CN110583579A - 电压门控质子通道Hv1在治疗肥胖中的功能和应用 - Google Patents
电压门控质子通道Hv1在治疗肥胖中的功能和应用 Download PDFInfo
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
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- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
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- A01K2267/03—Animal model, e.g. for test or diseases
- A01K2267/035—Animal model for multifactorial diseases
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Abstract
本发明公开了电压门控质子通道Hv1蛋白在肥胖发展过程中的作用，建立的良好的肥胖动物模型，属于医学领域。研究中采用高脂饲料喂养C57BL/6J野生型小鼠和具有相同遗传背景的Hv1基因敲除小鼠建立体内肥胖模型，发现Hv1缺失小鼠体内累积的白色脂肪组织、细胞体积以及体重明显高于野生型小鼠。血清中的胆固醇、胰岛素含量明显升高，即有高脂血症。通过计算小鼠血清中的血糖与胰岛素浓度发现Hv1缺失的小鼠具有更高的胰岛素抵抗系数，即高胰岛素血症。肝脏中也观察到饮食引起的脂肪变性和炎症。这些结果表明Hv1基因敲除会导致高脂饮食诱导的过度肥胖症。这种小鼠可以作为一种肥胖动物模型鼠供于研究应用。针对Hv1的功能，可用于制备预防，缓解和/或治疗肥胖的药物。
Description
技术领域
本发明属于基因的功能与应用领域，特别涉及建立电压门控质子通道Hv1敲除小鼠作为肥胖模型小鼠， Hv1作为药物标靶在筛选治疗肥胖疾病的药物中应用，以及Hv1的激活剂在制备和/或筛选预防，缓解和/ 或治疗肥胖疾病的药物中的应用。
技术背景
随着物质生活水平的提高和生活模式的改变，以肥胖、高血脂、动脉粥样硬化、高血压、糖尿病等为代表的代谢综合征已成为首要危害人民健康的一组疾病。大量研究显示，肥胖症是高血压、糖尿病、冠心病、脑血管疾病、慢性肾脏病等多种疾病的危险因子。建立肥胖动物模型，对于研究肥胖及其相关疾病的发生发展和机制具有不可替代的作用。目前常用营养性、精神抑制药、维生素D、下丘脑损伤性、双侧卵巢切除法等五种肥胖动物模型，其造模方法、肥胖指标的变化和应用均有较大差异，造模不易于操作，不规范，且成功率低。因此开发一种新的肥胖小鼠模型十分重要。
目前科研中常用瘦素基因缺失(ob/ob)小鼠作为肥胖动物模型。利用这种小鼠曾进行了许多关于肥胖症的生化、症理、激素及药物治疗等的研究。除ob突变形外，后来又发现ad即成年肥胖和糖尿症。ad/ad 型的肥胖症体重相当于正常鼠的两倍，与ob/ob型一样，通常不育，7～10周龄时表现出高血糖和糖尿症。因为这些种类的鼠无生育力，所以必须用杂合子交配以保持此基因。这就导致饲养操作程序繁琐、饲养成本高、可用的纯合子产率降低，数量少。
