{"title":"血清细胞外囊泡的蛋白质组分析显示，Fibulin-3 是预测 MASLD 中肝脏相关事件的新标记物。","authors":"Sadatsugu Sakane, Hayato Hikita, Kumiko Shirai, Tatsuya Sakamoto, Ryohei Narumi, Jun Adachi, Naruyasu Kakita, Yukinori Yamada, Hidenori Toyoda, Hirokazu Takahashi, Goki Suda, Machiko Kai, Yuki Tahata, Ryotaro Sakamori, Shusuke Kumazaki, Kenji Fukumoto, Yuta Myojin, Kazuhiro Murai, Takahiro Kodama, Tomohide Tatsumi, Takeshi Tomonaga, Naoya Sakamoto, Eiichi Morii, Tetsuo Takehara","doi":"10.1097/HC9.0000000000000448","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>There is a need for novel noninvasive markers for metabolic dysfunction-associated steatotic liver disease (MASLD) to stratify patients at high risk for liver-related events including liver cancer and decompensation. In the present study, we used proteomic analysis of proteins in extracellular vesicles (EVs) to identify new biomarkers that change with fibrosis progression and can predict the development of liver-related events.</p><p><strong>Methods: </strong>We analyzed serum EVs from 50 patients with MASLD assessed for liver fibrosis by biopsy and identified proteins that altered with advanced fibrosis. A further evaluation was conducted on another cohort of 463 patients with MASLD with biopsy.</p><p><strong>Results: </strong>Eight candidate proteins were identified by proteomic analysis of serum EVs. Among them, serum levels of Fibulin-3, Fibulin-1, and Ficolin 1 correlated with their EV levels. In addition, serum Fibulin-3 and serum Fibulin-1 levels changed significantly with advanced fibrosis. Using another cohort with biopsy, we found that the serum Fibulin-3 concentration was significantly greater in those with advanced fibrosis but that the serum Fibulin-1 concentration was not significantly different. Multivariate Cox proportional hazards analysis revealed that a higher Fibrosis-4 (FIB-4) index and higher serum Fibulin-3 concentration were independent risk factors for liver-related events. When the cutoff value for the serum Fibulin-3 concentration was 6.0 µg/mL according to the Youden index of AUROCs, patients with high serum Fibulin-3 significantly more frequently developed liver-related events than did other patients. Validation using another cohort of 226 patients with clinically diagnosed MASLD confirmed that high serum Fibulin-3 levels are associated with a greater frequency of liver-related events.</p><p><strong>Conclusions: </strong>Serum Fibulin-3 was identified as a biomarker for predicting liver-related events in patients with MASLD.</p>","PeriodicalId":5,"journal":{"name":"ACS Applied Materials & Interfaces","volume":null,"pages":null},"PeriodicalIF":8.3000,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11150025/pdf/","citationCount":"0","resultStr":"{\"title\":\"Proteomic analysis of serum extracellular vesicles reveals Fibulin-3 as a new marker predicting liver-related events in MASLD.\",\"authors\":\"Sadatsugu Sakane, Hayato Hikita, Kumiko Shirai, Tatsuya Sakamoto, Ryohei Narumi, Jun Adachi, Naruyasu Kakita, Yukinori Yamada, Hidenori Toyoda, Hirokazu Takahashi, Goki Suda, Machiko Kai, Yuki Tahata, Ryotaro Sakamori, Shusuke Kumazaki, Kenji Fukumoto, Yuta Myojin, Kazuhiro Murai, Takahiro Kodama, Tomohide Tatsumi, Takeshi Tomonaga, Naoya Sakamoto, Eiichi Morii, Tetsuo Takehara\",\"doi\":\"10.1097/HC9.0000000000000448\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>There is a need for novel noninvasive markers for metabolic dysfunction-associated steatotic liver disease (MASLD) to stratify patients at high risk for liver-related events including liver cancer and decompensation. In the present study, we used proteomic analysis of proteins in extracellular vesicles (EVs) to identify new biomarkers that change with fibrosis progression and can predict the development of liver-related events.</p><p><strong>Methods: </strong>We analyzed serum EVs from 50 patients with MASLD assessed for liver fibrosis by biopsy and identified proteins that altered with advanced fibrosis. A further evaluation was conducted on another cohort of 463 patients with MASLD with biopsy.</p><p><strong>Results: </strong>Eight candidate proteins were identified by proteomic analysis of serum EVs. Among them, serum levels of Fibulin-3, Fibulin-1, and Ficolin 1 correlated with their EV levels. In addition, serum Fibulin-3 and serum Fibulin-1 levels changed significantly with advanced fibrosis. Using another cohort with biopsy, we found that the serum Fibulin-3 concentration was significantly greater in those with advanced fibrosis but that the serum Fibulin-1 concentration was not significantly different. Multivariate Cox proportional hazards analysis revealed that a higher Fibrosis-4 (FIB-4) index and higher serum Fibulin-3 concentration were independent risk factors for liver-related events. When the cutoff value for the serum Fibulin-3 concentration was 6.0 µg/mL according to the Youden index of AUROCs, patients with high serum Fibulin-3 significantly more frequently developed liver-related events than did other patients. Validation using another cohort of 226 patients with clinically diagnosed MASLD confirmed that high serum Fibulin-3 levels are associated with a greater frequency of liver-related events.