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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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近年来，关于如何界定缓和医疗照护对象的讨论正在悄然展开，并已引起多个领域(包括但不限于临床专业、政策制定、医疗体制改革、法律伦理和投资实业等)专家的关注。本文从推广生前预嘱(living will)的角度就这一问题展开讨论。
北京生前预嘱推广协会是于2013年注册成立的公益性社团组织。生前预嘱是指人们在健康或意识清楚时事先签署的指示性文件，阐明当其在不可治愈的伤病末期或临终时要或不要哪种医疗照护[1]。目前，世界上所有提供缓和医疗服务的国家和地区，均将生前预嘱以及具有表达个人意愿功能的相似文件作为开展此项医疗服务的合法性前提[2]。缓和医疗相关国家政策、临床实践与理论的发展，则是生前预嘱推广的必要条件。因此，本协会将推广生前预嘱和缓和医疗作为并驾齐驱的两项日常工作。
2010—2016年，本协会委托多名两会代表(胡定旭、凌峰、陶斯亮、顾晋等)连续数年提案，在中国现有法律环境下推广生前预嘱，以期建立政府指导下全方位分层次的缓和医疗服务。2015年，本协会受邀参加由时任全国政协主席俞正声支持、全国政协教科文卫体委员会开展的全国调研，该项工作围绕如何“推动安宁疗护发展”展开，对多地进行了为期8个月的走访和深度观察。2016年4月，俞正声主持并召开全国政协第49次双周协商座谈会，围绕“推进安宁疗护工作”建言献策。时任协会总干事罗峪平和香港医管局局长、协会专委会主席胡定旭参加会议并发言[3]。在调研和会议准备的过程中，我们竭力主张中国现代缓和医疗应从一开始就把照护对象尽量扩大化，主要依据是缓和医疗的定义一直在变化。
最广为人知和接受的缓和医疗定义由世界卫生组织(World Health Organization，WHO) 于2002年制定：缓和医疗是一种提供给患有危及生命疾病的患者和家庭的，旨在提高其生活质量及应对危机能力的系统方法；通过对痛苦和疼痛的早期识别，以严谨的评估和有效管理，满足患者及家庭的所有(包括心理和精神)需求[4]。2020年WHO发布了该定义的修订版，简化了语言表述，之前难以翻译成各国语言的措辞也得到纠正：缓和医疗是一种改善患有危及生命疾病的患者(成人和儿童)及其家人生活质量的方法；其通过早期识别，正确评估、治疗疼痛和其他身体、心理、精神问题以预防和减轻痛苦[5]。更新版定义列出了可能需要缓和医疗的最常见病症，但这些常见病症并无一份详尽的清单，疾病本身的诊断也并非获得缓和医疗服务的标准，因此对于缓和医疗照护对象的界定仍存在争议。
与此同时，国际安宁缓和医疗协会(International Association for Hospice & Palliative Care，IAHPC)提出了更具专业视角的缓和医疗新定义：缓和医疗是对因严重疾病而遭受严重健康损害的所有年龄段的个人，尤其是对生命终末期患者，所进行的积极全面的照护。该定义旨在提高个人及其家属和照护者的生活质量[6]。尽管这一定义与WHO的定义存在差异，但优先考虑舒适、尊严和共同决策，界定的目标人群为“患有严重疾病的人，不论年龄大小”，并不强调疾病的死亡率，而仅强调其严重性，建议从疾病一开始就实施缓和医疗，此表述符合多数人对缓和医疗的期盼，其一经发布即得到全球180个安宁疗护与缓和医疗组织和学术中心的支持[7]。
通过与调研专家团进行充分讨论，最终大家一致认为，从国家目前医疗体制的实际情况出发，对以癌症为主的终末期患者进行照护(后来被命名为“安宁疗护”)开始，可更快地使国家职能部门找到推广的抓手，具有更好的操作性，也更符合我国国情。而医保支付系统和商业保险等各相关领域在逐步积累数据的过程中，也能够留出充足的计算和决策空间，从而促使缓和医疗理念以更合理的速度长入复杂社会的“肌体”。随后，国家卫生健康委正式发布了安宁疗护标准和管理规范，并陆续推出三批安宁疗护试点城市。自此，安宁疗护作为现代缓和医疗的一部分开始快速发展，使更多人在了解安宁疗护的同时也对缓和医疗理念有了深入了解。从目前所取得的成果来看，这一“小切口”的决策更趋合理，使得缓和医疗的推广更易落实和操作。
