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摘要:
癌胚抗原相关细胞黏附分子1 (carcinoembryonic antigen-related cell adhesion molecule 1，CEACAM1) 是一种免疫球蛋白超家族的跨膜蛋白，参与介导细胞黏附、组织转移、免疫反应控制以及机体代谢平衡。研究表明, CEACAM1主要通过促进胰岛素清除以防止脂肪沉积, 从而对肝脏发挥保护作用。CEACAM1表达水平下调会导致胰岛素抵抗状态发生恶性循环并加重代谢紊乱。由于CEACAM1在控制代谢功能障碍相关脂肪性肝病(metabolic dysfunction-associated steatotic liver disease, MASLD) 中的关键地位，刺激其作用途径或调节其表达水平有望成为MASLD的治疗新方法。本文就CEACAM1在MASLD中的有关研究进展作一综述。
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关键词:
- 代谢功能障碍相关脂肪性肝病 /
- 癌胚抗原相关细胞黏附分子1 /
- 胰岛素清除 /
- 脂质代谢
Abstract:Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), a transmembrane protein of the immunoglobulin superfamily, is involved in mediating cell adhesion, tissue metastasis, control of immune response, and metabolic homeostasis. Studies have shown that CEACAM1 protects the liver by promoting insulin clearance and preventing fat deposition. The down-regulation of the CEACAM1 expression level leads to a vicious cycle of insulin resistance and aggravates metabolic disorders. As CEACAM1 is critical in controlling metabolic dysfunction-associated steatotic liver disease (MASLD), stimulating its pathway or regulating its expression level might be a potential new therapeutic approach for MASLD. In this paper, therefore, we summarize the research progress of CEACAM1 in MASLD.
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非酒精性脂肪性肝病(nonalcoholic fatty liver disease, NAFLD) 是最常见的慢性肝病，全球范围内患病率高达30%[1]。近期，三大国际肝病学会发表了关于脂肪肝命名的共识声明[2]，指出NAFLD的定义难以概括肝脂肪变性与全身代谢紊乱的联系，且具有潜在的污名化含义，故将NAFLD更名为代谢功能障碍相关脂肪性肝病(metabolic dysfunction-associated steatotic liver disease, MASLD)。新定义反映了肝脂肪变性与代谢综合征、糖尿病、高血压、高脂血症以及肥胖等慢性代谢疾病的相关性。MASLD的特点是肝脏脂质过度积累导致肝脂肪变性，继而产生脂毒性并诱导免疫炎症反应引发肝损伤, 进一步发展可导致代谢功能障碍相关脂肪性肝炎(metabolic dysfunction-associated steatohepatitis, MASH)、肝纤维化甚至肝癌[3]。MASLD的发病机制十分复杂，可能受胰岛素抵抗(insulin resistance, IR)、慢性炎症、肠道微生物紊乱及遗传易感性等多种危险因素的共同影响。对于MASLD的治疗目前尚无特定手段，主要依赖于生活方式调节，因此，对其发病机制与治疗方法的探索具有重要临床意义[4]。