</p><p><strong>Conclusions: </strong>Serum Fibulin-3 was identified as a biomarker for predicting liver-related events in patients with MASLD.</p>\",\"PeriodicalId\":5,\"journal\":{\"name\":\"ACS Applied Materials & Interfaces\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":8.3000,\"publicationDate\":\"2024-06-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11150025/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"ACS Applied Materials & Interfaces\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1097/HC9.0000000000000448\",\"RegionNum\":2,\"RegionCategory\":\"材料科学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/6/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q1\",\"JCRName\":\"MATERIALS SCIENCE, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Applied Materials & Interfaces","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1097/HC9.0000000000000448","RegionNum":2,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/6/1 0:00:00","PubModel":"eCollection","JCR":"Q1","JCRName":"MATERIALS SCIENCE, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0
摘要
背景：代谢功能障碍相关性脂肪性肝病（MASLD）需要新的非侵入性标记物来对肝脏相关事件（包括肝癌和肝功能失代偿）的高风险患者进行分层。在本研究中，我们利用细胞外囊泡（EVs）中蛋白质的蛋白质组学分析来确定新的生物标志物，这些标志物会随着肝纤维化的进展而变化，并能预测肝脏相关事件的发生：我们分析了50名通过活检评估肝纤维化的MASLD患者的血清EVs，并确定了随晚期纤维化而改变的蛋白质。结果：通过活组织切片检查确定了8种候选蛋白质：结果：通过对血清EVs进行蛋白质组学分析，确定了8种候选蛋白质。其中，血清中纤维蛋白-3、纤维蛋白-1和Ficolin 1的水平与其EV水平相关。此外，血清Fibulin-3和血清Fibulin-1的水平随晚期纤维化而发生显著变化。我们利用另一个队列的活检结果发现，晚期纤维化患者的血清Fibulin-3浓度明显更高，但血清Fibulin-1浓度没有明显差异。多变量考克斯比例危险分析显示，纤维化-4（FIB-4）指数越高、血清纤维蛋白-3浓度越高，是发生肝脏相关事件的独立危险因素。根据尤登指数（Youden index of AUROCs），当血清纤维蛋白-3浓度的临界值为6.0微克/毫升时，血清纤维蛋白-3浓度高的患者发生肝脏相关事件的频率明显高于其他患者。使用另一个由226名临床诊断为MASLD的患者组成的队列进行的验证证实，血清纤维蛋白-3水平高的患者发生肝脏相关事件的频率更高：结论：血清纤维蛋白-3被确定为预测MASLD患者肝脏相关事件的生物标志物。
Proteomic analysis of serum extracellular vesicles reveals Fibulin-3 as a new marker predicting liver-related events in MASLD.
Background: There is a need for novel noninvasive markers for metabolic dysfunction-associated steatotic liver disease (MASLD) to stratify patients at high risk for liver-related events including liver cancer and decompensation. In the present study, we used proteomic analysis of proteins in extracellular vesicles (EVs) to identify new biomarkers that change with fibrosis progression and can predict the development of liver-related events.
Methods: We analyzed serum EVs from 50 patients with MASLD assessed for liver fibrosis by biopsy and identified proteins that altered with advanced fibrosis. A further evaluation was conducted on another cohort of 463 patients with MASLD with biopsy.
Results: Eight candidate proteins were identified by proteomic analysis of serum EVs. Among them, serum levels of Fibulin-3, Fibulin-1, and Ficolin 1 correlated with their EV levels. In addition, serum Fibulin-3 and serum Fibulin-1 levels changed significantly with advanced fibrosis. Using another cohort with biopsy, we found that the serum Fibulin-3 concentration was significantly greater in those with advanced fibrosis but that the serum Fibulin-1 concentration was not significantly different. Multivariate Cox proportional hazards analysis revealed that a higher Fibrosis-4 (FIB-4) index and higher serum Fibulin-3 concentration were independent risk factors for liver-related events. When the cutoff value for the serum Fibulin-3 concentration was 6.0 µg/mL according to the Youden index of AUROCs, patients with high serum Fibulin-3 significantly more frequently developed liver-related events than did other patients. Validation using another cohort of 226 patients with clinically diagnosed MASLD confirmed that high serum Fibulin-3 levels are associated with a greater frequency of liver-related events.
Conclusions: Serum Fibulin-3 was identified as a biomarker for predicting liver-related events in patients with MASLD.
期刊介绍：
ACS Applied Materials & Interfaces is a leading interdisciplinary journal that brings together chemists, engineers, physicists, and biologists to explore the development and utilization of newly-discovered materials and interfacial processes for specific applications. Our journal has experienced remarkable growth since its establishment in 2009, both in terms of the number of articles published and the impact of the research showcased. We are proud to foster a truly global community, with the majority of published articles originating from outside the United States, reflecting the rapid growth of applied research worldwide.
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