CN108721609B - Lcat在制备治疗和/或预防肝性骨病的药物中的用途 - Google Patents
Lcat在制备治疗和/或预防肝性骨病的药物中的用途 Download PDFInfo
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- CN108721609B CN108721609B CN201711153245.8A CN201711153245A CN108721609B CN 108721609 B CN108721609 B CN 108721609B CN 201711153245 A CN201711153245 A CN 201711153245A CN 108721609 B CN108721609 B CN 108721609B
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Abstract
本发明属于生物医药领域，具体涉及卵磷脂‑胆固醇酰基转移酶(LCAT)在制备治疗和/或预防肝性骨病的药物或保健品中的用途。经细胞及动物实验证实，LCAT能够实现胆固醇从骨细胞到肝细胞的逆转运，从而缓解骨质疏松，同时还能缓解慢性肝硬化过程中骨骼系统异常，增加骨密度，为目前在治疗慢性肝性骨病提供了一个全新的选择和思路，具有潜在的临床应用前景。
Description
技术领域
本发明属于生物医药领域，具体涉及卵磷脂-胆固醇酰基转移酶(LCAT)在制备治疗肝性骨病、骨质疏松或骨软化症的药物上的用途。
背景技术
肝脏作为机体的代谢中心，是维持机体稳态的重要代谢器官，大量肝细胞不仅承担着消化解毒的功能，同时还分泌大量的细胞因子，这些分泌蛋白分子通过血液循环至全身，对远端器官起着重要的调控作用。同样，作为人体另外一重要器官—骨骼，除了发挥应力支撑、运动功能外还可以通过分泌调控因子调节机体免疫，以及通过影响机体糖代谢平衡调控机体的稳态。目前关于肝脏对骨骼的调控已经有所研究。有研究发现：肝脏分泌维他命D在肝性骨病发生发展过程中具有重要调控作用；同时，肝脏分泌维他命B12依赖的牛磺酸合成可调控机体的生长及骨骼发育。可见肝脏在调控骨骼发育以及骨量积累过程中起到重要作用。
骨科临床研究发现，当肝脏受到外界应激如病毒、酒精、药物等作用下会引发肝脏的慢性损伤，引起骨量的丢失。大量研究表明：约有75％的慢性肝病患者罹患严重的骨质疏松。据报道约有20％的慢性病毒肝炎患者会伴发骨量降低或骨质疏松，在慢性胆囊炎患者中骨量丢失比例甚至高达60％。更有甚者，酒精性肝硬化与病毒性肝硬化并发骨质疏松症患者的比例高达90％以上。这类在慢性肝脏疾病患者中出现的骨矿物质密度整体改变的一种代谢性骨骼疾病，即肝性骨营养不良，也被称为肝性骨病。该病症主要表现为骨软化症和骨质疏松症，是慢性肝病患者常见而又经常被忽视的并发症。该疾病的发生是由肝脏与骨骼之间相互的稳态调节失衡所导致的,比如稳态调节失衡会将大量脂肪填充入骨松质中，引起骨质疏松。传统缓解和/或治疗肝性骨病的主要临床药物是双膦酸盐或其衍生物，该类药物会导致骨内有机质成分降低，骨脆性增加，使患者非常容易骨折,同时还可能对患者的其他器官造成不同程度的损伤。因此,目前亟待开发出新型的、副作用较小的治疗肝性骨病的药物。
卵磷脂-胆固醇脂酰转移酶(lecithin-cholesterol acyltransferase,LCAT)是一种由肝合成、含有416个氨基酸、分子量大约为60KDa的糖蛋白，其与脂蛋白有着密切联系，并在血浆中发挥催化作用的一种酶。LCAT在自由胆固醇的酯化以及高密度脂蛋白(highdensity-lipoprotein,HDL)的成熟过程中起到了非常重要的作用。LCAT在肝脏被合成后进入血浆，催化HDL上卵磷脂的C2位不饱和脂肪酸与自由胆固醇结合，生成溶血卵磷脂和胆固醇酯进而阻止了自由胆固醇在血浆中的堆积，同时LCAT通过此催化过程将胆固醇酯转移至HDL中，这样形成了从细胞内到细胞外的胆固醇浓度差，有利于细胞内的胆固醇及时排出。
