Annexin A1 可与 PDZ 和 LIM domain 7 结合,抑制脂肪生成,预防肥胖。

IF 40.8 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Lu Fang, Changjie Liu, Zong-Zhe Jiang, Mengxiao Wang, Kang Geng, Yangkai Xu, Yujie Zhu, Yiwen Fu, Jing Xue, Wenxin Shan, Qi Zhang, Jie Chen, Jiahong Chen, Mingming Zhao, Yuxuan Guo, K W Michael Siu, Y Eugene Chen, Yong Xu, Donghui Liu, Lemin Zheng
{"title":"Annexin A1 可与 PDZ 和 LIM domain 7 结合,抑制脂肪生成,预防肥胖。","authors":"Lu Fang, Changjie Liu, Zong-Zhe Jiang, Mengxiao Wang, Kang Geng, Yangkai Xu, Yujie Zhu, Yiwen Fu, Jing Xue, Wenxin Shan, Qi Zhang, Jie Chen, Jiahong Chen, Mingming Zhao, Yuxuan Guo, K W Michael Siu, Y Eugene Chen, Yong Xu, Donghui Liu, Lemin Zheng","doi":"10.1038/s41392-024-01930-0","DOIUrl":null,"url":null,"abstract":"<p><p>Obesity is a global issue that warrants the identification of more effective therapeutic targets and a better understanding of the pivotal molecular pathogenesis. Annexin A1 (ANXA1) is known to inhibit phospholipase A2, exhibiting anti-inflammatory activity. However, the specific effects of ANXA1 in obesity and the underlying mechanisms of action remain unclear. Our study reveals that ANXA1 levels are elevated in the adipose tissue of individuals with obesity. Whole-body or adipocyte-specific ANXA1 deletion aggravates obesity and metabolic disorders. ANXA1 levels are higher in stromal vascular fractions (SVFs) than in mature adipocytes. Further investigation into the role of ANXA1 in SVFs reveals that ANXA1 overexpression induces lower numbers of mature adipocytes, while ANXA1-knockout SVFs exhibit the opposite effect. This suggests that ANXA1 plays an important role in adipogenesis. Mechanistically, ANXA1 competes with MYC binding protein 2 (MYCBP2) for interaction with PDZ and LIM domain 7 (PDLIM7). This exposes the MYCBP2-binding site, allowing it to bind more readily to the SMAD family member 4 (SMAD4) and promoting its ubiquitination and degradation. SMAD4 degradation downregulates peroxisome proliferator-activated receptor gamma (PPARγ) transcription and reduces adipogenesis. Treatment with Ac2-26, an active peptide derived from ANXA1, inhibits both adipogenesis and obesity through the mechanism. In conclusion, the molecular mechanism of ANXA1 inhibiting adipogenesis was first uncovered in our study, which is a potential target for obesity prevention and treatment.</p>","PeriodicalId":21766,"journal":{"name":"Signal Transduction and Targeted Therapy","volume":"9 1","pages":"218"},"PeriodicalIF":40.8000,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11341699/pdf/","citationCount":"0","resultStr":"{\"title\":\"Annexin A1 binds PDZ and LIM domain 7 to inhibit adipogenesis and prevent obesity.\",\"authors\":\"Lu Fang, Changjie Liu, Zong-Zhe Jiang, Mengxiao Wang, Kang Geng, Yangkai Xu, Yujie Zhu, Yiwen Fu, Jing Xue, Wenxin Shan, Qi Zhang, Jie Chen, Jiahong Chen, Mingming Zhao, Yuxuan Guo, K W Michael Siu, Y Eugene Chen, Yong Xu, Donghui Liu, Lemin Zheng\",\"doi\":\"10.1038/s41392-024-01930-0\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Obesity is a global issue that warrants the identification of more effective therapeutic targets and a better understanding of the pivotal molecular pathogenesis. Annexin A1 (ANXA1) is known to inhibit phospholipase A2, exhibiting anti-inflammatory activity. However, the specific effects of ANXA1 in obesity and the underlying mechanisms of action remain unclear. Our study reveals that ANXA1 levels are elevated in the adipose tissue of individuals with obesity. Whole-body or adipocyte-specific ANXA1 deletion aggravates obesity and metabolic disorders. ANXA1 levels are higher in stromal vascular fractions (SVFs) than in mature adipocytes. Further investigation into the role of ANXA1 in SVFs reveals that ANXA1 overexpression induces lower numbers of mature adipocytes, while ANXA1-knockout SVFs exhibit the opposite effect. This suggests that ANXA1 plays an important role in adipogenesis. Mechanistically, ANXA1 competes with MYC binding protein 2 (MYCBP2) for interaction with PDZ and LIM domain 7 (PDLIM7). This exposes the MYCBP2-binding site, allowing it to bind more readily to the SMAD family member 4 (SMAD4) and promoting its ubiquitination and degradation. SMAD4 degradation downregulates peroxisome proliferator-activated receptor gamma (PPARγ) transcription and reduces adipogenesis. Treatment with Ac2-26, an active peptide derived from ANXA1, inhibits both adipogenesis and obesity through the mechanism. In conclusion, the molecular mechanism of ANXA1 inhibiting adipogenesis was first uncovered in our study, which is a potential target for obesity prevention and treatment.</p>\",\"PeriodicalId\":21766,\"journal\":{\"name\":\"Signal Transduction and Targeted Therapy\",\"volume\":\"9 1\",\"pages\":\"218\"},\"PeriodicalIF\":40.8000,\"publicationDate\":\"2024-08-23\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11341699/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Signal Transduction and Targeted Therapy\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1038/s41392-024-01930-0\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Signal Transduction and Targeted Therapy","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41392-024-01930-0","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

