Vascular adhesion protein 1 in nonalcoholic steatohepatitis: a novel biomarker?
Vascular adhesion protein 1 in nonalcoholic steatohepatitis: a novel biomarker?
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非酒精性脂肪性肝炎中的血管粘附蛋白 1：一种新型生物标志物？
DOI：
10.1002/hep.27942
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发表时间：
2015
期刊：
影响因子：
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通讯作者：
Torok,NatalieJ
中科院分区：
文献类型：
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作者：
Torok,NatalieJ
非酒精性脂肪性肝病/非酒精性脂肪性肝炎（NASH）是一系列疾病，范围从单纯脂肪变性到进行性脂肪性肝炎，其特征是坏死性炎症、白细胞浸润和脂肪凋亡导致纤维化和肝硬化。诊断NASH的一个主要障碍是目前没有可接受的血清生物标志物来区分单纯性脂肪变性和脂肪性肝炎。在Weston等人的文章中，在三种不同的脂肪性肝炎动物模型中，血管粘附蛋白1 （VAP-1）被描述为可溶性（sap -1）和受体形式的白细胞的重要化学引诱剂。此外，他们表明VAP-1直接参与星状细胞活化，是一种强的促纤维化刺激。因此，靶向VAP-1可能导致白细胞募集减少，炎症和纤维化减少。根据目前的概念，在NASH中，病原性刺激，如氧化应激、未折叠蛋白反应失调、自噬或炎性体激活，导致白细胞浸润触发免疫反应。在肝脏中诱导吸引这些细胞的关键归巢信号尚未被很好地描述。与其他组织不同，在肝脏中，已知白细胞在没有选择素的帮助下直接与窦状内皮细胞（SECs）相连，而是使用不同的粘附分子，包括透明质酸CD44或VAP-1 （AOC3）。VAP-1也被称为氨基脲敏感胺氧化酶（SSAO），是一种由多种细胞表达的多功能外酶，催化伯胺脱胺产生醛、氨和H2O2。在慢性而非急性炎症性肝病中，它在淋巴细胞粘附和转运中起作用。过去的研究表明，VAP-1缺陷小鼠仅表现出轻微的肠道黏膜免疫改变，并且没有增加感染的风险，6表明靶向VAP-1可能是一种减少慢性炎症损伤期间白细胞粘附/转运的可行方法。由于VAP-1水平升高在肥胖和糖尿病中也有描述，因此它可能在NASH的发病机制中起重要作用。Weston等人证明，在74例组织学证实的NASH患者队列中，与体重指数和代谢表型匹配的对照患者相比，血清sap -1显著升高；在单变量分析中，它与体内平衡模型评估-估计的胰岛素抵抗和糖尿病状态相关。经多因素分析，血清sVAP-1与纤维化分期独立相关。sVAP-1预测组织学NASH的受试者工作曲线下面积（AUROC）为0.82(95%可信区间[CI]: 0.74-0.9)，估计敏感性为67.7%，特异性为89.7%。预测f2纤维化的AUROC为0.71 (95% CI: 0.62-0.79)，截止值为1,018 ng/mL，估计敏感性为45.2%，特异性为91.5%。有趣的是，VAP-1不仅存在于内皮细胞中，也存在于纤维化隔膜中，并与α -平滑肌肌动蛋白阳性的肌成纤维细胞共定位。机制研究表明，体外激活的肝星状细胞（hsc）和分离的活性肌成纤维细胞均表达VAP-1 (AOC3信使RNA)，并具有与sec中VAP-1相当的胺氧化酶活性。激活的造血干细胞诱导氨基氧化酶依赖的淋巴细胞在体外迁移，这可以通过去除H2O2或抑制GPCR信号传导来减少。VAP-1在体内的作用首次在CCl4…
Nonalcoholic fatty liver disease/nonalcoholic steatohepatitis (NASH) is a spectrum of disorders ranging from simple steatosis to progressive steatohepatitis characterized by necroinflammation, leukocyte infiltration, and lipoapoptosis leading to fibrosis and cirrhosis. A major obstacle for diagnosing NASH is that there currently are no acceptable serum biomarkers to distinguish simple steatosis from steatohepatitis. 1 In the article by Weston et al., 2 vascular adhesion protein 1 (VAP-1) is described as an important chemoattractant for leukocytes both in soluble (sVAP-1) and receptor forms in three different animal models of steatohepatitis. Furthermore, they show that VAP-1 is directly involved in stellate cell activation and is a strong profibrogenic stimulus. Thus, targeting VAP-1 may result in a decrease in leukocyte recruitment and reduction of inflammation and fibrosis. According to current concepts, during NASH, pathogenic stimuli, such as oxidative stress, dysregulation of the unfolded protein response, autophagy, or inflammasome activation, result in the infiltration of leukocytes triggering immune responses. The key homing signals that are induced in the liver to attract these cells have not been well described. Unlike in other tissues, in the liver, leukocytes are known to tether directly to sinusoidal endothelial cells (SECs) without the help of selectins and instead use a different array of adhesion molecules, including hyaluronan CD44 or VAP-1 (AOC3). 3 VAP-1, also known as semicarbazide-sensitive amine oxidase (SSAO), is a multifunctional ectoenzyme expressed by a variety of cells4 and catalyzes the deamination of primary amines producing aldehyde, ammonia, and H2O2. It plays a role in lymphocyte adhesion and transmigration in chronic, but not acute, inflammatory liver diseases. 5 Past studies showed that VAP-1-deficient mice exhibited only mild alterations in gut mucosal immunity and did not have an increased risk for infection, 6 suggesting that targeting VAP-1 could be a feasible approach to decrease leukocyte adhesion/transmigration during chronic inflammatory injury. Because elevated VAP-1 levels were also described in obesity and diabetes, 7 it was plausible that it could have a significant role in the pathogenesis of NASH. Weston et al. demonstrated that, in a cohort of 74 patients with histologically confirmed NASH, serum sVAP-1 was significantly increased, compared to body mass index and metabolic phenotype-matched control patients; and in a univariate analysis, it was correlated to homeostasis model assessment-estimated insulin resistance and diabetes status. After multivariate analysis, serum sVAP-1 was independently associated with fibrosis stage. The area under the receiver operating curve (AUROC) for sVAP-1 to predict histological NASH was 0.82 (95% confidence interval [CI]: 0.74-0.9) with estimated sensitivity of 67.7% and specificity of 89.7%. The AUROC to predict F 2 fibrosis was 0.71 (95% CI: 0.62-0.79), and with a cutoff of 1,018 ng/mL, sensitivity was estimated to be 45.2% and specificity 91.5%. Interestingly, VAP-1 was present not only in endothelial cells, but also in fibrotic septae and colocalized with alpha-smooth muscle actin–positive myofibroblasts. Mechanistic studies demonstrated that both in vitro activated hepatic stellate cells (HSCs) and isolated, active myofibroblasts express VAP-1 (AOC3 messenger RNA) and possess amine oxidase activity that is comparable to that of VAP-1 in SECs. Activated HSCs induced amineoxidase–dependent lymphocyte migration in vitro, and this was reduced either by removal of H2O2 or by inhibiting GPCR signaling.The role of VAP-1 in vivo was first studied in the CCl4 …