研究发现，LCAT的上述作用与诸多疾病有着很紧密的关联，包括鱼眼病)以及冠心病、动脉粥样硬化等心血管疾病。然而目前没有任何有关LCAT在治疗肝性骨病方面的报道。
发明内容
有鉴于此，本发明的目的在于提供LCAT在制备治疗肝性骨病和骨质疏松骨软化症的药物上的用途。
为达上述目的，发明人首先通过构建原代成骨细胞/原代破骨细胞与原代肝实质细胞共培养体系，以探究LCAT是否能够实现胆固醇从骨细胞到肝细胞的逆转运，从而影响骨细胞中的脂肪含量。
进一步地，发明人构建了肝性骨病小鼠模型，以探究LCAT对肝性骨病骨细胞骨量和骨骼微结构的影响。
经实验验证，本发明具有以下有益效果：
(1)本发明涉及的LCAT可实现能够实现胆固醇从骨细胞到肝细胞的逆转运，使骨细胞中的脂肪含量下降，缓解骨质疏松。
(2)本发明涉及的LCAT对于成骨细胞具有显著的促进作用，对于破骨细胞则呈现一定的抑制效果，因而能够调控机体的骨量平衡，具有防治肝性骨病和骨质疏松的疗效。
(3)LCAT作为生物酶，其毒副作用远低于双膦酸类化合物，不会增加患者的骨脆性，且制备途径多样、取材方便，可在体内或体外重组合成，为目前治疗肝性骨病药物提供了一种全新的选择和思路，拓宽了治疗肝性骨病药物的选择领域。
本发明中所述药物可包含LCAT和药学上可接受的载体。
其中，所述LCAT可为外源性重组LCAT(rLCAT)；所述药物的给药途径可包括口服、肌肉注射、静脉输注、皮下注射及鞘内注射。
附图说明
图1为胆固醇在LCAT作用下从骨细胞到肝细胞的逆转运过程。A图为原代细胞的共培养体系模型，其中，上层为预孵育NBD荧光标记胆固醇的原代成骨细胞或原代破骨细胞，下层为原代肝实质细胞；B图与C图表示上层细胞中加入外源性rLCAT后，上层细胞中的NBD荧光标记胆固醇转移至下层原代肝细胞中。
图2中的A图为LCAT在CCL4诱导的肝性骨病小鼠肝脏中和健康小鼠肝脏(对照组)中的荧光染色图；B图为CCL4诱导的肝性骨病小鼠肝脏和对照组小鼠肝脏中LCAT荧光阳性区域统计学比较图，A图和B图显示LCAT在肝性骨病小鼠肝脏中的表达量与对照组相比明显增高。C图为肝性骨病患者血清中LCAT含量与股骨骨密度的关系图，其显示两者成正相关。
图3中的A-C图分别表示成骨细胞加入重组LCAT后，其相关生物学标志物Runx2、Ocn及Sp7的含量表达量与不加重组LCAT的对照组的对比图；D-F图分别表示破骨细胞加入重组LCAT后，其相关生物学标志物CTSK、Trap及OSCAR的表达量与不加重组LCAT的对照组的对比图。图2显示成骨细胞与破骨细胞分别加入重组LCAT后，成骨细胞相关生物学标志物表达量明显增加，破骨细胞相关生物学标志物表达量则明显降低。
图4为肝性骨病小鼠尾静脉注射重组LCAT后的骨量变化图，其中A图为小鼠股骨micro-CT 3D重建图，其显示经重组LCAT静脉注射的小鼠的松质骨骨量与没有注射重组LCAT的对照组相比增加明显；图B-G为小鼠股骨微观数据分析图,分别对比了两组小鼠的骨量/组织量、骨表面积/骨体积、骨小梁骨矿物质密度、骨小梁厚度、骨小梁分离度及骨小梁数量，其中，经重组LCAT静脉注射的小鼠的骨量/组织量、骨小梁骨矿物质密度、骨小梁厚度及骨小梁数量与对照组相比显著增加，而骨表面积/骨体积及骨小梁分离度与对照组相比显著降低。
上述附图中的rLCAT表示人工合成的重组LCAT；“*”表示P<0.05；“**”表示P<0.01；以及“***”表示P<0.001。
