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2020 Volume 42 Issue 8
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Bing-ke QIAO, Xing-yu MA, Ling-yun HAN, et al. Estrogen Enhances Liver Repair by Regulating Hepatic Cell Regeneration[J]. Journal of Southwest University Natural Science Edition, 2020, 42(8): 49-58. doi: 10.13718/j.cnki.xdzk.2020.08.007
Citation: Bing-ke QIAO, Xing-yu MA, Ling-yun HAN, et al. Estrogen Enhances Liver Repair by Regulating Hepatic Cell Regeneration[J]. Journal of Southwest University Natural Science Edition, 2020, 42(8): 49-58. doi: 10.13718/j.cnki.xdzk.2020.08.007
shu

Estrogen Enhances Liver Repair by Regulating Hepatic Cell Regeneration

  • School of Animal Science, Southwest University, Chongqing 400715, China

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  • Corresponding author: An-fang LIU
  • Received Date: 01/02/2020
    Available Online: 20/08/2020

  • MSC: Q958

  • In order to investigate the effects of estrogen on liver repair of CCl4-induced liver injury mice, the differences between male and female mice were assessed based on the CCl4-induced liver injury model. Then the effects of ovaries on liver injury were analyzed by histological analysis, cell proliferation and cell apoptosis analysis of the livers of ovariectomized mice and sham-operated mice. Finally, the effects of estrogen on liver repair were investigated by exogenous estrogen supplementation to ovariectomized mice. The results showed that the acute liver injury, infiltration of inflammatory cells into liver and liver fibrosis were significantly lower in female mice than in male mice. The liver damage became worse in ovariectomized mice than that in sham-operated female mice. Compared with those in sham-operated mice, both proliferation of hepatic parenchymal cells and apoptosis of non-hepatic parenchymal cells were reduced in ovariectomized mice. The liver damage was reversed by administering exogenous estrogen to ovariectomized mice, thus suggesting that estrogen is involved in the regulation of liver repair, which provides implications in the effects of sex hormones on liver diseases.
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Estrogen Enhances Liver Repair by Regulating Hepatic Cell Regeneration

    Corresponding author: An-fang LIU
  • Received Date: 01/02/2020
  • Available Online: 20/08/2020

Abstract: In order to investigate the effects of estrogen on liver repair of CCl4-induced liver injury mice, the differences between male and female mice were assessed based on the CCl4-induced liver injury model. Then the effects of ovaries on liver injury were analyzed by histological analysis, cell proliferation and cell apoptosis analysis of the livers of ovariectomized mice and sham-operated mice. Finally, the effects of estrogen on liver repair were investigated by exogenous estrogen supplementation to ovariectomized mice. The results showed that the acute liver injury, infiltration of inflammatory cells into liver and liver fibrosis were significantly lower in female mice than in male mice. The liver damage became worse in ovariectomized mice than that in sham-operated female mice. Compared with those in sham-operated mice, both proliferation of hepatic parenchymal cells and apoptosis of non-hepatic parenchymal cells were reduced in ovariectomized mice. The liver damage was reversed by administering exogenous estrogen to ovariectomized mice, thus suggesting that estrogen is involved in the regulation of liver repair, which provides implications in the effects of sex hormones on liver diseases.

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  • 肝脏是体内最大的消化腺，也是糖、脂类和蛋白质代谢的核心器官，此外肝脏还担负着食物、药物及内源性毒物的解毒作用[1].肝脏的生理特点导致其易受到物理性、化学性及生物性侵害损伤，严重肝损伤将导致肝脏功能障碍和疾病；肝脏疾病严重影响着人类的健康及生活质量并造成公共医疗压力[2-3].肝脏病变会表现出多种肝损伤表型，如气球样变性、炎症反应和肝纤维化等.肝组织纤维化是肝脏慢性损伤的重要标志，晚期的肝纤维化会转变为肝硬化及肝功能衰竭，是大多数肝病发病和引起死亡的主要原因[4].

    肝脏流行病学调查显示，不同性别之间肝病的发生和发展有显著差异.其中病毒性肝炎、肝硬化、肝癌、肝衰竭患者的男性比例显著高于女性，男女发病率之比为2:1~2.6:1[5-6].育龄期妇女雌激素分泌旺盛，很少有肝硬化发生，但女性在绝经后肝病发生与男性几乎没有差别[7].已有的研究表明多种肝病的发生与发展存在性别间差异，且性腺类固醇激素的变化与肝脏疾病的发展密切相关.但导致性别间肝损伤差异的原因还不确切，性腺类固醇激素对肝损伤的调控作用需进一步阐明.