全球老龄化日益加剧、感染性疾病大流行以及战争和气候变化带来的人道灾难，均将继续影响缓和医疗照护对象的界定。各国政府和各类组织将依据自身所处的不同环境作出不同决策，并不断修正和完善。不仅如此，生前预嘱的概念和推广方式也在经历一轮又一轮的更新和变化。
预立照护计划(advance care planning，ACP)是针对原有生前预嘱概念的迭代性文件。完整的ACP一般包括充分的个人意愿表达、指定的医疗代理人和可被执行的临床医嘱三部分，旨在通过患者、家属(或医疗代理人)和临床医生的充分协商，对诸如临终是否使用生命支持系统、是否充分镇痛等作出最大限度优化患者利益的共同决策。其优点在于可最大限度保障在长期照护机构、养老院、护理院、紧急医疗部门和医院各科室之间完整信息的传送和使用。目前，此类由医护人员主张形成的具有专业特点的措施，已经展现出良好的效果。2019年，由美国政府购买服务的美国生前预嘱注册中心(U.S. Living Will Registry)也因此改名为美国预立照护计划注册中心(U.S. Advance Care Plan Registry)[1]。
鉴于此，未来本协会的生前预嘱推广工作将增添新的重要内容——积极推动在现有法律环境下，在医政医管职权范围内，将统一制作的ACP文本放入住院病案首页，纳入病案级管理。这不仅有利于缓和医疗照护全过程的正确对接，还能够指导临床医护人员深入了解和掌握缓和医疗的基本概念和技能。标准ACP制作流程见图 1。
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缓和医疗的本质是对人的尊重，是在科技时代人们对生命本质重新认识的产物，而缓和医疗照护对象的界定亦无可争议地会随着国家经济和文明水平的发展而不断被修正和完善。北京生前预嘱推广协会作为推广生前预嘱和“尊严死”理念的社会组织，秉承“推广生前预嘱，让更多人知道，按照本人意愿，尽量以自然和有尊严的方式离世，是对生命的珍惜和热爱”的使命，殷切而充满信心地期待安宁缓和医疗在不久的将来，能够成为人人享有的基本权利。
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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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[1] Younossi Z M, Golabi P, Paik J M, et al. The global epidemiology of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH): a systematic review[J]. Hepatology, 2023, 77(4): 1335-1347. DOI: 10.1097/HEP.0000000000000004
[2] Loomba R, Wong V W S. Implications of the new nomenclature of steatotic liver disease and definition of metabolic dysfunction-associated steatotic liver disease[J]. Aliment Pharmacol Ther, 2024, 59(2): 150-156. DOI: 10.1111/apt.17846
[3] Harrison S A, Dubourg J, Knott M, et al. Hyperinsuline-mia, an overlooked clue and potential way forward in metabolic dysfunction-associated steatotic liver disease[J/OL]. Hepatology, 2023. doi: 10.1097/hep.0000000000000710.