具体实施方式
下面结合实施例对本发明作进一步说明。所举实施例是为了更好地对本发明的内容进行说明，但并不是本发明的内容仅限于所举实施例。所以熟悉本领域的技术人员根据上述发明内容对实施方案进行非本质的改进和调整，仍属于本发明的保护范围。
为了使本领域的技术人员更好的理解本发明的技术方案，下面结合具体实施例对本发明作进一步的详细说明。
实验材料.外源性rLCAT的准备
化学合成纯度大于98％的外源性rLCAT(序列详见所附序列表)将合成的外源性rLCAT粉末溶于双蒸水，配制浓度为1mg/ml的外源性rLCAT溶液，分装后冷冻保存备用。使用时用双蒸水稀释成相应浓度。
实施例1.构建原代成骨细胞/原代破骨细胞与原代肝实质细胞共培养体系
实施方法：将分离的原代成骨细胞/原代破骨细胞加入微孔滤膜培养小室(MerckMillipore，USA)中，加入NBD荧光标记的胆固醇孵育24小时后，采用PBS溶液清洗掉未吞噬入原代成骨细胞/原代破骨细胞外的NBD荧光标记的胆固醇。将原代肝实质细胞转移至微孔滤膜培养小室下层。根据不同处理将微孔滤膜培养小室系统分为三组,即PBS处理组，外源性rLCAT处理组(100ng/ml)，CCl4预损伤肝实质细胞组(1mM),处理方式如下：
PBS处理组：上层细胞与下层细胞中均加入PBS溶液
外源性rLCAT处理组：上层细胞中加入100ng/ml外源性rLCAT溶液
CCL4预损伤肝实质细胞组：下层细胞中加入1mM CCl4
上述加入的溶液均等体积，处理后，三个组的上、下层细胞均共同孵育24小时，移除上层微孔滤膜培养小室，对下层细胞进行鬼笔环肽以及DAPI染色，采用荧光显微镜对结果进行观察以及拍照记录。
实施例结果：将外源性rLCAT加入共培养体系中或CCl4预损伤肝实质细胞(CCl4预损伤肝实质细胞会短暂应激性合成大量LCAT)均可以使预孵育NBD标记胆固醇的原代成骨细胞/原代破骨细胞，将已吞噬的NBD标记胆固醇转移至下层原代肝实质细胞中(图4中的B图和C图)，实现了胆固醇从成骨细胞/破骨细胞向肝实质细胞的逆向转运，有利于缓解肝性骨病过程中的肝脏损伤以及缓解骨量丢失。
实施例2.肝性骨病小鼠体内LCAT的表达情况及肝性骨病患者体内LCAT的表达与骨密度的关系
为了验证肝性骨病小鼠体内LCAT表达情况以及肝性骨病患者体内LCAT的表达与骨密度是否有一定的关系，我们构建了肝性骨病小鼠模型，并在临床收集肝性骨病患者血清及测得的骨密度数据。
实施方法：1.选择8周龄雌鼠(C57BL/6)，将其分成两组，即肝性骨病组和对照组，每组6只。肝性骨病组小鼠腹腔注射CCl46周(注射频率为每两天每克体重注射2ul)，对照组腹腔注射橄榄油(注射频率与注射量和肝性骨病组相同)。6周后取两组小鼠肝脏、血清。
2.将获得的肝性骨病模型小鼠肝脏切片后进行LCAT免疫荧光染色，LCAT蛋白采用PE荧光素标记，细胞核蛋白采用DAPI标记，分别在592nm、358nm的激发光下显示红光和蓝光。3.每组选取8张切片，在100x放大倍数下每张切片拍取10张照片，统计红色阳性蛋白数量作柱状图(图1中的B图)，选取较为典型的荧光照片构图(图1中的A图)。4.临床收集肝性骨病患者的股骨BMD数据、血清，采用ELISA技术检测血清中LCAT的含量。5.比较肝性骨病患者BMD值与血清中LCAT含量的关系。
实施例结果：如图2中的A、B图所示，肝性骨病小鼠肝脏组织中的LCAT表达量，与对照组相比明显增加。如图1中的C图所示，肝性骨病血清中LCAT的含量与临床收集肝性骨病患者的股骨骨密度(BMD)成正相关
实施例3.LCAT对成骨细胞和破骨细胞的影响
