CH25H和25-HC与冠状动脉性心脏病
CH25H and 25-HC in Coronary Artery Disease
摘要: 冠状动脉性心脏病(coronary artery disease, CAD)显著影响着我国居民的健康，也给全球医疗带来巨大的经济负担。动脉粥样硬化(atherosclerosis, AS)是CAD的病理基础。胆固醇-25-羟化酶(cholesterol 25-hydroxylase, CH25H)是一种参与脂质代谢的酶，它可以将胆固醇催化生成25-羟基胆固醇(25-hydroxycholesterol, 25-HC)，而25-HC是众所周知的胆固醇的氧化产物，即氧甾醇。既往的研究表明CH25H和25-HC在调节胆固醇的代谢、炎症反应、AS以及免疫反应和抗病毒感染等方面发挥多种作用。近年来越来越多的研究聚焦于CH25H和25-HC与AS和CAD的相关性。因此本文就CH25H和25-HC在AS和CAD中已知的作用机制简单作一综述。
Abstract: Coronary artery disease (CAD) significantly affects the health of Chinese residents and imposes a huge economic burden on global healthcare. Atherosclerosis (AS) is the pathological basis of CAD. Cholesterol 25 hydroxylase (CH25H) is an enzyme involved in lipid metabolism. It catalyzes the conversion of cholesterol into 25-hydroxycholesterol (25-HC), which is a well-known oxidation product of cholesterol. Previous studies have shown that CH25H and 25-HC play multiple roles in regulating cholesterol metabolism, inflammatory response, AS, immune response, and antiviral infection. In recent years, more and more research has focused on the correlation between CH25H and 25-HC with AS and CAD. Therefore, this article provides a brief overview of the known mechanisms of action of CH25H and 25-HC in AS and CAD.
文章引用：张姿霄, 张爱文. CH25H和25-HC与冠状动脉性心脏病[J]. 临床医学进展, 2025, 15(1): 1040-1045. https://doi.org/10.12677/acm.2025.151139

1. CH25H的概述

胆固醇-25-羟化酶(cholesterol 25-hydroxylase, CH25H)是一种内质网(Endoplasmic reticulum, ER)相关糖蛋白，属于氧化还原酶家族，由人和小鼠细胞中的298个和272个氨基酸组成，CH25H主要定位于ER和高尔基体，CH25H是一个分子小家族的成员，它利用二铁辅因子催化疏水底物的羟基化[1]。CH25H以胆固醇和分子氧为底物，以NADPH为辅因子催化生成25-羟基胆固醇(25-hydroxycholesterol, 25-HC)，一种氧甾醇[2]。氧甾醇是胆固醇的氧化衍生物，具有不同于母体胆固醇的生物学特性。胆固醇过量在AS因果关系已得到充分证明，并且内源性促炎性氧甾醇与AS有关[2]。CH25H表达和25-HC产生与器官或组织的炎症和免疫状况密切相关。在正常情况下，CH25H在造血细胞、上皮细胞和内皮细胞(EC)、巨噬细胞和淋巴器官中低水平表达，25-HC在血液和大多数组织中的水平较低甚至检测不到[1]。CH25H在疾病环境中的多个组织(如肝脏、肺、结肠、肠道、脑、肾脏、脾脏、心脏、胸腺、皮肤和肌肉)中上调[2]。细胞内25-HC含量主要由CH25H活性决定；因此，CH25H的调节在25-HC生产中非常重要。CH25H是一种高度动态调节的酶，尤其是在炎症条件下[1]。CH25H已被鉴定为干扰素(IFN)刺激的基因，并且CH25H的表达受到脂多糖(LPS)、IFN、LXR、病毒感染和Toll样受体(TLR)激活的强烈诱导，导致25-HC浓度升高[1]。表明CH25H的代谢和炎症途径之间存在联系。