[4] Yanai H, Adachi H, Hakoshima M, et al. Metabolic- dysfunction-associated steatotic liver disease-its pathophysiology, association with atherosclerosis and cardiovascular disease, and treatments[J]. Int J Mol Sci, 2023, 24(20): 15473. DOI: 10.3390/ijms242015473
[5] Kube-Golovin I, Lyndin M, Wiesehöfer M, et al. CEACAM expression in an in-vitro prostatitis model[J]. Front Immunol, 2023, 14: 1236343. DOI: 10.3389/fimmu.2023.1236343
[6] Thomas J, Klebanov A, John S, et al. CEACAMS 1, 5, and 6 in disease and cancer: interactions with pathogens[J]. Genes Cancer, 2023, 14: 12-29. DOI: 10.18632/genesandcancer.230
[7] Lee W. The CEACAM1 expression is decreased in the liver of severely obese patients with or without diabetes[J]. Diagn Pathol, 2011, 6(1): 40. DOI: 10.1186/1746-1596-6-40
[8] Heinrich G, Ghadieh H E, Ghanem S S, et al. Loss of hepatic CEACAM1: a unifying mechanism linking insulin resistance to obesity and non-alcoholic fatty liver disease[J]. Front Endocrinol (Lausanne), 2017, 8: 8.
[9] Lee W H, Najjar S M, Kahn C R, et al. Hepatic insulin receptor: new views on the mechanisms of liver disease[J]. Metabolism, 2023, 145: 155607. DOI: 10.1016/j.metabol.2023.155607
[10] Russo L, Muturi H T, Ghadieh H E, et al. Liver-specific rescuing of CEACAM1 reverses endothelial and cardi-ovascular abnormalities in male mice with null deletion of Ceacam1 gene[J]. Mol Metab, 2018, 9: 98-113. DOI: 10.1016/j.molmet.2018.01.009
[11] Hajihassan Z, Mohammadpour Saray M, Yaseri A. Engineering a CEACAM1 variant with the increased binding affinity to TIM-3 receptor[J]. Iran Biomed J, 2023, 27(4): 191-198.
[12] Dery K J, Kojima H, Kageyama S, et al. Alternative splicing of CEACAM1 by hypoxia-inducible factor-1α enhances tolerance to hepatic ischemia in mice and humans[J]. Sci Transl Med, 2023, 15(707): eadf2059. DOI: 10.1126/scitranslmed.adf2059
[13] 刘传, 李丽娟, 王嵘, 等. CEACAM5在肺腺癌中的表达及临床意义[J]. 临床肺科杂志, 2022, 27(2): 256-261. DOI: 10.3969/j.issn.1009-6663.2022.02.020 Liu C, Li L J, Wang R, et al. Expression and clinical significance of CEACAM5 in lung adenocarcinoma[J]. J Clin Pulm Med, 2022, 27(2): 256-261. DOI: 10.3969/j.issn.1009-6663.2022.02.020
[14] 马凯, 王鸽, 孙建兵, 等. HopQ与人CEACAM1相互作用的研究进展[J]. 医学综述, 2019, 25(17): 3433-3437. DOI: 10.3969/j.issn.1006-2084.2019.17.020 Ma K, Wang G, Sun J B, et al. Research progress of HopQ interaction with human CEACAM1[J]. Med Recapitulate, 2019, 25(17): 3433-3437. DOI: 10.3969/j.issn.1006-2084.2019.17.020
[15] Fan Y J, Yan Z P, Li T T, et al. Primordial drivers of diabetes heart disease: comprehensive insights into insulin resistance[J]. Diabetes Metab J, 2024, 48(1): 19-36. DOI: 10.4093/dmj.2023.0110
[16] Schwärzler J, Grabherr F, Grander C, et al. The pathophysiology of MASLD: an immunometabolic perspective[J]. Expert Rev Clin Immunol, 2024, 20(4): 375-386. DOI: 10.1080/1744666X.2023.2294046
