{"title":"COPII囊泡贩运功能受损导致斑马鱼糖源性肝病","authors":"Yuxi Yang, Xue Zhang, Qingshun Zhao, Jingzi Zhang, Xin Lou","doi":"10.1242/dmm.050748","DOIUrl":null,"url":null,"abstract":"<p><p>Being a vital cellular process, coat protein complex II (COPII) vesicle trafficking has been found to play a crucial role in liver metabolism. However, its functions and the underlying mechanisms in systemic metabolic homeostasis have not been fully understood. Here, with a newly identified gene trap zebrafish line (sec31anju221), we show that compromised COPII vesicle trafficking leads to biphasic abnormal hepatic metabolism. During the larval stage, deficiency of COPII-mediated trafficking leads to activation of the unfolded protein response and the development of hepatic steatosis. By using epistasis analysis, we found that the eIF2α-ATF4 pathway serves as the primary effector for liver steatosis. In adult sec31anju221 fish, the hepatosteatosis was reversed and the phenotype switched to glycogenic hepatopathy. Proteomic profiling and biochemical assays indicate that sec31anju221 fish are in a state of hypothyroidism. Moreover, our study shows that thyroid hormone treatment alleviates the metabolic defects. This study provides insights into processes of liver diseases associated with vesicle trafficking impairments and expands our understanding of the pathological interplay between thyroid and liver.</p>","PeriodicalId":11144,"journal":{"name":"Disease Models & Mechanisms","volume":null,"pages":null},"PeriodicalIF":4.0000,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11463966/pdf/","citationCount":"0","resultStr":"{\"title\":\"Compromised COPII vesicle trafficking leads to glycogenic hepatopathy.\",\"authors\":\"Yuxi Yang, Xue Zhang, Qingshun Zhao, Jingzi Zhang, Xin Lou\",\"doi\":\"10.1242/dmm.050748\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Being a vital cellular process, coat protein complex II (COPII) vesicle trafficking has been found to play a crucial role in liver metabolism. However, its functions and the underlying mechanisms in systemic metabolic homeostasis have not been fully understood. Here, with a newly identified gene trap zebrafish line (sec31anju221), we show that compromised COPII vesicle trafficking leads to biphasic abnormal hepatic metabolism. During the larval stage, deficiency of COPII-mediated trafficking leads to activation of the unfolded protein response and the development of hepatic steatosis. By using epistasis analysis, we found that the eIF2α-ATF4 pathway serves as the primary effector for liver steatosis. In adult sec31anju221 fish, the hepatosteatosis was reversed and the phenotype switched to glycogenic hepatopathy. Proteomic profiling and biochemical assays indicate that sec31anju221 fish are in a state of hypothyroidism. Moreover, our study shows that thyroid hormone treatment alleviates the metabolic defects. This study provides insights into processes of liver diseases associated with vesicle trafficking impairments and expands our understanding of the pathological interplay between thyroid and liver.</p>\",\"PeriodicalId\":11144,\"journal\":{\"name\":\"Disease Models & Mechanisms\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.0000,\"publicationDate\":\"2024-09-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11463966/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Disease Models & Mechanisms\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1242/dmm.050748\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/9/30 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q2\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Disease Models & Mechanisms","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1242/dmm.050748","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/9/30 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
作为一个重要的细胞过程,人们发现 COPII 囊泡的运输在肝脏代谢中起着至关重要的作用。然而,人们对其在系统代谢平衡中的功能和内在机制还不完全了解。在这里,我们通过一个新发现的基因诱捕斑马鱼品系(sec31anju221)表明,COPII囊泡贩运功能受损会导致双相异常肝脏代谢。在幼鱼阶段,COPII 介导的贩运缺陷会导致未折叠蛋白反应(UPR)的激活和肝脏脂肪变性的发生。通过外显子分析,我们发现eIF2a/ATF4分支是肝脏脂肪变性的主要效应因子。在成鱼sec31anju221中,肝脂肪变性被逆转,表型转变为糖原性肝炎。蛋白质组分析和生化检测表明,sec31anju221鱼处于甲状腺机能减退状态。此外,我们的研究表明,甲状腺激素治疗可缓解代谢缺陷。这项研究深入揭示了与囊泡运输障碍相关的肝脏疾病的过程,并拓展了我们对甲状腺与肝脏之间病理相互作用的认识。
Compromised COPII vesicle trafficking leads to glycogenic hepatopathy.
Being a vital cellular process, coat protein complex II (COPII) vesicle trafficking has been found to play a crucial role in liver metabolism. However, its functions and the underlying mechanisms in systemic metabolic homeostasis have not been fully understood. Here, with a newly identified gene trap zebrafish line (sec31anju221), we show that compromised COPII vesicle trafficking leads to biphasic abnormal hepatic metabolism. During the larval stage, deficiency of COPII-mediated trafficking leads to activation of the unfolded protein response and the development of hepatic steatosis. By using epistasis analysis, we found that the eIF2α-ATF4 pathway serves as the primary effector for liver steatosis. In adult sec31anju221 fish, the hepatosteatosis was reversed and the phenotype switched to glycogenic hepatopathy. Proteomic profiling and biochemical assays indicate that sec31anju221 fish are in a state of hypothyroidism. Moreover, our study shows that thyroid hormone treatment alleviates the metabolic defects. This study provides insights into processes of liver diseases associated with vesicle trafficking impairments and expands our understanding of the pathological interplay between thyroid and liver.
期刊介绍:
Disease Models & Mechanisms (DMM) is an online Open Access journal focusing on the use of model systems to better understand, diagnose and treat human disease.