    CCl4诱导的肝损伤机制明确且损伤稳定，与不同病因产生的肝损伤疾病具有共同特征，能产生氧化应激、炎症反应、细胞凋亡、脂肪变性和肝组织纤维化等，被广泛应用于肝脏损伤调控机制的研究中[8].

    本研究在CCl4诱导的小鼠肝损伤模型的基础上，分析卵巢及雌激素对肝损伤的影响，以期为理解性别间肝损伤调控差异提供理论基础.

1.   材料与方法

    1.1.   实验动物

  • 选取6~8周龄KM小鼠作为实验动物.所有动物饲养环境温度在24±2 ℃，相对湿度为40%~70%，饲喂啮齿类动物标准饲粮，自由采食和饮水.光照循环条件为12 h光12 h暗.本研究所有实验动物操作均符合西南大学实验动物伦理审查标准.

    • 1.2.   CCl4诱导的小鼠肝损伤模型

  • 用芝麻油配置0.2%的CCl4(阿拉丁，上海)溶液，以10 mL/kg体质量的注射剂量，每2 d腹腔注射1次，连续处理2周(7次)建立肝损伤模型.处理结束后24 h采集肝脏组织，用于后续分析.

    • 1.3.   卵巢摘除小鼠模型

  • 小鼠腹腔注射0.5%戊巴比妥钠(Sigma，USA)溶液(10 mL/kg体质量)麻醉后，外科手术法分别摘除两侧卵巢.假手术组，通过背部切口暴露卵巢后重新复原，不摘除卵巢.

    • 1.4.   小鼠雌激素处理

  • 按照5mg/mL浓度配制17，β-雌二醇(E2)(Sigma，USA)酒精溶液，再按照1:200比例与芝麻油混合用于小鼠注射处理.实验小鼠在CCl4处理的同时进行雌激素补偿或溶剂对照注射.雌激素处理组(Ov-X+E)每2 d腹腔注射1次0.2% CCl4溶液，同时17，β-雌二醇(E2)处理，处理剂量为250 μg/kg体质量；溶剂对照组(Veh)每2 d腹腔注射1次0.2% CCl4溶液和酒精-芝麻油溶剂，处理2周后(第14 d，最后1次处理后24 h)采集肝脏样品.

    • 1.5.   肝脏组织的采集

  • CCl4处理第14 d采集肝脏样品，采样前3 h，按照50 mg/kg体质量的剂量通过腹腔注射5-BrdU(Sigma，USA)用于细胞增殖分析.通过颈椎脱臼法处死小鼠，采集肝脏组织，经4%中性多聚甲醛固定后进行石蜡组织包埋.

    • 1.6.   肝脏组织形态结构分析

  • 制作5 μm组织切片，经脱蜡后通过苏木精-伊红(HE)染色及光学显微镜分析肝脏组织的形态和结构.统计气球样水肿数量，利用Image J软件分析炎性细胞浸润面积比例.

    • 1.7.   肝纤维化分析

  • 利用Masson染色试剂盒(索莱宝，北京)对肝脏组织切片进行染色分析，利用Image J软件分析蓝色染色(纤维化)面积的比例.

    • 1.8.   细胞增殖分析

  • 利用BrdU掺入法分析细胞增殖比例.肝脏组织切片经脱蜡后利用免疫组织化学染色法，统计分析BrdU阳性细胞比例. BrdU鼠源单克隆抗体(ProteinTech，武汉)稀释比例为1:100，4 ℃孵育过夜，辣根过氧化物酶标记的山羊抗鼠IgG(GAM-HRP)1:200稀释，室温孵育2 h，漂洗后二氨基联苯胺(DAB)染色试剂盒(中杉金桥，北京)显色，苏木精复染，中性树胶封片，光学显微镜拍照分析.

    • 1.9.   细胞凋亡分析

  • 利用TUNEL试剂盒(翊圣生物，上海)，按照说明书操作标记凋亡细胞，DAPI(索莱宝，北京)复染后荧光显微镜拍照分析肝脏组织凋亡细胞比例.

    • 1.10.   雌激素受体的免疫组织化学分析

  • 利用免疫组织化学法分析雌激素受体α(ERα)和β(ERβ)在肝脏中的分布.石蜡组织切片脱蜡后，经Tris-EDTA抗原修复液高压锅处理3 min，正常山羊血清封闭30 min.兔源雌激素受体α多克隆抗体(RA-ERα)(ProteinTech，武汉)和兔源雌激素受体β多克隆抗体(RA-ERβ)(ProteinTech，武汉)稀释比例均为1:200，4 ℃过夜孵育.辣根过氧化物酶标记的山羊抗兔IgG(10 mmol/L PBS配制，GAR-HRP，1:150)，室温孵育2 h，漂洗后按照DAB显色试剂说明，在显微镜下观察显色后苏木精复染，中性树胶封片，显微镜拍照分析.