癌胚抗原相关细胞黏附分子1(carcinoembryonic antigen-related cell adhesion molecule 1，CEACAM1) 是高度糖基化细胞黏附分子CEA家族的成员，主要表达于上皮与内皮细胞[5]。研究发现，CEACAM1参与诱导肝细胞分化，且在多种恶性肿瘤组织中可观察到CEACAM1表达水平下调[6]。多项研究表明，CEACAM1对肝脏具有显著保护作用，其可促进肝内胰岛素清除并减少肝脏脂肪生成，在肝脂肪变性大鼠与MASLD患者的肝脏中均发现CEACAM1水平下降[7-8]，因此CEACAM1表达水平上调可能使MASLD患者获益。本文对CEACAM1在MASLD发生发展中的作用机制及治疗作一综述, 旨在为MASLD的诊治提供新思路。
1. CEACAM1概述
CEACAM1最早发现于胆汁中，被认为是人体消化道正常组织抗原而得名为胆汁糖蛋白。CEACAM1由细胞外糖基化免疫球蛋白结构域、跨膜区与胞质结构组成，细胞外结构域有长或短的细胞质尾区，胞质域内含有2个酪氨酸残基, 可被胰岛素受体、表皮生长因子受体及其他酪氨酸激酶磷酸化从而参与信号传导[9]。CEACAM1基因位于染色体19q13.2区，含有9个外显子，转录修饰过程大量存在选择性剪接，可产生12种剪接亚型, 不同亚型根据胞外结构域的数量及胞质尾区的长度进行区分[10]。人类和小鼠两种主要的CEACAM1亚型含有4个胞外结构域和1个长或短的胞质尾区, 即CEACAM1-4L和CEACAM1-4S。第7外显子通过选择性剪接形成2种不同的CEACAM1亚型: CEACAM1-L和CEACAM1-S。
CEACAM1-L的特殊之处在于其胞质尾区含有2个基于免疫受体酪氨酸的抑制基团，啮齿动物CEACAM1-L中含有2个基于免疫受体酪氨酸的开关基团，这些结构特征表明CEACAM1-L磷酸化时会向胞内传递抑制信号[11]。CEACAM1-S可与钙调素、肌球蛋白、球状肌动蛋白、附件蛋白Ⅱ和聚合酶δ相互作用蛋白p38 (polymerase delta interacting protein p38, PDIP38) 结合，并被蛋白激酶磷酸化，从而调节细胞骨架的动态变化[12]。CEACAM1主要在上皮细胞、内皮细胞和白细胞中表达，但在骨骼肌细胞和软骨细胞中不表达。CEACAM1蛋白在人类和啮齿类动物中的结构和功能高度保守，且具有相同的组织表达模式，最常见的是不同CEACAM1亚型在同一细胞中共同表达，其相对表达水平决定了细胞信号传导的结果[13]。亚型的多样性赋予了CEACAM1多种生物学功能，包括介导细胞黏附、参与机体炎症反应与胰岛素代谢、促进血管增生及影响免疫应答等[14]。
2. CEACAM1影响MASLD发生发展的作用机制
2.1 胰岛素清除
胰岛素拮抗脂肪分解，不仅介导甘油三酯(triglyceride, TG) 在脂肪组织中的储存，且促进脂肪酸的酯化和储存。IR是指肌肉组织、脂肪组织及肝脏等胰岛素靶组织对其敏感性下降，临床上主要表现为高胰岛素血症。IR状态下脂肪分解增加，游离脂肪酸(free fatty acids, FFAs) 大量释放, 过量的FFAs进入肝脏并刺激富含TG的极低密度脂蛋白(very low-density lipoprotein, VLDL)分泌，最终形成脂质的异位沉积[15]。同时，大量FFAs在非脂肪组织积聚产生的脂毒性会进一步加重IR，导致高胰岛素血症状态发生恶性循环[16]。IR是引起MASLD发生发展的重要机制，既往研究表明二者之间存在密切联系[17]。
CEACAM1是肝脏中胰岛素受体酪氨酸激酶的内源性底物，但在骨骼肌和脂肪组织等其他胰岛素敏感组织中却无这种特性[18]。生理学实验发现胰岛素自胰腺β细胞中脉冲式释放, 导致门静脉胰岛素浓度急剧升高并促使肝细胞中胰岛素受体自身酪氨酸激酶的磷酸化激活, 进而通过信号传递引发其底物发生磷酸化, 包括CEACAM1[19]。肝脏可清除80%从胰腺β细胞释放至门静脉循环中的胰岛素, 动物模型表明CEACAM1在此过程中发挥核心作用，即磷酸化的CEACAM1可促进经受体介导的胰岛素进入具有内吞作用的网格蛋白小泡，最终在溶酶体中被降解[20-21]。高胰岛素血症与胰岛素脉冲式释放受损可抑制CEACAM1的磷酸化过程。Bril等[22]将190例研究对象分为非MASLD组、单纯肝脂肪变性组及MASH组进行研究，结果发现与胰岛素分泌增加相比，MASLD患者高胰岛素血症与胰岛素清除率降低的关系更为密切。1型糖尿病(type 1 diabetes mellitus, T1DM)患者通过外源性胰岛素给药可导致胰岛素的脉冲式释放受到干扰，由此可推测T1DM患者的CEACAM1功能受损，但De Vries等[23-24]的研究并未发现T1DM患者MASLD患病率高于正常人群，因此这一假设尚需更深入的研究加以证实。
