Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Sciences, Niigata University, Japan.
Future Medical Research Center for Exosome and Designer Cells (F-DEC), Niigata University, Japan.
FEBS Open Bio. 2024 Aug;14(8):1264-1276. doi: 10.1002/2211-5463.13842. Epub 2024 Jun 9.
Chronic liver injury leads to decreased liver function and increased fibrosis. Fibrosis is not only associated with the development of portal hypertension and carcinogenesis, but with the occurrence of events and a poor prognosis, highlighting the importance of non-invasive fibrosis assessment in patients. In the present study, we searched for markers related to liver fibrosis via proteomic analysis of small extracellular vesicles (sEVs). In the discovery cohort, proteomic analysis was carried out in the sEVs extracted from the sera of 5 patients with decompensated cirrhosis, 5 patients with compensated cirrhosis, and 5 controls without liver disease. Interestingly, in this cohort, fibulin-4 was significantly associated with cirrhosis while in the validation cohort [formed by 191 patients: 7 patients without disease, 16 patients without liver disease (other diseases), 38 patients with chronic liver disease (CLD), 75 patients with cirrhosis of Child-Pugh class A (36 without hepatocellular carcinoma [HCC], 29 with HCC), and 65 patients with cirrhosis of Child-Pugh class B-C (39 without HCC, 26 with HCC)], fibulin-4/CD9 levels increased with cirrhosis progression. Furthermore, the fibulin-4/CD9 ratio was significantly higher in patients with varices. Immunostaining also revealed strong fibulin-4 expression in cholangiocytes within the fibrous areas and mesothelial cells in liver tissue blood vessels. Taken together, our results suggest that fibulin-4, essential for lysyl oxidase activation, might be a new liver fibrosis marker found in the sEVs of patients with cirrhosis.
慢性肝损伤导致肝功能下降和纤维化增加。纤维化不仅与门脉高压和癌变的发展有关，而且与事件的发生和不良预后有关，这凸显了在患者中进行非侵入性纤维化评估的重要性。在本研究中，我们通过对小细胞外囊泡 (sEV) 的蛋白质组学分析寻找与肝纤维化相关的标志物。在发现队列中，对来自 5 例失代偿性肝硬化患者、5 例代偿性肝硬化患者和 5 例无肝病对照者血清中提取的 sEV 进行了蛋白质组学分析。有趣的是，在该队列中，纤维调蛋白-4 与肝硬化显著相关，而在验证队列中[由 191 例患者组成：7 例无疾病，16 例无肝脏疾病（其他疾病），38 例慢性肝病 (CLD)，75 例 Child-Pugh 分级 A 肝硬化患者（36 例无肝细胞癌 [HCC]，29 例 HCC），65 例 Child-Pugh 分级 B-C 肝硬化患者（39 例无 HCC，26 例 HCC）]，纤维调蛋白-4/CD9 水平随着肝硬化的进展而增加。此外，静脉曲张患者的纤维调蛋白-4/CD9 比值明显更高。免疫染色还显示纤维蛋白-4 在肝组织血管中的胆管细胞和间皮细胞内的强表达。综上所述，我们的结果表明，纤维调蛋白-4 作为赖氨酰氧化酶激活所必需的物质，可能是在肝硬化患者的 sEV 中发现的新的肝纤维化标志物。