电压门控质子通道是一种依赖细胞膜电位或细胞内外pH值来调节的对质子具有特异选择性的质子通道。Hv1对质子具有高选择性和高电导率，该通道活性依赖于细胞膜电位和细胞内外的pH值。Hv1在巨噬细胞呼吸爆发(respiratory burst)过程中把NADPH氧化酶(NOX)产生的H+离子排出细胞内从而维持细胞内恒定的pH值和NOX蛋白的活性，维持ROS的产生，我们之前研究发现Hv1在胰岛上表达并且调节胰岛素的分泌[7]，Hv1的缺失减弱了STZ诱导的胰岛的损伤和胰岛的糖氧化毒性。以往的研究表明，在很大程度上脂肪细胞中过量的葡萄糖和棕榈酸盐不是通过线粒体氧化进行代谢，而是通过多戊糖磷酸途径 (PPP)，产生大量的NADPH和H+，这也是细胞NADPH的主要来源，并导致NADPH氧化酶(NOX)激活。在生物体内PPP除提供能量外，为脂肪酸、胆固醇的生物合成提供NADPH原料。脂肪细胞在这个代谢过程中将产生大量的H+，Hv1可能通过排出H+维持细胞内恒定的pH值和NOX蛋白的活性，从而维持脂肪细胞的正常代谢以及胰岛素敏感性。
发明内容
为了解决上述现有技术的缺陷和不足，本发明的目的在于提供一种新的方便的肥胖小鼠模型，应用于肥胖发展过程中机制的研究及减肥药物的筛选及研发。同时说明Hv1与肥胖发生发展之间的关系，进而把 Hv1的抑制剂和激活剂等相关药物应用于肥胖的治疗。
本发明的目的通过以下技术方案实现：
本发明以野生型C57小鼠(WT)与电压门控质子通道Hv1基因敲除小鼠(KO)为实验对象，同时采用正常饮食喂养(NCD)和高脂饲料喂养(HFD)来对比研究Hv1基因的功能，发现在高脂饮食诱导肥胖组Hv1 基因敲除小鼠相比于WT小鼠表现出各种过度肥胖症状。Hv1基因缺失的小鼠体内白色脂肪组织的积累、脂肪细胞的体积以及体重明显高于野生型小鼠。同时血清中的胆固醇、胰岛素含量明显升高，即有高脂血症。此外，通过比较小鼠禁食血清中的血糖浓度与胰岛素浓度发现Hv1基因缺失的小鼠具有更高的胰岛素抵抗系数，即有高胰岛素血症。小鼠附睾脂肪组织中的炎症因子以及炎细胞浸润明显增加，肝脏组织中也观察到更严重的饮食引起的脂肪变性和炎症。这些结果表明Hv1基因敲除会导致高脂饮食诱导的过度肥胖症。
一种电压门控质子通道Hv1基因在肥胖发生发展中的功能，具体体现在电压门控质子通道Hv1维持脂肪细胞代谢平衡，尤其在体内营养过多的时候，Hv1基因缺失导致白色脂肪堆积。
针对电压门控质子通道Hv1具有维持细胞代谢稳态和改善脂肪过度积累的功能，以Hv1为靶向可用于制备预防，缓解和/或治疗肥胖的药物。
针对电压门控质子通道Hv1具有维持细胞代谢稳态和改善脂肪过度积累的功能，敲除Hv1可制作肥胖小鼠模型，用于肥胖发生发展机制的研究及制备预防，缓解和/或治疗肥胖药物的开发研究。
本发明相对于现有技术具有如下的优点及效果：
(1)本发明发现Hv1基因的新功能，即Hv1蛋白具有调节脂肪细胞代谢和体内代谢稳态的功能和减肥的作用。
(2)基于Hv1在脂肪细胞代谢中的作用，Hv1的抑制剂和激活剂可用于制备预防/缓解和/或治疗肥胖的药物。
(3)基于Hv1在调节脂肪细胞中的作用，敲除Hv1可用于制备肥胖小鼠模型，用于肥胖发生发展机制的研究及制备预防，缓解和/或治疗肥胖的药物的开发研究。
附图说明
图1 Hv1缺失导致高脂饮食诱导的体重过度增加。
A：本次研究的实验设计图。
B和C：经过16周高脂饲料喂养后WT和KO小鼠体型外观以及解剖的内部对比图。
D、E和F：小鼠的体重变化的统计结果图。
G和H：高脂饮食组WT和KO小鼠能量的摄取以及转化效率。
图2高脂饮食导致Hv1缺失小鼠体内脂肪的过度累积。
A：高脂喂养WT和KO小鼠体内附睾脂肪、肝以及肾脏和其周围脂肪堆积的对比图。比例尺1厘米。
B：高脂饲料喂养后WT和KO小鼠附睾脂肪和肝脏重量统计结果图。
C和D：正常喂养以及高脂喂养组的WT和KO的附睾脂肪组织的形态学观察苏木素和伊红(HE)染色图片和细胞体积的统计结果图。比例尺100微米。
图3高脂喂养的WT和KO小鼠体内的葡萄糖和胰岛素稳态。
A和B：高脂喂养组小鼠通过腹腔注射葡萄糖后的血糖水平以及曲线下面积的统计结果图。
C：高脂喂养组小鼠通过腹腔注射葡萄糖后的体内胰岛素水平的统计结果图。