实施方法：分别从6天雄鼠(C57BL/6)头骨中提取成骨细胞，从6周雄鼠(C57BL/6)下肢骨髓腔中提取破骨细胞前体并用Rankl诱导呈成熟破骨细胞后，将200ng/ml的外源性rLCAT溶液加入两种细胞内，并设对照组加入等体积PBS溶液，各组细胞均孵育24小时，提取RNA，采用实时定量PCR法检测成骨细胞的生物学标记物Runx2、Ocn及Sp7(图3中的A-C图)，以及破骨细胞生物学标记物CTSK、Trap及OSCAR(图3中的D-F图)表达量。
实施例结果：如图3所示，外源性rLCAT溶液分别加入成骨细胞、破骨细胞中各孵育
24h后，成骨细胞相关标记物Runx2，Ocn以及Sp7的表达水平与对照组相比明显增加(A-C图)，表明外源性rLCAT促进了成骨细胞的活性，而破骨细胞相关标记物CTSK，Trap和OSCAR的表达水平与对照组相比显著降低(D-F图)，表明外源性rLCAT抑制破骨细胞的活性。上述结果表明，外源性rLCAT能够通过有效的促进成骨细胞活性抑制破骨细胞活性从而改善骨质疏松。
实施例4.注射外源性rLCAT对肝性骨病小鼠骨量的影响
实施方法：选择8周龄雌鼠(C57BL/6)，将其分成两组，即实验组和对照组，每组6只。所有小鼠都腹腔注射CCl46周(注射频率为每两天每克体重注射2ul)，其中每隔2周，给实验组小鼠进行尾静脉注射外源性rLCAT溶液(每克体重注射50ng)，给对照组小鼠进行尾静脉注射等体积PBS，6周后取各组小鼠股骨进行微型CT检测(Micro-CT)，并对检测结果进行数据分析。
实施例结果：如图4所示，实验组的肝性骨病小鼠在接受尾静脉注射重组LCAT溶液6周后，其骨量与对照组相比明显增加。小鼠股骨micro-CT 3D重建图显示，经重组LCAT溶液静脉注射的实验组小鼠的松质骨骨量与对照组相比增加明显(A图)；小鼠股骨微观数据分析显示,经重组LCAT溶液静脉注射的实验组小鼠与对照组相比，其骨量/组织量(B图)、骨小梁骨矿物质密度(D图)、骨小梁厚度(E图)和骨小梁数量(G图)明显增加，而其骨表面积/骨体积(C图)和骨小梁分离度(F图)显著降低。上述结果表明外源性rLCAT显著的改善了肝性骨病小鼠骨量的丢失，缓解了骨质疏松，有效的减轻了肝性骨病的症状。
以上实施例仅用以说明本发明的技术方案而非限制，尽管参照较佳实施例对本发明进行了详细说明，本领域的普通技术人员应当理解，可以对本发明的技术方案进行修改或者等同替换，而脱离本发明技术方案的宗旨和范围，其均应涵盖在本发明的权利要求范围当中。
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<110> 南京大学
<120> LCAT在制备治疗和/或预防肝性骨病的药物中的用途
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Claims (7)
1.卵磷脂-胆固醇脂酰转移酶在制备治疗肝性骨病的药物中的用途。
2.卵磷脂-胆固醇脂酰转移酶在制备治疗骨质疏松症或骨软化症的药物中的用途。
3.根据权利要求1所述的用途，其特征在于，所述肝性骨病的病症为肝性引起的骨软化症或骨质疏松症。
4.根据权利要求2所述的用途，其特征在于，卵磷脂-胆固醇脂酰转移酶将累积在骨细胞中的胆固醇逆转运到肝脏细胞中，缓解骨质疏松或骨软化症。
5.根据权利要求1所述的用途，其特征在于，所述药物包含卵磷脂-胆固醇脂酰转移酶和药学上可接受的载体。
6.根据权利要求4所述的用途，其特征在于，所述卵磷脂-胆固醇脂酰转移酶是外源性重组卵磷脂-胆固醇脂酰转移酶。
7.根据权利要求4所述的用途，其特征在于，所述药物的给药方式为肌肉注射、静脉输注、皮下注射或鞘内注射。
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