Inhibition of intracellular versus extracellular cathepsin D differentially alters the liver lipidome of mice with metabolic dysfunction-associated steatohepatitis.

Isabeau Vermeulen, Mengying Li, Hester van Mourik, Tulasi Yadati, Gert Eijkel, Benjamin Balluff, Roger Godschalk, Lieve Temmerman, Erik A L Biessen, Aditya Kulkarni, Jan Theys, Tom Houben, Berta Cillero-Pastor, Ronit Shiri-Sverdlov
{"title":"Inhibition of intracellular versus extracellular cathepsin D differentially alters the liver lipidome of mice with metabolic dysfunction-associated steatohepatitis.","authors":"Isabeau Vermeulen, Mengying Li, Hester van Mourik, Tulasi Yadati, Gert Eijkel, Benjamin Balluff, Roger Godschalk, Lieve Temmerman, Erik A L Biessen, Aditya Kulkarni, Jan Theys, Tom Houben, Berta Cillero-Pastor, Ronit Shiri-Sverdlov","doi":"10.1111/febs.17358","DOIUrl":null,"url":null,"abstract":"<p><p>The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) progressing to metabolic dysfunction-associated steatohepatitis (MASH), characterized by hepatic inflammation, has significantly increased in recent years due to unhealthy dietary practices and sedentary lifestyles. Cathepsin D (CTSD), a lysosomal protease involved in lipid homeostasis, is linked to abnormal lipid metabolism and inflammation in MASH. Although primarily intracellular, CTSD can be secreted extracellularly. Our previous proteomics research has shown that inhibition of extracellular CTSD results in more anti-inflammatory effects and fewer potential side effects compared to intracellular CTSD inhibition. However, the correlation between reduced side effects and alterations in the hepatic lipid composition remains unknown. This study aims to investigate the correlation between intra- and extracellular CTSD inhibition and potential alterations in the hepatic lipid composition in MASH. Low-density lipoprotein receptor knockout (Ldlr<sup>-/-</sup>) mice were fed a high-fat diet for 10 weeks and received subcutaneous injections every 2 days of vehicle, intracellular CTSD inhibitor (GA-12), or extracellular CTSD inhibitor (CTD-002). Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) was used to visualize and compare the lipid composition in liver tissues. Hepatic phosphatidylcholine remodeling was observed with both inhibitors, suggesting their therapeutic potential in treating MASH. Treatment with an intracellular CTSD inhibitor resulted in elevated levels of cardiolipin, reactive oxygen species, phosphatidylinositol, phosphatidylethanolamine, and lipids that are linked to mitochondrial dysfunction and inflammation, and induced more oxidative stress. The observed modifications in lipid composition demonstrate the clinical advantages of extracellular CTSD inhibition as a potentially beneficial therapeutic approach for MASH.</p>","PeriodicalId":94226,"journal":{"name":"The FEBS journal","volume":" ","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"The FEBS journal","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1111/febs.17358","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0

Abstract

The prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) progressing to metabolic dysfunction-associated steatohepatitis (MASH), characterized by hepatic inflammation, has significantly increased in recent years due to unhealthy dietary practices and sedentary lifestyles. Cathepsin D (CTSD), a lysosomal protease involved in lipid homeostasis, is linked to abnormal lipid metabolism and inflammation in MASH. Although primarily intracellular, CTSD can be secreted extracellularly. Our previous proteomics research has shown that inhibition of extracellular CTSD results in more anti-inflammatory effects and fewer potential side effects compared to intracellular CTSD inhibition. However, the correlation between reduced side effects and alterations in the hepatic lipid composition remains unknown. This study aims to investigate the correlation between intra- and extracellular CTSD inhibition and potential alterations in the hepatic lipid composition in MASH. Low-density lipoprotein receptor knockout (Ldlr-/-) mice were fed a high-fat diet for 10 weeks and received subcutaneous injections every 2 days of vehicle, intracellular CTSD inhibitor (GA-12), or extracellular CTSD inhibitor (CTD-002). Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) was used to visualize and compare the lipid composition in liver tissues. Hepatic phosphatidylcholine remodeling was observed with both inhibitors, suggesting their therapeutic potential in treating MASH. Treatment with an intracellular CTSD inhibitor resulted in elevated levels of cardiolipin, reactive oxygen species, phosphatidylinositol, phosphatidylethanolamine, and lipids that are linked to mitochondrial dysfunction and inflammation, and induced more oxidative stress. The observed modifications in lipid composition demonstrate the clinical advantages of extracellular CTSD inhibition as a potentially beneficial therapeutic approach for MASH.

求助全文
约1分钟内获得全文 求助全文
来源期刊
自引率
0.00%
发文量
0
×
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