[17] Vesković M, Šutulović N, Hrnčić D, et al. The interconnection between hepatic insulin resistance and metabolic dysfunction-associated steatotic liver disease-the transition from an adipocentric to liver-centric approach[J]. Curr Issues Mol Biol, 2023, 45(11): 9084-9102. DOI: 10.3390/cimb45110570
[18] Margolis R N, Taylor S I, Seminara D, et al. Identification of pp120, an endogenous substrate for the hepatocyte insulin receptor tyrosine kinase, as an integral membrane glycoprotein of the bile canalicular domain[J]. Proc Natl Acad Sci U S A, 1988, 85(19): 7256-7259. DOI: 10.1073/pnas.85.19.7256
[19] Najjar S M. Regulation of insulin action by CEACAM1[J]. Trends Endocrinol Metab, 2002, 13(6): 240-245. DOI: 10.1016/S1043-2760(02)00608-2
[20] Choice C V, Howard M J, Poy M N, et al. Insulin stimulates pp120 endocytosis in cells co-expressing insulin receptors[J]. J Biol Chem, 1998, 273(35): 22194-22200. DOI: 10.1074/jbc.273.35.22194
[21] Bergman R N, Kabir M, Ader M. The physiology of insulin clearance[J]. Int J Mol Sci, 2022, 23(3): 1826. DOI: 10.3390/ijms23031826
[22] Bril F, Lomonaco R, Orsak B, et al. Relationship between disease severity, hyperinsulinemia, and impaired insulin clearance in patients with nonalcoholic steatohepatitis[J]. Hepatology, 2014, 59(6): 2178-2187. DOI: 10.1002/hep.26988
[23] De Vries M, El-Morabit F, Van Erpecum K J, et al. Non-alcoholic fatty liver disease: identical etiologic factors in patients with type 1 and type 2 diabetes[J]. Eur J Intern Med, 2022, 100: 77-82. DOI: 10.1016/j.ejim.2022.03.025
[24] De Vries M, Westerink J, Kaasjager K H A H, et al. Prevalence of nonalcoholic fatty liver disease (NAFLD) in patients with type 1 diabetes mellitus: a systematic review and meta-analysis[J]. J Clin Endocrinol Metab, 2020, 105(12): 3842-3853. DOI: 10.1210/clinem/dgaa575
[25] Poy M N, Ruch R J, Fernstrom M A, et al. Shc and CEACAM1 interact to regulate the mitogenic action of insulin[J]. J Biol Chem, 2002, 277(2): 1076-1084. DOI: 10.1074/jbc.M108415200
[26] Yousef A A, Behiry E G, Allah W M A, et al. IRS-1 genetic polymorphism (r.2963G > A) in type 2 diabetes mellitus patients associated with insulin resistance[J]. Appl Clin Genet, 2018, 11: 99-106. DOI: 10.2147/TACG.S171096
[27] Poy M N, Yang Y, Rezaei K, et al. CEACAM1 regulates insulin clearance in liver[J]. Nat Genet, 2002, 30(3): 270-276. DOI: 10.1038/ng840
[28] Nagaishi T, Pao L, Lin S H, et al. SHP1 phosphatase-dependent T cell inhibition by CEACAM1 adhesion molecule isoforms[J]. Immunity, 2006, 25(5): 769-781. DOI: 10.1016/j.immuni.2006.08.026
[29] Mahmoud A M, Szczurek M R, Blackburn B K, et al. Hyperinsulinemia augments endothelin-1 protein expression and impairs vasodilation of human skeletal muscle arterioles[J]. Physiol Rep, 2016, 4(16): e12895. DOI: 10.14814/phy2.12895
[30] Abu Helal R, Muturi H T, Lee A D, et al. Aortic fibrosis in insulin-sensitive mice with endothelial cell-specific deletion of Ceacam1 gene[J]. Int J Mol Sci, 2022, 23(8): 4335. DOI: 10.3390/ijms23084335
