{"title":"阿片苷激活肝脏 NRF2 信号,刺激线粒体代谢,恢复高脂饮食诱导的 MAFLD 的脂质稳态","authors":"","doi":"10.1016/j.ejphar.2024.177003","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><p>Nutrient overload predisposes the development of metabolic dysfunction-associated fatty liver disease (MAFLD). However, there are no specific pharmacological therapies for MAFLD. Asperuloside (ASP), an iridoid glycoside extracted from <em>Eucommia ulmoides</em> leaves, can alleviate obesity and MAFLD. However, the underlying mechanism and pharmacological effects of ASP on ameliorating MAFLD remain largely investigated. This study aimed to explore the effects of ASP in ameliorating MAFLD and to unravel its underlying mechanism using a high fat diet-induced MAFLD mice model.</p></div><div><h3>Methods</h3><p>Six-week-old C57BL/6 male mice were fed a high fat diet for 12 weeks to induce MAFLD, followed by daily ASP treatment (50 mg/kg via oral gavage) for 7 weeks. HepG2 cells were used for <em>in vitro</em> studies. Nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor, ML385, was employed to explore the mechanisms of ASP's action.</p></div><div><h3>Results</h3><p>ASP stimulated lipolysis and inhibited de novo lipogenesis, contributing to alleviating lipid deposition in obese mice livers and HepG2 cells. ASP restored ATP production and reversed the impairments of mitochondrial energetics and biogenesis in obese mice livers and HepG2 cells. ASP attenuated oxidative stress in obese mice livers and HepG2 cells, exhibiting its antioxidant value. Impressively, ASP significantly promotes Nrf2 nuclear translocation and Nrf2/ARE binding, thereby activating Nrf2/ARE pathway in obese mice livers and HepG2 cells, demonstrating its potential as a hepatic Nrf2 activator. Nrf2 inhibition abolishes the protective effects of ASP against lipid deposition, oxidative stress and mitochondrial dysfunction, emphasizing the critical role of ASP-activated hepatic Nrf2 signaling in ameliorating MAFLD.</p></div><div><h3>Conclusions</h3><p>This study provides the first line of evidence demonstrating the pivotal role of ASP-stimulated Nrf2 activation in alleviating MAFLD, emphasizing its potential as a hepatic Nrf2 activator targeting fatty liver diseases. These findings offer new evidence of ASP-stimulated mitochondrial metabolism and lipolysis in MAFLD, paving the way for the development of ASP as a therapeutic agent and dietary supplement to attenuate MAFLD progression.</p></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":null,"pages":null},"PeriodicalIF":4.2000,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Asperuloside activates hepatic NRF2 signaling to stimulate mitochondrial metabolism and restore lipid homeostasis in high fat diet-induced MAFLD\",\"authors\":\"\",\"doi\":\"10.1016/j.ejphar.2024.177003\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><p>Nutrient overload predisposes the development of metabolic dysfunction-associated fatty liver disease (MAFLD). However, there are no specific pharmacological therapies for MAFLD. Asperuloside (ASP), an iridoid glycoside extracted from <em>Eucommia ulmoides</em> leaves, can alleviate obesity and MAFLD. However, the underlying mechanism and pharmacological effects of ASP on ameliorating MAFLD remain largely investigated. This study aimed to explore the effects of ASP in ameliorating MAFLD and to unravel its underlying mechanism using a high fat diet-induced MAFLD mice model.</p></div><div><h3>Methods</h3><p>Six-week-old C57BL/6 male mice were fed a high fat diet for 12 weeks to induce MAFLD, followed by daily ASP treatment (50 mg/kg via oral gavage) for 7 weeks. HepG2 cells were used for <em>in vitro</em> studies. Nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor, ML385, was employed to explore the mechanisms of ASP's action.</p></div><div><h3>Results</h3><p>ASP stimulated lipolysis and inhibited de novo lipogenesis, contributing to alleviating lipid deposition in obese mice livers and HepG2 cells. ASP restored ATP production and reversed the impairments of mitochondrial energetics and biogenesis in obese mice livers and HepG2 cells. ASP attenuated oxidative stress in obese mice livers and HepG2 cells, exhibiting its antioxidant value. Impressively, ASP significantly promotes Nrf2 nuclear translocation and Nrf2/ARE binding, thereby activating Nrf2/ARE pathway in obese mice livers and HepG2 cells, demonstrating its potential as a hepatic Nrf2 activator. Nrf2 inhibition abolishes the protective effects of ASP against lipid deposition, oxidative stress and mitochondrial dysfunction, emphasizing the critical role of ASP-activated hepatic Nrf2 signaling in ameliorating MAFLD.