆酸具有很好的治疗肥胖和体脂积累的作用。
Angptl8负责抑制脂肪细胞内脂滴裂解的功能。由图3可知,与HFD组相比,HFD+DCA组显著降低肝脏中抑制脂滴裂解的关键基因Angptl8的转录表达情况,显著降低脂肪组织中抑制脂滴裂解的关键基因Angptl8,显著升高脂肪组织中促进脂滴裂解的关键基因ATGL和促进脂肪酸β氧化的关键基因Acad10。由图4可知,与HFD组相比,HFD+DCA组显著降低肝脏中甘油三脂的含量,说明了脱氧胆酸能通过促进脂肪组织和肝脏中脂滴裂解来治疗或减轻肥胖。
实施例2
一、动物实验设计
脱氧胆酸口服短期干预试验
脱氧胆酸(Deoxycholic acid),是广泛使用的商业化化合物,为公众可获取的资源。
试验设置2组分别为:
①正常组(阴性对照,CON,n=5/组):基础饲料+1周自由饮水;
②脱氧胆酸组(简称DCA,n=5/组):基础饲料+1周自由饮含脱氧胆酸水。
每组5只,进行1周的脱氧胆酸口服短期干预试验。脱氧胆酸采用饮水补充,饮水DCA浓度为100μg/mL。试验结束后,经CO2安乐死,收集血样和组织器官待测。
二、指标测定方法
脂肪组织和肝脏中脂滴裂解关键基因Angptl8的分析
qPCR技术:液氮分别碾磨肝脏和脂肪组织,提取组织中总RNA,采用反转录试剂盒将RNA转化为cDNA,再采用关键基因的引物序列,使用qPCR荧光染色试剂盒,测定脂滴裂解的关键基因Angptl8的转录表达情况。
三、实验结果
由图5可知,脱氧胆酸饮水干预后,与CON组相比,DCA组显著降低脂肪组织和肝脏中抑制脂滴裂解的关键基因Angptl8,说明了脱氧胆酸能体内靶向Angptl8促进脂肪细胞和肝脏中的脂滴裂解。
实施例3
一、实验设计
脱氧胆酸处理原代肝细胞试验
脱氧胆酸(Deoxycholic acid),是广泛使用的商业化化合物,为公众可获取的资源。
试验设置3组分别为:
①正常组(阴性对照,CON,n=5/组):不加脱氧胆酸;
②脱氧胆酸组1(简称DCA1,n=5/组):加20μg/mL脱氧胆酸。
③脱氧胆酸组2(简称DCA2,n=5/组):加40μg/mL脱氧胆酸。
每组5个重复平板。原代肝细胞分离自6周龄的雄性C57BL/6J小鼠。分离得到原代肝细胞采用高糖DMEM细胞培养液外加10%胎牛血清和1%的青霉素和链霉素双抗试剂。培养条件为37℃和5% CO2。贴壁培养24小时后,换新鲜细胞培养液,采用20μg/mL和40μg/mL两个剂量处理细胞24小时后,收集新鲜细胞待测。
二、指标测定方法
肝脏和脂肪组织脂滴分解关键基因Angptl8的分析
qPCR技术:液氮分别碾磨细胞,提取组织中总RNA,采用反转录试剂盒将RNA转化为cDNA,再采用关键基因的引物序列,使用qPCR荧光染色试剂盒,测定脂滴裂解的关键基因Angptl8的转录表达情况。
三、实验结果
由图6可知,不同浓度脱氧胆酸直接处理细胞后,与CON组相比,20μg/mL和40μg/mLDCA组均能显著降低细胞中抑制脂滴裂解的关键基因Angptl8,说明了脱氧胆酸能直接激活Angptl8相关的胞内脂滴裂解途径来治疗或减轻肥胖。
Claims (9)
1.脱氧胆酸在制备促进脂滴裂解药物中的应用,所述脱氧胆酸的化学式为C24H40O4,结构式为:
2.如权利要求1所述的应用,其特征在于,脱氧胆酸通过降低脂肪细胞中血管生成素样蛋白8Angptl8的表达促进脂肪组织中脂滴裂解。
3.如权利要求1所述的应用,其特征在于,脱氧胆酸通过降低肝脏中血管生成素样蛋白8Angptl8的表达促进肝脏中脂滴裂解。
4.脱氧胆酸在制备血管生成素样蛋白8Angptl8表达抑制药物中的应用。
5.一种血管生成素样蛋白8Angptl8表达抑制药物,其特征在于,所述的药物包括脱氧胆酸和脱氧胆酸盐中的一种或多种。
6.一种促进肝脏细胞或脂肪细胞中脂滴裂解的药物,其特征在于,所述的药物包括脱氧胆酸和脱氧胆酸盐中的一种或多种。
7.如权利要求5或6所述的药物,其特征在于,所述的脱氧胆酸盐为脱氧胆酸钠和脱氧胆酸钾中的一种或多种。
8.如权利要求5或6所述的药物,其特征在于,所述的药物包括可药用载体。
9.如权利要求5或6所述的药物,其特征在于,所述的药物为口服,活性成分给药量为:每天10ng/kg体重到33.3mg/kg体重。
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