Poy等[25]发现CEACAM1胞尾区Tyr488连接并封闭含有SH2适配蛋白(SH2-containg adapter protein, SHC) 的SH2结构域，不仅限制生长因子受体结合蛋白2与胰岛素受体的偶联，还抑制由Ras/MAPK信号通路介导的有丝分裂途径，降低了肝细胞有丝分裂活性。同时, CEACAM1与SHC的结合增强了其与胰岛素受体底物1(insulin receptor substrate 1, IRS-1) 竞争被胰岛素受体磷酸化的能力，下调促进细胞增殖的IRS-1/PI3K/AKT通路，从而抑制肝细胞的增殖。此外, CEACAM1的磷酸化受到与Tyr488结合的非受体蛋白酪氨酸磷酸酶SHP-2的调控, SHP-2可使IRS-1去磷酸化并抑制其作用，CEACAM1连接SHP-2并阻止其与IRS-1结合，从而使IRS-1在肝内持续传导胰岛素信号[26]。肝脏中IR的条件性无效突变(conditional null mutation of the IR in the liver, LIRKO) 小鼠证实，肝脏中的正常胰岛素信号通路是调节全身胰岛素敏感性所必需的, 肝细胞中的胰岛素信号缺失会导致严重的原发性肝IR和慢性高胰岛素血症[27]。动物实验发现，CEACAM1磷酸化基因位点突变的小鼠会出现胰岛素清除障碍并导致继发性IR[27]。此外，CEACAM1基因突变小鼠可发生肝炎并出现桥接纤维化，这是MASH的主要特征[28]。肝纤维化主要由TGFβ-Smad2/3通路介导，并受内皮素-1 (endothelin-1, ET-1) 和血小板源性生长因子-B(platelet derived growth factor-B, PDGF-B) 两种关键的促纤维化因子驱动[29-30]。CEACAM1缺失导致的高胰岛素血症可促使ET-1水平升高并激活核转录因子κB(nuclear factor kappa-B, NF-κB)，活化的NF-κB促进PDGF-B基因转录, PDGF-B与ET-1通过刺激肝星状细胞增殖以诱导胶原蛋白的产生, 从而促进肝纤维化[30-31]。另一项动物实验发现，肝脏CEACAM1过表达可逆转高胰岛素血症诱发的MASH相关症状并防止肝纤维化，CEACAM1可能通过胰岛素清除改善IR状态并抑制脂毒性及炎症因子释放, 使ET-1和PDGF-B恢复正常[32-33]。综上所述，CEACAM1在肝脏胰岛素清除中发挥核心作用，但有关CEACAM1介导胰岛素清除与肝纤维化之间关系的机制仍有待进一步研究。
2.2 脂质代谢
门静脉的胰岛素浓度是体循环的2~3倍[34]，高浓度的胰岛素诱导肝脏新生脂肪合成(de novo lipogenesis, DNL), 其可能机制是肝细胞中的固醇调节元件结合蛋白(sterol regulatory element-binding proteins, SREBPs) 转录因子被胰岛素激活, 造成脂肪生成所必需的关键酶活性提高，如葡萄糖激酶、肝型丙酮酸激酶(liver-type pyruvate kinase, LPK)、脂肪酸合成酶(fatty acid synthase, FASN) 和乙酰辅酶A羧基酶(acetyl-CoA-carboxylase, ACC)[35]。FASN是DNL过程中催化丙二酰辅酶A转化为软脂酸的关键酶, 然而，生理情况下肝脏FASN活性很低, Matveyenko等[36]发现这与胰岛素脉冲式释放导致的CEACAM1迅速磷酸化有关, 大量磷酸化的CEACAM1可下调FASN酶活性，保护肝脏免受高胰岛素水平带来的潜在脂肪生成效应。
相应的, 高脂肪通过过氧化物酶体增殖物激活受体α (peroxisome-proliferator-activated receptor α, PPARα)依赖性下调CEACAM1的表达。PPARα是一种核受体，参与脂肪酸β氧化关键基因的表达，可通过降低CEACAM1基因mRNA水平以抑制CEACAM1蛋白转录[37]。肥胖人群体循环中的FFAs水平远高于正常体质量者, 且CEACAM1水平更低，加速了肝脂肪变性[38]。高脂水平促进MASLD的另一重要机制是脂肪浸润刺激骨髓衍生细胞, 使其分化为促炎巨噬细胞并释放多种促炎细胞因子, 如肿瘤坏死因子α(tumor necrosis factor-α, TNF-α)、白细胞介素(interleukin)-1β、IL-6、干扰素-γ (interferon-γ, IFN-γ) 等[39]。诸多研究发现, 促炎因子水平在MASH患者及小鼠体内显著升高, 并与病变程度呈正相关[40-41]。