2. CH25H与胆固醇代谢

细胞胆固醇稳态对细胞存活至关重要，主要由甾醇调节因子结合蛋白(SREBP)和肝脏X受体(LXR)的调节，CH25H和25-HC被认为是通过对SREBP和LXR的调节来维持胆固醇稳态的重要调节因子[3]。SREBP促进3-羟基-3-甲基戊二酰辅酶A还原酶(HMGCR)的表达和随后的胆固醇合成[4]，而CH25H将胆固醇转化为25-HC，而25-HC已被证明通过抑制SREBP前体的蛋白水解对胆固醇合成具有负调控作用，阻止胆固醇合成所需的转录事件。而25HC本身可以激活CH25H表达，建立一个正反馈回路。25-HC作为LXR的配体，可进入细胞核诱导CH25H、ATP结合盒转运蛋白G1 (ABCG1)、ATP结合盒转运蛋白A1 (ABCA1)、胆固醇磺基转移酶-2B1b (SULT2B1b)和干扰素γ (IFN-γ)表达，活化的IFN-γ可通过反馈调节增强CH25H的表达[3]，CH25H增加随后促进25-HC的产生，这表明25HC不仅可以调节脂质代谢稳态，还可以通过LXR通路调节IFN γ介导的免疫反应[1]。另外，在胆固醇过高的情况下，25-HC与跨膜ER蛋白–胰岛素诱导基因2 (INSIG2)蛋白结合形成SREBP/INSIG2/SCAP复合物，这些复合物保留在ER上，不能转运到高尔基体，导致细胞内甾醇代谢失调[3]。在肝脏代谢方面，CH25H缺乏减少了LXRα调节的胆固醇外排，增加了SREBP-2介导的胆固醇的合成，并增加了NLRP3炎症小体蛋白的表达[3]。炎症应激会破坏肝脏SREBP-2介导的LDLR和HMG-CoA还原酶反馈调节，导致肝细胞中胆固醇积累加剧[4]。总之，细胞内胆固醇的高浓度会增加25-HC的产生，这反过来又通过两种不同的分子机制降低了HMGCR水平，从而降低了胆固醇合成。通过阻断SCAP/SREBP-2通路，25-HC还阻断了LDL摄取[1]。因此，增加25-HC合成导致胆固醇合成和摄取减少。产生的25-HC还可以通过抑制SREBP来增强IL-8、IL-6和巨噬细胞集落刺激因子(MCSF)的表达并抑制IL1-β的产生[3]。但是值得注意的是过量的25-HC会对产生细胞毒性作用，导致细胞凋亡或坏死过程死亡。不仅如此25-HC还会对血管壁产生促炎作用，导致内皮功能障碍、氧化应激增加和促炎细胞因子产生。

3. CH25H和25-HC与炎症反应

炎症反应毫无疑问是慢性疾病进展和并发症的主要驱动力。作为一种调节胆固醇代谢的关键因子，CH25H和25-HC在炎症反应方面发挥了重要作用。既往研究表明25-HC可以促进炎性细胞因子的表达和合成，这大部分密切依赖于NF-κB和ERK1/2通路的激活[5] [6]。在流感感染模型中，发现CH25H缺乏可以保护小鼠免受炎症诱导，可能的机制是25-HC通过诱导转录因子激活蛋白-1 (AP-1)成分(Jun原癌基因(JUN)和FBJ骨肉瘤癌基因(FOS))的募集以及TLR反应基因亚群的启动子放大炎症信号[7]。在一项动物研究中发现25-HC还可以通过激活类维生素A相关孤儿受体α (RORα)从而促进炎症介质的表达[8] Wang F等人研究了视网膜诱导基因I (RIG-I)信号在介导AS炎症中的作用，发现RIG-I可以在巨噬细胞和ECs中诱导25-HC，RIG-I通过与下游分子线粒体抗病毒信号蛋白(MAVS)、转化生长因子β活化激酶1 (TAK-1)和丝裂原活化蛋白激酶(MAPK/ERK/P38/JNK)，结合来转导25-HC的信号，从而激活转录因子如NF-κB和AP-1的表达诱导IL-8的产生[9]。在慢性阻塞性肺疾病(chronic obstructive pulmonary disease, COPD)患者中，CH25H在肺泡巨噬细胞和肺泡细胞中的表达升高，可能与中性粒细胞炎症相关，但在这项研究中并未阐明25-HC诱导的中性粒细胞炎症的转录因子介导机制[10]。Russo L等人在饮食诱导的肥胖模型中发现CH25H的整体缺乏可减少脂肪组织炎症，还报道了25-HC水平与体重指数相关，在该项研究中指出CH25H激活LPS经典促炎刺激途径促进TNF-α等基因的表达，并且在脂肪细胞中诱导IL6、IL1b的表达[11]。Zhou S等人在致病性分枝杆菌感染的小鼠模型中发现CH25H被诱导上调，我们还发现在分枝杆菌感染期间CH25H的缺失减少了泡沫细胞的形成，减轻了小鼠的病理反应，表明CH25H在一定程度上可以参与泡沫细胞的形成[12]。以上研究均支持25-HC促进体内炎症的观点。

