Cyclic infusion mitigates liver dysfunction associated with continuous total parenteral nutrition in a novel murine model.

IF 3.3 3区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Nathaniel B Willis, Tahliyah S Mims, Karen Antunes, Hubert Peng, Mei-I Yen, Chi-Liang Eric Yen, Joseph F Pierre
{"title":"Cyclic infusion mitigates liver dysfunction associated with continuous total parenteral nutrition in a novel murine model.","authors":"Nathaniel B Willis, Tahliyah S Mims, Karen Antunes, Hubert Peng, Mei-I Yen, Chi-Liang Eric Yen, Joseph F Pierre","doi":"10.1152/ajpgi.00033.2025","DOIUrl":null,"url":null,"abstract":"<p><p>Parenteral nutrition (PN) is a lifesaving intervention for patients unable to feed enterally but is often associated with parenteral nutrition-associated liver disease (PNALD), also called intestinal failure-associated liver disease (IFALD). This disease is characterized by steatosis, cholestasis, and elevated liver stress markers. Continuous PN induces hepatic injury through mechanisms including insulin resistance, lipotoxicity, systemic inflammation, and oxidative stress. Infusion cycling is known to ameliorate clinical markers of liver injury, but metabolic underpinnings have not been thoroughly investigated. Therefore, we modeled PN-induced liver injury in mice to investigate how differential infusion patterns impacted hepatic metabolism. Intermittent infusions protected against increased circulating alanine aminotransferase levels and improved histopathology to more closely resemble chow controls. Transcriptomic analyses revealed 804 differentially expressed genes between PN groups, highlighting pathways related to peroxisome proliferator-activated receptor signaling, fatty acid metabolism, and peroxisomes. Relative to the continuous group, intermittent PN infusion specifically downregulated <i>Acaa1b</i>, <i>Aldh3a2</i>, <i>Inmt</i>, and <i>Acot4</i>; transcripts involved in peroxisomal lipid oxidation, dicarboxylic acid synthesis, and one-carbon metabolism. This study suggests that infusion cycling may attenuate metabolic burden induced by alternate lipid oxidation pathways. Future work can therapeutically leverage these metabolic pathways to deepen our understanding of PNALD/IFALD and guide PN treatments to improve patient outcomes.<b>NEW & NOTEWORTHY</b> This work demonstrated that the infusion schedule, independent of nutrient and caloric concentration, is a modulator of hepatic lipid metabolism in a novel murine model of parenteral nutrition. This cyclic infusion paradigm attenuated transcripts involved in microsomal and peroxisomal lipid oxidation, which were upregulated in the continuous infusion group. These data support the clinical use of cyclic infusion to improve hepatic parameters known to be adversely affected by parenteral nutrition.</p>","PeriodicalId":7725,"journal":{"name":"American journal of physiology. Gastrointestinal and liver physiology","volume":" ","pages":"G536-G545"},"PeriodicalIF":3.3000,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12456138/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"American journal of physiology. Gastrointestinal and liver physiology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1152/ajpgi.00033.2025","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/8/11 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Parenteral nutrition (PN) is a lifesaving intervention for patients unable to feed enterally but is often associated with parenteral nutrition-associated liver disease (PNALD), also called intestinal failure-associated liver disease (IFALD). This disease is characterized by steatosis, cholestasis, and elevated liver stress markers. Continuous PN induces hepatic injury through mechanisms including insulin resistance, lipotoxicity, systemic inflammation, and oxidative stress. Infusion cycling is known to ameliorate clinical markers of liver injury, but metabolic underpinnings have not been thoroughly investigated. Therefore, we modeled PN-induced liver injury in mice to investigate how differential infusion patterns impacted hepatic metabolism. Intermittent infusions protected against increased circulating alanine aminotransferase levels and improved histopathology to more closely resemble chow controls. Transcriptomic analyses revealed 804 differentially expressed genes between PN groups, highlighting pathways related to peroxisome proliferator-activated receptor signaling, fatty acid metabolism, and peroxisomes. Relative to the continuous group, intermittent PN infusion specifically downregulated Acaa1b, Aldh3a2, Inmt, and Acot4; transcripts involved in peroxisomal lipid oxidation, dicarboxylic acid synthesis, and one-carbon metabolism. This study suggests that infusion cycling may attenuate metabolic burden induced by alternate lipid oxidation pathways. Future work can therapeutically leverage these metabolic pathways to deepen our understanding of PNALD/IFALD and guide PN treatments to improve patient outcomes.NEW & NOTEWORTHY This work demonstrated that the infusion schedule, independent of nutrient and caloric concentration, is a modulator of hepatic lipid metabolism in a novel murine model of parenteral nutrition. This cyclic infusion paradigm attenuated transcripts involved in microsomal and peroxisomal lipid oxidation, which were upregulated in the continuous infusion group. These data support the clinical use of cyclic infusion to improve hepatic parameters known to be adversely affected by parenteral nutrition.

在一种新的小鼠模型中,循环输注减轻了与持续全肠外营养相关的肝功能障碍。
肠外营养(PN)是一种挽救生命的干预措施,用于无法肠内进食的患者,但通常与肠外营养相关肝病(PNALD)有关,也称为肠衰竭相关肝病(IFALD)。这种疾病的特征是脂肪变性、胆汁淤积和肝脏应激标志物升高。连续PN通过胰岛素抵抗、脂肪毒性、全身性炎症和氧化应激等机制诱导肝损伤。众所周知,输注循环可以改善肝损伤的临床标志物,但代谢基础尚未得到彻底的研究。因此,我们模拟PN诱导的小鼠肝损伤,研究不同输注方式对肝脏代谢的影响。间歇性输注可防止循环ALT水平升高,并改善组织病理学,使其更接近鼠粮对照组。转录组学分析显示,TPN组之间存在804个差异表达基因(DEGs),突出了与PPAR信号传导、脂肪酸代谢和过氧化物酶体相关的途径。与连续输注TPN组相比,间断输注TPN可特异性下调Acaa1b、Aldh3a2、Inmt和Acot4;参与过氧化物酶体脂质氧化、二羧酸合成和单碳代谢的转录本。本研究提示循环输注可减轻脂质氧化途径交替引起的代谢负担。未来的工作可以在治疗上利用这些代谢途径来加深我们对PNALD/IFALD的理解,并指导TPN治疗以改善患者的预后。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
9.40
自引率
2.20%
发文量
104
审稿时长
1 months
期刊介绍: The American Journal of Physiology-Gastrointestinal and Liver Physiology publishes original articles pertaining to all aspects of research involving normal or abnormal function of the gastrointestinal tract, hepatobiliary system, and pancreas. Authors are encouraged to submit manuscripts dealing with growth and development, digestion, secretion, absorption, metabolism, and motility relative to these organs, as well as research reports dealing with immune and inflammatory processes and with neural, endocrine, and circulatory control mechanisms that affect these organs.
×
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:604180095
Book学术官方微信