    • 1.11.   数据统计分析方法

  • 利用Image J软件分析炎性细胞浸润面积比例和肝纤维化面积比例，通过计数法获得每张切片气球样水肿数量，计数获得增殖凋亡数量和切片细胞全部数量计算增殖凋亡比例，每个样本选择5张同倍数下不同的切片进行分析获得样本的平均数据，并通过t检验分析处理组和对照组间的差异显著性.结果中*表示p＜0.05，**表示p＜0.01，差异有统计学意义.

2.   结果与分析

    2.1.   雌性小鼠卵巢内分泌参与肝脏损伤调控作用

  • 本研究首先比较了CCl4诱导的肝损伤模型下雌性小鼠和雄性小鼠肝损伤差异.结果显示，雌性小鼠肝脏组织的炎性细胞浸润面积、气球样变性数量与纤维化面积均显著少于雄性小鼠(图 1).表明性别间存在肝损伤差异，且雌性小鼠对肝损伤具有更强的抵抗作用.肝脏作为非性别相关器官表现出性别间的损伤差异，提示肝损伤调控可能与性腺内分泌有关.

    为了探究卵巢内分泌对肝组织损伤修复的影响，在CCl4诱导的肝损伤模型基础上比较了双侧卵巢摘除处理(Ov-X)和卵巢摘除假手术对照组(sham)小鼠之间的肝脏损伤差异.结果显示，双侧卵巢摘除处理组的肝组织炎症浸润面积、气球样变性数量和肝组织纤维化程度均极显著高于卵巢摘除假手术对照组(p＜0.01)(图 2).该结果表明，双侧卵巢摘除会加重CCl4造成的肝损伤，提示卵巢内分泌可能参与了肝损伤的调控过程.

    分别利用BrdU掺入法和脱氧核糖核苷酸末端转移酶介导的缺口末端标记法(TUNEL)分析了双侧卵巢摘除对肝脏细胞增殖和凋亡的影响.结果显示，卵巢摘除显著减弱了肝实质细胞增殖和非肝实质细胞的凋亡(p＜0.01)(图 3).由于肝脏损伤修复和组织再生主要通过肝实质细胞的增殖完成[9-10].因此，以上结果显示，卵巢内分泌可能参与了肝组织调控的更新，卵巢摘除减弱了肝实质细胞的增殖和肝损伤修复.而非肝实质细胞凋亡减少可能与肝星状细胞的激活及免疫细胞浸润有关.因此，雌性小鼠可能通过卵巢内分泌调控肝组织更新，影响肝损伤修复.

    • 2.2.   雌激素显著减弱CCl4对卵巢摘除小鼠产生的肝损伤效应

  • 雌激素是雌性动物卵巢分泌的重要激素，也是机体生理内分泌调控的重要组成.雌激素的主要作用机制是与其细胞核内的受体结合激活靶基因表达，从而发挥作用[11-12].肝脏中雌激素受体α(ERα)和β(ERβ)在肝脏中的分布显示，ERα主要定位在肝实质细胞核，且具有强阳性表达(图 4a)；ERβ免疫染色阳性细胞数量较少，且主要为非肝实质细胞(图 4b).

    为了进一步揭示雌激素是否参与肝损伤修复的调控作用，本研究在CCl4肝损伤模型的基础上，利用卵巢摘除雌鼠外源性雌激素补偿实验分析了雌激素对肝损伤的影响.结果显示，雌激素处理组(Ov-X+E)小鼠肝脏组织的炎性细胞浸润区域面积、气球样变性数量和肝组织纤维化面积都极显著低于对照组(Ov-X+Veh)(图 5).表明雌激素参与了肝损伤的调控，对肝脏起到了保护作用.

    对肝脏中细胞增殖和凋亡分析显示，雌激素能显著促进小鼠肝实质细胞的增殖(p＜0.01)，同时雌激素可显著促进非肝细胞凋亡(p＜0.01)，而非肝实质细胞增殖和肝实质细胞凋亡差异无统计学意义(p＞0.05)(图 6).以上结果表明，雌激素既能促进肝脏中实质细胞增殖，也能促进非肝实质细胞凋亡，由此增强了肝组织更新和清除炎性因子的能力，从而促进了肝损伤修复.