D、E和F：小鼠禁食血糖和血清胰岛素浓度的统计以及胰岛素抵抗系数计算结果图。胰岛素抵抗系数＝(禁食血糖浓度mM×禁食胰岛素浓度mU/L)÷22.5
G：高脂喂养组小鼠通过腹腔注射胰岛素后的体内血糖水平的统计结果图。
H和I：禁食小鼠的血清总胆固醇和甘油三酯的浓度统计结果图。
图4 Hv1缺失小鼠在高脂喂养后出现明显的肝脂肪变性以及炎细胞浸润。
A和B：小鼠肝脏冰冻切片的油红O染色图以及阳性面积占总面积的百分比统计图。比例尺50微米。
C和D：小鼠肝脏石蜡切片的CD68免疫组织化学染色图以及阳性面积占总面积的百分比统计图。比例尺100微米。数据统计结果为平均值±SEM。*，p＜0.05；**，p＜0.01；***，p＜0.001vs.标准喂养WT鼠，#，P＜0.05；##，P＜0.01；###，P＜0.001，高脂喂养WT vs.高脂喂养KO鼠。
具体实施方式
下面结合实例及附图对本发明作进一步详细的描述，但本发明的实施方式不限于此。
实验用动物及饲养
实验动物种属，性别，周龄及来源：C57BL/6J(WT)小鼠和Hv1基因缺失小鼠(KO)，雄性，周龄均为5周(除明确说明小鼠周龄外)。C57BL/6J小鼠购自北京维通利华实验动物技术有限公司；Hv1基因敲除小鼠(南开大学自制)。
实验动物饲料：正常喂养组为标准维持饲料，购自北京科奥协力饲料有限公司，热量百分比：蛋白质 20％，碳水化合物70％，脂肪10％；总的热量质量比3.85kcal/g。高脂饮食组为高脂饲料，热量百分比：蛋白质20％，碳水化合物35％，脂肪45％；总的热量质量比4.73kcal/g。
动物饲养及环境条件：所有的实验小鼠均饲养在南开大学生命科学学院SPF级动物房。每12小时交替照明，温度20±2℃，湿度40％-70％，小鼠自由饮水进食。
实施例1 小鼠体重，血糖血脂水平测定
将小鼠分为四组分别为正常喂养组野生型(NCD-WT，n＝15)、正常喂养组Hv1基因敲除鼠(NCD-KO， n＝18)，高脂喂养组野生型(HFD-WT，n＝16)以及高脂喂养组Hv1基因敲除鼠(HFD-KO，n＝12)。
体重测量：四组小鼠分别从5周龄起，每周测量体重并记录数据。
禁食血清采集及各生化指标测量：分别将四组小鼠在上午8：00开始禁食(不禁水)，下午2：00从尾尖取血。眼科剪迅速在距离鼠尾末端0.2cm左右处剪下鼠尾，待血滴自行流出，弃第一滴血，用血糖仪测量血糖浓度。再收集血液于肝素化的离心管中，静置4小时后，离心收集血清用于另一离心管存放于 -80℃，用于后续生化指标的测量。
血糖仪(美国强生公司，ONE TOUCH)；总胆固醇以及甘油三酯检测试剂盒(合肥博美生物技术公司)；胰岛素检测试剂盒(默克公司，瑞典)。
体重和血糖血脂水平是判断肥胖的重要指标，正常喂养组WT小鼠和KO小鼠在体重上无显著差别，但在高脂饮食诱导后KO小鼠体重明显升高，摄食的能量转化效率明显变高(图1)，禁食血清中胰岛素以及总胆固醇的含量明显升高(图3)，这表明Hv1基因对调节体内营养代谢平衡有重要作用，Hv1基因的缺失会显著影响小鼠高脂饮食后的营养代谢，导致小鼠特别容易发胖。
实施例2 葡萄糖耐量实验(IPGTT)以及葡萄糖刺激的胰岛素分泌实验
在高脂喂养16周后，分别对WT和KO组小鼠进行腹腔注射葡萄糖实验(IPGTT)，以评价小鼠机体对糖耐受能力。每组各取6只，在小鼠称重后，根据2g/kg计算葡萄糖的注射体积，葡萄糖的使用浓度是20％。分别于腹腔注射后15/30/60/120分钟时间点剪尾测小鼠血糖值，并记录血糖数值和监测时间。同时收集腹腔注射后2/5/15/30分钟的时间点剪尾取小鼠血液，静置离心后取上清测量血清中的胰岛素浓度。
实施例3 胰岛素耐量实验(IPITT)