这些促炎因子能够调节脂质代谢与炎症反应, 例如, TNF-α可干扰胰岛素信号传导, 下调葡萄糖转运体-4(glucose transporter-4, GLUT-4)的表达而加剧IR[42]。一项动物实验表明，高脂饮食(high fat diet, HFD)3周后小鼠肝脏CEACAM1水平降低, 导致胰岛素清除受到损害而出现高胰岛素血症，高胰岛素血症刺激下丘脑摄食中枢引起食欲亢进并刺激棕色脂肪生成基因的表达, 加剧了肝脂肪的变性。其他相关研究亦发现，与野生型小鼠相比，肝脏特异性失活(liver-specific inactivation, L-SACC1)和CEACAM1完全零突变(global null mutation of ceacam1, Cc1-/-) 小鼠均表现出体质量上升和内脏脂肪增多[43-44]。该实验进一步发现即使在维持HFD的情况下, 肝脏重新输注CEACAM1仍可去除IR带来的不良代谢影响[45]。肝脏CEACAM1水平上调对脂肪组织胰岛素敏感性的积极作用部分是通过成纤维细胞生长因子21(fibroblast growth factor 21, FGF21) 介导的，FGF21能够作用于中枢系统诱导产热基因的表达并刺激交感神经活动, 从而引起运动量和能量消耗增加[46]。一项针对亚洲男性的研究证实，在骨骼肌和白色脂肪组织不受其他代谢因素影响的情况下，高脂肪饮食摄入降低了胰岛素的敏感性, 胰岛素清除障碍与肝脏IR风险增加有关[47]。
2.3 肠道免疫
肠-肝轴异常和肠道通透性升高是肝脏代谢功能障碍的重要危险因素，可能导致肝脏炎症并引起MASLD/MASH[48]。CEACAM1控制粒细胞的生成并延迟中性粒细胞的凋亡, 可防止过度炎症反应[49-50]。肠道和肝脏之间的免疫串扰可显著促进炎症性肠病(inflammatory bowel disease, IBD) 的肠外表现，其可能机制是黏膜T细胞的非典型免疫细胞归巢或胸腔导管的黏膜T细胞循环, 然而目前尚不确定黏膜T细胞是否可进入肝脏并释放炎症信号[51-52]。研究表明, CEACAM1通过介导T细胞激活与调节性T细胞(regulatory T cell, Treg) 在肝脏的表达而维持肠道黏膜免疫稳定性，抑制IBD及其肠外表现[53]。与正常人群相比，MASLD患者的肠道微生物群种类减少，肠道病原体防御屏障减弱[54], 但研究发现CEACAM1-S过度表达的小鼠肠道微生物群种类有所增加[55]。此外，CEACAM1是幽门螺杆菌、大肠杆菌、沙门氏菌及白色念珠菌等多种致病胃肠道微生物的受体, 可通过释放细菌代谢产物来调节肠道相关免疫耐受并诱导T细胞群从肠道迁移, 以抑制肝脏免疫炎症反应[56]。
3. 依赖CEACAM1对MASLD的潜在治疗药物
过氧化物酶体增殖物激活受体γ (peroxisome proliferator-activated receptor γ, PPARγ) 是一种配体依赖的转录调节因子, 已被发现可促进肝细胞中CEACAM1蛋白的合成[57]。经肠道合成的激素胰高血糖素样肽-1 (glucagon-like peptide-1, GLP-1) 能够刺激PPARγ表达水平上调，国外一项研究发现慢性高胰岛素血症患者GLP-1活性降低[58]。因此, 激活GLP-1的表达或可作为增强CEACAM1肝脏保护作用的一种疗法。研究发现，GLP-1受体激动剂艾塞那肽诱导HFD饲养小鼠肝脏CEACAM1的表达，有助于促进胰岛素清除并增强其敏感性，降低小鼠肝脂肪变性的风险[59]。另一项动物实验发现, 艾塞那肽逆转了HFD带来的小鼠肝脏炎性改变并抑制TGFβ/Smad2/Smad3促纤维化信号通路的激活[60]。这两项研究证实通过调节CEACAM1的表达水平维持胰岛素稳态对于肝脂肪变性的治疗意义，临床转化前景广阔。
4. 小结
MASLD是最常见的慢性肝病, CEACAM1水平上调促进胰岛素的清除, 限制了高胰岛素状态并减少了肝脏中的脂质沉积。MASLD患者的肝脏CEACAM1水平下调与病变严重程度呈正向关系。针对CEACAM1表达的小鼠试验模型进一步揭示了肝脏CEACAM1独特的代谢调节作用，CEACAM1基因缺失会损害胰岛素清除，引起高胰岛素血症并导致继发性IR和肝脏脂质生成增加。CEACAM1在MASLD/MASH发病机制中发挥关键作用(图 1)，对CEACAM1分子机制的深入研究有望为MASLD患者开辟新的治疗途径。一些药物，如GLP-1受体激动剂，已显示出对肝脏脂肪变性的拮抗作用，但其治疗MASLD的有效性, 尚需在患病人群中深入研究。