4. CH25H和25-HC与细胞凋亡

25-HC引起的ER应激似乎在这种氧甾醇介导的促进细胞凋亡作用中起关键作用。在一项动物实验中发现中性胆固醇酯水解酶1 (Nceh1)缺乏会导致小鼠动脉粥样硬化病变的加速生长，其潜在机制可能涉及Nceh1的缺陷增加了25-HC在ER中的积累而激活ER应激信号和细胞凋亡[13]。另有研究发现25-HC可能通过氧甾醇结合蛋白相关蛋白8 (ORP8)诱导细胞的ER应激和细胞凋亡[14]。Zhong W等人发现在巨噬细胞中，氧甾醇结合蛋白相关蛋白4L (ORP4L)共表达并与Gαq/11和磷脂酶C-(PLC-) β3形成复合物。ORP4L促进PLCβ3激活、IP3产生和Ca2+从ER中释放。通过这种机制，ORP4L通过Ca2+介导的c-AMP反应元件结合蛋白转录调节维持抗凋亡Bcl-XL表达，从而保护巨噬细胞免于细胞凋亡。然而，过量的25-HC会将这些ORP4L/Gαq/11/PLCβ3复合物分解，从而降低PLCβ3活性、IP3产生和Ca2+释放，导致巨噬细胞凋亡[15]。

5. CH25H和25-HC与内皮功能障碍

内皮功能障碍也会影响AS的进展，25-HC在ECs中发挥多种作用，包括促进炎症、增加氧化应激和影响内皮屏障完整性[16] [17]。25-HC降低了VE-钙粘蛋白水平和内皮完整性，这种现象的可能机制之一是Wnt/β-catenin信号传导[18]。在人脐血管内皮细胞(HUVEC)中，25-HC可以增加活性氧(ROS)的产生，并诱导DNA单链断裂(SSB)，以及对嘌呤和嘧啶的氧化损伤来影响ECs损伤[17]。25-HC可以通过解偶联和抑制内皮NO合酶(eNOS)活性以及诱导ECs凋亡来损害ECs的功能[16]。25-HC还通过降低Bcl-2表达和增加裂解的caspase-9和裂解的caspase-3表达以及caspase-3活性来增强ECs凋亡[19]。

6. CH25H与动脉粥样硬化

甾醇代谢和炎症通路之间的串扰已被证明会显着影响AS的发展。既往的研究发现25-HC在泡沫细胞形成中发挥作用，并诱导人动脉粥样硬化斑块在单核细胞/巨噬细胞中分泌促炎细胞因子和趋化因子，IL-1、IL-6、IL-8、CCL5和M-CSF。CH25H是促进巨噬细胞分化为泡沫细胞的关键参与者，介导巨噬细胞中脂滴的积累以触发AS形成的开始[20]。25-HC通过可以促进炎症细胞因子的产生、泡沫细胞的形成、增加基质金属蛋白酶-9 (MMP-9)的表达，并通过氧化作用导致血管功能障碍[20] [21]参与AS的发病机制。但25-HC在AS中的作用仍不清楚，有研究表明CH25H缺乏加速了AS，Krüppel样因子4 (KLF4)反式激活CH25H和LXR，从而促进ECs与巨噬细胞之间的协同作用，防止AS易感性[22]。但另一项得出结论指出通过ATF3介导的CH25H表达抑制降低25-HC，防止泡沫细胞形成和AS，ATF3缺陷小鼠由于CH25H表达增加而表现出AS病变的增强[20]。Canfrán-Duque A等人研究发现25-HC在人类冠状动脉粥样硬化病变中积聚，并且CH25H在斑块中的促炎性巨噬细胞中表达，巨噬细胞衍生的25-HC可以通过自分泌和旁分泌作用加速AS进展，促进斑块不稳定，也可以放大载脂巨噬细胞的炎症反应并抑制VSMCs在斑块内的迁移，还可以通过修饰质膜中可接近的胆固醇库来增强载脂巨噬细胞的炎症反应，从而改变Toll样受体4(TLR4)信号传导，促进核因子-κB (NF-κB)介导的促炎基因表达，并增加细胞凋亡易感性，在这项研究中指出这些作用独立于25-HC介导的LXR或SREBP转录活性的调节[23]。另外，众所周知血管紧张素II (angiotensin II, Ang II)是一种血管活性肽激素，Ang II产生过多可以对脉管系统产生不利影响，在VSMCs中Ang II促进了CH25H的上调，该过程主要依赖于AT1R和随后的Gq/11激活以及p38 MAPK的参与，表明CH25H参与了血管损伤的发病机制[24]。AS斑块形成的另一个标志是VSMCs的表型改变和血管钙化，而这些过程也可以由25-HC促进[24] [25]。VSMCs凋亡在症状斑块中很明显，既往研究表明25-HC通过增加Ca2+诱导细胞凋亡[26]。因此，CH25H与AS和CAD中的作用值得进一步探讨。

7. 总结与展望

既往研究表明CH25H和25-HC作为调节脂质代谢的中间介质也参与了炎症反应，这使得脂质代谢和炎症反应之间建立了密切的联系。大量基础研究和动物实验已经证实了CH25H与AS和CAD存在相关性，因此CH25H可能成为AS的潜在生物标志物和治疗靶点。但是CH25H在AS中的作用机制很复杂，目前还需要大量基础实验和动物研究来探索具体的影响机制。

NOTES

*通讯作者。

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