在高脂喂养16周后，分别对WT和KO组小鼠进行腹腔注射葡萄糖实验(IPITT)，以评价小鼠机体对胰岛素的耐受能力。每组各取6只，在小鼠称重后，根据0.75U/kg计算胰岛素的注射体积，胰岛素的使用浓度是300mU/3ml。分别于腹腔注射后15/30/60/120分钟的时间点剪尾测小鼠血糖值，并记录血糖数值和监测时间。
通过IPGTT和IPITT实验能进一步评估小鼠体内代谢平衡是否紊乱。通过图3我们可以看到高脂饮食诱导了Hv1基因敲除鼠的糖不耐受的提高和胰岛素抵抗更加明显与WT鼠相比。这表明Hv1基因敲除营养代谢能力降低，导致了严重的营养代谢紊乱。
实施例4 附睾脂肪和肝脏组织的收集与形态学观察
所有动物肝脏组织和附睾脂肪取出后立即称重并记录数据。用于油红O(ORO)分析的肝脏组织，取约五分之一的部分嵌入包埋剂(OCT)(tissu-tek，Sakura Finetek USA)中，在干冰上冷冻，并保存在- 80℃，以备将来切片。随后，在冷冻包埋机上切出7μm厚的组织切片。将组织切片按照说明书用苏木精和 ORO(珠海贝索企业公司)进行染色。用于组织形态学观察的组织，放在4％的福尔马林缓冲液中过夜，随后放在70％的乙醇中储存。在梯度脱水后浸二甲苯使组织透并于石蜡包埋机中包埋。用石蜡组织切片机 (Leica)切成5μm厚的组织切片用于苏木精和伊红(HE)染色。用ImageJ软件测量脂肪细胞大小。
实施例5 免疫组织化学染色观察肝脏炎细胞浸润程度
分别取来源于四组小鼠肝脏组织的石蜡切片，在经过切片复温、脱蜡水化、pH9的抗原修复、0.5％TritonX-100打孔、去除内源性过氧化氢酶、血清封闭抗原后，用CD68兔多克隆抗体(Proteintech) 以1∶500稀释后于4℃孵育组织切片过夜。切片在PBS中冲洗三次，然后用辣根过氧化物酶标记的山羊抗兔二抗(Sigma-Aldrich)孵育1小时，然后过氧化物酶和过氧化物酶底物显色。通过计算cd68阳性区域来定量巨噬细胞。
肥胖症是高血压、高血脂、动脉粥样化、糖尿病、冠心病、脑血管疾病、慢性肾脏病等多种疾病的危险因子，通过对小鼠附睾脂肪与肝脏体积以及组织形态学观察，Hv1缺失小鼠的白色脂肪显著积累，脂肪细胞体积也明显变大(图2)，相应表现是出现了高血脂症和胰岛素抵抗。同时脂肪细胞在肝脏的过度累积也导致肝脏组织的脂肪变性以及炎细胞浸润增加(图4)，这也将提高小鼠胰岛素抗性。这表明Hv1缺失导致了饮食诱导的肥胖以及肥胖引起的慢性炎症。
上述结果说明Hv1基因影响小鼠体内营养代谢平衡以及脂肪的生成，对脂肪组织的正常代谢有重要保护作用。本发明说明敲除Hv1基因会引起高脂饮食诱导的脂肪组织的积累以至体重过度肥胖，体内胰岛素敏感性明显下降，并导致高胰岛素血症和高脂血症。本发明说明Hv1基因敲除小鼠可作为新的肥胖小鼠模型使用。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所做的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。
Claims (4)
1.电压门控质子通道Hv1敲除小鼠在作为肥胖模型小鼠中的应用。
2.电压门控质子通道Hv1作为药物靶标在筛选治疗肥胖的药物中的应用。
3.电压门控质子通道Hv1的激活剂在制备预防，缓解和/或治疗肥胖药物中的应用。
4.一种预防，缓解和/或治疗肥胖的药物，其特征在于：作用于电压门控质子通道Hv1。
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| CN111357979A (zh) * | 2019-12-26 | 2020-07-03 | 浙江欧谱生物科技有限公司 | 抑制高脂引起的肥胖及骨丢失的保健食品组合物及其应用 |
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