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图 1 CEACAM1在MASLD发生发展中的作用机制MASLD(metabolic dysfunction-associated steatotic liver disease): 代谢功能障碍相关脂肪性肝病；MASH(metabolic dysfunction-associated steatohepatitis): 代谢功能障碍相关脂肪性肝炎；FFAs(free fatty acids): 游离脂肪酸；TG(triglyceride): 甘油三酯；VLDL(very low-density lipoprotein): 极低密度脂蛋白；ET-1(endothelin-1): 内皮素-1；PDGF-B(platelet derived growth factor-B): 血小板源性生长因子B；IR(insulin resistance): 胰岛素抵抗；TNF-α(tumor necrosis factor-α): 肿瘤坏死因子α；IL(interleukin): 白细胞介素；IFN-γ(interferon-γ): 干扰素-γ；HFD(high fat die): 高脂饮食；Obese: 肥胖；Fat: 脂肪；FASN(fatty acid synthase): 脂肪酸合成酶；FGF21(fibroblast growth factor 21): 成纤维细胞生长因子21；CEACAM1(carcinoembryonic antigen-related cell adhesion molecule 1): 癌胚抗原相关细胞黏附分子1；Insulin level: 胰岛素水平；IRS-1(insulin receptor substrate 1): 胰岛素受体底物-1；T-cell: T细胞；Intestinal flora: 肠道菌群；PPAR(peroxisome-proliferator-activated receptor): 过氧化物酶体增殖物激活受体；Exenatide: 艾塞那肽Figure 1. Mechanism of CEACAM1 in the occurrence and development of MASLD -
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图 1 CEACAM1在MASLD发生发展中的作用机制
MASLD(metabolic dysfunction-associated steatotic liver disease): 代谢功能障碍相关脂肪性肝病；MASH(metabolic dysfunction-associated steatohepatitis): 代谢功能障碍相关脂肪性肝炎；FFAs(free fatty acids): 游离脂肪酸；TG(triglyceride): 甘油三酯；VLDL(very low-density lipoprotein): 极低密度脂蛋白；ET-1(endothelin-1): 内皮素-1；PDGF-B(platelet derived growth factor-B): 血小板源性生长因子B；IR(insulin resistance): 胰岛素抵抗；TNF-α(tumor necrosis factor-α): 肿瘤坏死因子α；IL(interleukin): 白细胞介素；IFN-γ(interferon-γ): 干扰素-γ；HFD(high fat die): 高脂饮食；Obese: 肥胖；Fat: 脂肪；FASN(fatty acid synthase): 脂肪酸合成酶；FGF21(fibroblast growth factor 21): 成纤维细胞生长因子21；CEACAM1(carcinoembryonic antigen-related cell adhesion molecule 1): 癌胚抗原相关细胞黏附分子1；Insulin level: 胰岛素水平；IRS-1(insulin receptor substrate 1): 胰岛素受体底物-1；T-cell: T细胞；Intestinal flora: 肠道菌群；PPAR(peroxisome-proliferator-activated receptor): 过氧化物酶体增殖物激活受体；Exenatide: 艾塞那肽
Figure 1. Mechanism of CEACAM1 in the occurrence and development of MASLD
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