肥胖症是一个全球性问题,需要找到更有效的治疗靶点,并更好地了解其关键的分子发病机制。众所周知,Annexin A1(ANXA1)可抑制磷脂酶 A2,具有抗炎活性。然而,ANXA1 在肥胖症中的具体作用及其作用机制仍不清楚。我们的研究发现,肥胖症患者脂肪组织中的 ANXA1 水平升高。全身或脂肪细胞特异性 ANXA1 缺失会加重肥胖和代谢紊乱。基质血管组分(SVF)中的 ANXA1 水平高于成熟脂肪细胞。对ANXA1在SVFs中作用的进一步研究发现,ANXA1过表达会诱导成熟脂肪细胞数量减少,而ANXA1基因敲除的SVFs则表现出相反的效果。这表明,ANXA1 在脂肪生成过程中发挥着重要作用。从机理上讲,ANXA1 与 MYC 结合蛋白 2(MYCBP2)竞争与 PDZ 和 LIM 结构域 7(PDLIM7)的相互作用。这暴露了 MYCBP2 的结合位点,使其更容易与 SMAD 家族成员 4(SMAD4)结合,促进其泛素化和降解。SMAD4 降解会下调过氧化物酶体增殖激活受体γ(PPARγ)的转录并减少脂肪生成。用从 ANXA1 提取的活性肽 Ac2-26 治疗,可通过该机制抑制脂肪生成和肥胖。总之,我们的研究首次发现了ANXA1抑制脂肪生成的分子机制,这是预防和治疗肥胖症的潜在靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Annexin A1 binds PDZ and LIM domain 7 to inhibit adipogenesis and prevent obesity.

Annexin A1 binds PDZ and LIM domain 7 to inhibit adipogenesis and prevent obesity.

Obesity is a global issue that warrants the identification of more effective therapeutic targets and a better understanding of the pivotal molecular pathogenesis. Annexin A1 (ANXA1) is known to inhibit phospholipase A2, exhibiting anti-inflammatory activity. However, the specific effects of ANXA1 in obesity and the underlying mechanisms of action remain unclear. Our study reveals that ANXA1 levels are elevated in the adipose tissue of individuals with obesity. Whole-body or adipocyte-specific ANXA1 deletion aggravates obesity and metabolic disorders. ANXA1 levels are higher in stromal vascular fractions (SVFs) than in mature adipocytes. Further investigation into the role of ANXA1 in SVFs reveals that ANXA1 overexpression induces lower numbers of mature adipocytes, while ANXA1-knockout SVFs exhibit the opposite effect. This suggests that ANXA1 plays an important role in adipogenesis. Mechanistically, ANXA1 competes with MYC binding protein 2 (MYCBP2) for interaction with PDZ and LIM domain 7 (PDLIM7). This exposes the MYCBP2-binding site, allowing it to bind more readily to the SMAD family member 4 (SMAD4) and promoting its ubiquitination and degradation. SMAD4 degradation downregulates peroxisome proliferator-activated receptor gamma (PPARγ) transcription and reduces adipogenesis. Treatment with Ac2-26, an active peptide derived from ANXA1, inhibits both adipogenesis and obesity through the mechanism. In conclusion, the molecular mechanism of ANXA1 inhibiting adipogenesis was first uncovered in our study, which is a potential target for obesity prevention and treatment.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Signal Transduction and Targeted Therapy
Signal Transduction and Targeted Therapy Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
44.50
自引率
1.50%
发文量
384
审稿时长
5 weeks
期刊介绍: Signal Transduction and Targeted Therapy is an open access journal that focuses on timely publication of cutting-edge discoveries and advancements in basic science and clinical research related to signal transduction and targeted therapy. Scope: The journal covers research on major human diseases, including, but not limited to: Cancer,Cardiovascular diseases,Autoimmune diseases,Nervous system diseases.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信