3.   讨论

  • 肝病的发生和调控机制是多样和复杂的，在多种肝病存在的性别差异以及肝脏的性别特异性使性别因素成为肝病领域的研究焦点.本研究利用CCl4诱导的肝损伤模型及卵巢摘除和雌激素补偿实验，证明雌性小鼠相对于雄性小鼠对肝损伤具有更强的抵抗性，且雌激素通过卵巢内分泌对肝损伤修复发挥重要的调控作用.通过实验动物模型研究和人类的肝脏流行病学调查表明，肝脏疾病的进展速度受性别影响，雌性在肝癌、非酒精性脂肪肝的发病率要低于雄性，而酒精性脂肪肝发病率则高于雄性，雌性在部分肝切除或门静脉分支结扎后的存活率明显更高，提示了性别因素调控肝病的可能性[2-3, 13].本研究结果显示在CCl4诱导的肝损伤模型下，雌性小鼠损伤弱于雄性，表明了雌性有较强的抗损伤能力.在化学药物诱导的肝损伤模型中，雄性大鼠肝纤维化的反应较雌性大鼠强烈得多，而且卵巢切除显著加重了肝纤维化的程度[14].卵巢摘除后肝损伤加重，肝细胞增殖和凋亡数量显著减少，表明卵巢内分泌参与了肝损伤的调控，对肝脏有保护作用.细胞的增殖和生长在肝脏的胚胎发育中起着重要的作用，并且肝脏损伤修复和疾病的治疗也依赖于肝脏组织的更新，肝细胞的增殖和炎症因子及损伤细胞的凋亡是肝脏组织更新能力的主要方式[15-17].卵巢内分泌可以通过影响肝细胞的增殖能力和细胞凋亡，调控肝脏组织的更新，以上研究均表明卵巢内分泌与肝损伤密切相关，支持了本研究结果.

    雌激素是卵巢内分泌的重要组成，也是雌性和雄性动物内分泌差异的关键因素之一.雌激素是一类有广泛生物活性的甾体激素，其作用机制为通过质膜进入细胞，直接与其核受体结合，形成激素-受体复合物，影响下游基因的转录，最终产生生物效应[11-12].本研究发现肝脏中两种雌激素受体(ERα和ERβ)均有分布，且ERα在肝实质细胞中高表达，提示雌激素可以通过这些受体调控肝脏生理功能. Zhou等[18]研究发现，给予雄性大鼠一定剂量的雌激素处理，能产生明显的抑制肝纤维化的作用.有研究发现雌二醇参与调控免疫反应及炎性细胞间信号转导，下调炎症相关基因的表达、阻止炎症发展的进程和组织器官的损害等[19].

    CCl4会引起肝组织的炎症反应，导致肝细胞变性坏死及多种细胞因子的过度表达，进而引起肝星状细胞(HSC)激活和细胞外基质(ECM，主要为胶原蛋白)的大量合成[20].炎症反应激活枯否细胞分泌多种细胞因子，同肝细胞、血小板和窦内皮细胞等分泌的细胞因子、脂质过氧化产物等化学递质共同作用于HSC，使后者激活并转变为肌样成纤维细胞，分泌ECM，引起肝纤维化[21-22].有研究发现雌激素能抑制体外培养的HSC分泌Ⅰ型胶原和HSC增殖[12-23]. CCl4经细胞色素450激活后生成CCl3，引起脂质过氧化是破坏膜脂质层结构完整性的重要机制[8].研究发现雌激素及其衍生物是强抗氧化剂，可降低肝和血清脂质过氧化物的水平[24-25]；雌二醇可以抑制CCl4导致的丙二醛(MDA)升高，并维持超氧化物歧化酶(SOD)的活性[19].本研究发现卵巢雌激素能够减弱肝急性损伤和肝纤维化，其机制可能与雌激素调控HSC激活及抗氧化有关.

    雌激素对细胞增殖和凋亡的调控作用尚未完全阐明.研究显示，雌激素参与了肠道和皮肤细胞的增殖，但其对肝脏组织更新的影响还未阐明[26-27].研究表明，雌激素对大鼠和人肝切除手术或肝移植后的肝脏再生起促进作用[28].有研究发现雌激素能够诱导肝癌细胞凋亡增加，而本研究也发现雌激素能促进肝实质细胞的增殖和非肝实质细胞凋亡，表明雌激素可能具有增强肝脏损伤后组织的更新作用.

    综上所述，雌激素可能通过抑制炎症反应、HSC激活及ECM生成和抗氧化作用，减弱CCl4引起的肝急性损伤和肝纤维化，同时促进肝脏损伤后组织的更新能力，加快肝损伤修复.本研究的结果为雌激素作为潜在的肝脏相关疾病的治疗药物提供了重要的支持，为性别间肝脏损伤及肝病发生和发展的机理提供重要理论基础，为肝病的治疗提供一定参考.

Figure (6)  Reference (28)

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