[31] Muturi H T, Ghadieh H E, Abdolahipour R, et al. Loss of CEACAM1 in endothelial cells causes hepatic fibrosis[J]. Metabolism, 2023, 144: 155562. DOI: 10.1016/j.metabol.2023.155562
[32] Helal R A, Russo L, Ghadieh H E, et al. Regulation of hepatic fibrosis by carcinoembryonic antigen-related cell adhesion molecule 1[J]. Metabolism, 2021, 121: 154801. DOI: 10.1016/j.metabol.2021.154801
[33] Yan M L, Li H, Xu S Y, et al. Targeting endothelial necroptosis disrupts profibrotic endothelial-hepatic stellate cells crosstalk to alleviate liver fibrosis in nonalcoholic steatohepatitis[J]. Int J Mol Sci, 2023, 24(14): 11313. DOI: 10.3390/ijms241411313
[34] Laurenti M C, Dalla Man C, Varghese R T, et al. Insulin pulse characteristics and insulin action in non-diabetic humans[J]. J Clin Endocrinol Metab, 2021, 106(6): 1702-1709. DOI: 10.1210/clinem/dgab100
[35] DeBose-Boyd R A, Ye J. SREBPs in lipid metabolism, insulin signaling, and beyond[J]. Trends Biochem Sci, 2018, 43(5): 358-368. DOI: 10.1016/j.tibs.2018.01.005
[36] Matveyenko A V, Liuwantara D, Gurlo T, et al. Pulsatile portal vein insulin delivery enhances hepatic insulin action and signaling[J]. Diabetes, 2012, 61(9): 2269-2279. DOI: 10.2337/db11-1462
[37] Ramakrishnan S K, Khuder S S, Al-Share Q Y, et al. PPARα (peroxisome proliferator-activated receptor α) activation reduces hepatic CEACAM1 protein expression to regulate fatty acid oxidation during fasting-refeeding transition[J]. J Biol Chem, 2016, 291(15): 8121-8129. DOI: 10.1074/jbc.M116.714014
[38] Najjar S M, Caprio S, Gastaldelli A. Insulin clearance in health and disease[J]. Annu Rev Physiol, 2023, 85: 363-381. DOI: 10.1146/annurev-physiol-031622-043133
[39] Barreby E, Chen P, Aouadi M. Macrophage functional diversity in NAFLD-more than inflammation[J]. Nat Rev Endocrinol, 2022, 18(8): 461-472. DOI: 10.1038/s41574-022-00675-6
[40] Ruck L, Wiegand S, Kühnen P. Relevance and consequence of chronic inflammation for obesity development[J]. Mol Cell Pediatr, 2023, 10(1): 16. DOI: 10.1186/s40348-023-00170-6
[41] Hayakawa F, Soga K, Fujino J, et al. Utility of ultrasonography in a mouse model of non-alcoholic steatohepatitis induced by a choline-deficient, high-fat diet and dextran sulfate sodium[J]. Biochem Biophys Rep, 2023, 36: 101575.
[42] Kakino S, Ohki T, Nakayama H, et al. Pivotal role of TNF-α in the development and progression of nonalcoholic fatty liver disease in a murine model[J]. Horm Metab Res, 2018, 50(1): 80-87. DOI: 10.1055/s-0043-118666
[43] DeAngelis A M, Heinrich G, Dai T, et al. Carcinoembry-onic antigen-related cell adhesion molecule 1: a link between insulin and lipid metabolism[J]. Diabetes, 2008, 57(9): 2296-2303. DOI: 10.2337/db08-0379
[44] Park S Y, Cho Y R, Kim H J, et al. Mechanism of glucose intolerance in mice with dominant negative mutation of CEACAM1[J]. Am J Physiol Endocrinol Metab, 2006, 291(3): E517-E524.