</p></div><div><h3>Conclusions</h3><p>This study provides the first line of evidence demonstrating the pivotal role of ASP-stimulated Nrf2 activation in alleviating MAFLD, emphasizing its potential as a hepatic Nrf2 activator targeting fatty liver diseases. These findings offer new evidence of ASP-stimulated mitochondrial metabolism and lipolysis in MAFLD, paving the way for the development of ASP as a therapeutic agent and dietary supplement to attenuate MAFLD progression.</p></div>\",\"PeriodicalId\":12004,\"journal\":{\"name\":\"European journal of pharmacology\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.2000,\"publicationDate\":\"2024-09-14\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"European journal of pharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0014299924006939\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"European journal of pharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0014299924006939","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}
引用次数: 0
摘要
背景营养过剩易导致代谢功能障碍相关性脂肪肝(MAFLD)的发生。然而,目前还没有针对代谢功能障碍相关性脂肪肝的特效药物疗法。杜仲苷(ASP)是从杜仲叶中提取的一种鸢尾甙,可减轻肥胖和脂肪肝。然而,ASP 对改善 MAFLD 的潜在机制和药理作用仍有待深入研究。本研究旨在利用高脂饮食诱导的 MAFLD 小鼠模型,探讨 ASP 在改善 MAFLD 方面的作用,并揭示其潜在机制。HepG2 细胞用于体外研究。结果ASP刺激脂肪分解并抑制新脂肪生成,有助于减轻肥胖小鼠肝脏和HepG2细胞的脂质沉积。ASP 恢复了 ATP 的产生,并逆转了肥胖小鼠肝脏和 HepG2 细胞线粒体能量和生物生成的损伤。ASP 可减轻肥胖小鼠肝脏和 HepG2 细胞的氧化应激,显示出其抗氧化价值。令人印象深刻的是,ASP能明显促进Nrf2核转位和Nrf2/ARE结合,从而激活肥胖小鼠肝脏和HepG2细胞中的Nrf2/ARE通路,显示了其作为肝脏Nrf2激活剂的潜力。抑制 Nrf2 可消除 ASP 对脂质沉积、氧化应激和线粒体功能障碍的保护作用,这强调了 ASP 激活的肝 Nrf2 信号在改善 MAFLD 中的关键作用。这些发现提供了 ASP 刺激 MAFLD 线粒体代谢和脂肪分解的新证据,为开发 ASP 作为治疗剂和膳食补充剂以减轻 MAFLD 的进展铺平了道路。
Asperuloside activates hepatic NRF2 signaling to stimulate mitochondrial metabolism and restore lipid homeostasis in high fat diet-induced MAFLD
Background
Nutrient overload predisposes the development of metabolic dysfunction-associated fatty liver disease (MAFLD). However, there are no specific pharmacological therapies for MAFLD. Asperuloside (ASP), an iridoid glycoside extracted from Eucommia ulmoides leaves, can alleviate obesity and MAFLD. However, the underlying mechanism and pharmacological effects of ASP on ameliorating MAFLD remain largely investigated. This study aimed to explore the effects of ASP in ameliorating MAFLD and to unravel its underlying mechanism using a high fat diet-induced MAFLD mice model.
Methods
Six-week-old C57BL/6 male mice were fed a high fat diet for 12 weeks to induce MAFLD, followed by daily ASP treatment (50 mg/kg via oral gavage) for 7 weeks. HepG2 cells were used for in vitro studies. Nuclear factor erythroid 2-related factor 2 (Nrf2) inhibitor, ML385, was employed to explore the mechanisms of ASP's action.
Results
ASP stimulated lipolysis and inhibited de novo lipogenesis, contributing to alleviating lipid deposition in obese mice livers and HepG2 cells. ASP restored ATP production and reversed the impairments of mitochondrial energetics and biogenesis in obese mice livers and HepG2 cells. ASP attenuated oxidative stress in obese mice livers and HepG2 cells, exhibiting its antioxidant value. Impressively, ASP significantly promotes Nrf2 nuclear translocation and Nrf2/ARE binding, thereby activating Nrf2/ARE pathway in obese mice livers and HepG2 cells, demonstrating its potential as a hepatic Nrf2 activator. Nrf2 inhibition abolishes the protective effects of ASP against lipid deposition, oxidative stress and mitochondrial dysfunction, emphasizing the critical role of ASP-activated hepatic Nrf2 signaling in ameliorating MAFLD.
Conclusions
This study provides the first line of evidence demonstrating the pivotal role of ASP-stimulated Nrf2 activation in alleviating MAFLD, emphasizing its potential as a hepatic Nrf2 activator targeting fatty liver diseases. These findings offer new evidence of ASP-stimulated mitochondrial metabolism and lipolysis in MAFLD, paving the way for the development of ASP as a therapeutic agent and dietary supplement to attenuate MAFLD progression.
期刊介绍:
The European Journal of Pharmacology publishes research papers covering all aspects of experimental pharmacology with focus on the mechanism of action of structurally identified compounds affecting biological systems.
The scope includes:
Behavioural pharmacology
Neuropharmacology and analgesia
Cardiovascular pharmacology
Pulmonary, gastrointestinal and urogenital pharmacology
Endocrine pharmacology
Immunopharmacology and inflammation
Molecular and cellular pharmacology
Regenerative pharmacology
Biologicals and biotherapeutics
Translational pharmacology
Nutriceutical pharmacology.