[45] Al-Share Q Y, DeAngelis A M, Lester S G, et al. Forced hepatic overexpression of CEACAM1 curtails Diet-Induced insulin resistance[J]. Diabetes, 2015, 64(8): 2780-2790. DOI: 10.2337/db14-1772
[46] Wang Z Y, Sun T T, Yu J J, et al. FGF21: a sharp weapon in the process of exercise to improve NAFLD[J]. Front Biosci (Landmark Ed), 2023, 28(12): 351. DOI: 10.31083/j.fbl2812351
[47] Bakker L E H, Van Schinkel L D, Guigas B, et al. A 5-day high-fat, high-calorie diet impairs insulin sensitivity in healthy, young South Asian men but not in Caucasian men[J]. Diabetes, 2014, 63(1): 248-258. DOI: 10.2337/db13-0696
[48] Pezzino S, Sofia M, Mazzone C, et al. Exploring public interest in gut microbiome dysbiosis, NAFLD, and probiotics using Google Trends[J]. Sci Rep, 2024, 14(1): 799. DOI: 10.1038/s41598-023-50190-5
[49] Park D J, Sung P S, Kim J H, et al. EpCAM-high liver cancer stem cells resist natural killer cell-mediated cytotoxicity by upregulating CEACAM1[J]. J Immunother Cancer, 2020, 8(1): e000301. DOI: 10.1136/jitc-2019-000301
[50] Khairnar V, Duhan V, Patil A M, et al. CEACAM1 promotes CD8+ T cell responses and improves control of a chronic viral infection[J]. Nat Commun, 2018, 9(1): 2561. DOI: 10.1038/s41467-018-04832-2
[51] Adams D H, Eksteen B. Aberrant homing of mucosal T cells and extra-intestinal manifestations of inflammatory bowel disease[J]. Nat Rev Immunol, 2006, 6(3): 244-251. DOI: 10.1038/nri1784
[52] He R H, Zhao S B, Cui M Y, et al. Cutaneous manifestations of inflammatory bowel disease: basic characteristics, therapy, and potential pathophysiological associations[J]. Front Immunol, 2023, 14: 1234535. DOI: 10.3389/fimmu.2023.1234535
[53] Horst A K, Wegscheid C, Schaefers C, et al. Carcinoembryonic antigen-related cell adhesion molecule 1 controls IL-2-dependent regulatory T-cell induction in immune-mediated hepatitis in mice[J]. Hepatology, 2018, 68(1): 200-214. DOI: 10.1002/hep.29812
[54] Vallianou N, Christodoulatos G S, Karampela I, et al. Understanding the role of the gut microbiome and microbial metabolites in non-alcoholic fatty liver disease: current evidence and perspectives[J]. Biomolecules, 2021, 12(1): 56. DOI: 10.3390/biom12010056
[55] Chen L F, Chen Z G, Baker K, et al. The short isoform of the CEACAM1 receptor in intestinal T cells regulates mucosal immunity and homeostasis via Tfh cell induction[J]. Immunity, 2012, 37(5): 930-946. DOI: 10.1016/j.immuni.2012.07.016
[56] Gruzdev S K, Podoprigora I V, Gizinger O A. Immunology of gut microbiome and liver in non-alcoholic fatty liver disease (NAFLD): mechanisms, bacteria, and novel therapeutic targets[J]. Arch Microbiol, 2024, 206(2): 62. DOI: 10.1007/s00203-023-03752-0
[57] Najjar S M, Perdomo G. Hepatic insulin clearance: mechanism and physiology[J]. Physiology (Bethesda), 2019, 34(3): 198-215.
[58] Salehi M, Aulinger B, Prigeon R L, et al. Effect of endogenous GLP-1 on insulin secretion in type 2 diabetes[J]. Diabetes, 2010, 59(6): 1330-1337. DOI: 10.2337/db09-1253
[59] Ghadieh H E, Muturi H T, Russo L, et al. Exenatide induces carcinoembryonic antigen-related cell adhesion molecule 1 expression to prevent hepatic steatosis[J]. Hepatol Commun, 2018, 2(1): 35-47. DOI: 10.1002/hep4.1117
[60] Ghadieh H E, Muturi H T, Najjar S M. Exenatide prevents diet-induced hepatocellular injury in a CEACAM1-dependent mechanism[J]. J Diabetes Treat, 2017, 2017(4): JDBT-133.
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