下调钙调磷酸酶2调节因子可促进eb转录因子介导的脂质吞噬，预防非酒精性脂肪性肝病。

IF 3.3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Toxicology and applied pharmacology Pub Date : 2025-02-01 DOI:10.1016/j.taap.2024.117210

Lei Shan, Pengzhan Guo, Mumeike Wen, Yue Sun, Fei Gao, Kai Zhang, Ning Zhang, Baoshan Yang

{"title":"下调钙调磷酸酶2调节因子可促进eb转录因子介导的脂质吞噬，预防非酒精性脂肪性肝病。","authors":"Lei Shan, Pengzhan Guo, Mumeike Wen, Yue Sun, Fei Gao, Kai Zhang, Ning Zhang, Baoshan Yang","doi":"10.1016/j.taap.2024.117210","DOIUrl":null,"url":null,"abstract":"<div><div>Non-alcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease. The present work aimed to explore the function of regulator of Calcineurin 2 (RCAN2) in NAFLD and its related mechanisms. Mice were fed with high-fat diet (HFD) to construct NAFLD model. Adeno-associated virus injection was performed to interference with RCAN2 in mice. RCAN2 knockdown meliorated HFD-induced NAFLD and impaired glucose metabolism. Abnormal lipid metabolism and inflammation in HFD-fed mice were relieved when RCAN2 was downregulated. Besides, hepatocyte Huh-7 cells, treated with free fatty acids (oleic acid and palmitic acid), were used as NAFLD models in vitro. We found that knockdown of RCAN2 inhibited the accumulation of lipid droplets and inflammation induced by free fatty acids. RCAN2 interference increased the activity of calcineurin (CaN), which enhanced the nuclear translocation of Transcription factor EB (TFEB). Autophagosome and lysosome biogenesis was augmented, and autophagy-dependent lipid degradation (lipophagy) was promoted. Collectively, we demonstrate that RCAN2 insufficiency protects against NAFLD by promoting TFEB-mediated lipophagy.</div></div>","PeriodicalId":23174,"journal":{"name":"Toxicology and applied pharmacology","volume":"495 ","pages":"Article 117210"},"PeriodicalIF":3.3000,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Knockdown of regulator of Calcineurin 2 promotes transcription factor EB-mediated lipophagy to prevent non-alcoholic fatty liver disease\",\"authors\":\"Lei Shan, Pengzhan Guo, Mumeike Wen, Yue Sun, Fei Gao, Kai Zhang, Ning Zhang, Baoshan Yang\",\"doi\":\"10.1016/j.taap.2024.117210\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Non-alcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease. The present work aimed to explore the function of regulator of Calcineurin 2 (RCAN2) in NAFLD and its related mechanisms. Mice were fed with high-fat diet (HFD) to construct NAFLD model. Adeno-associated virus injection was performed to interference with RCAN2 in mice. RCAN2 knockdown meliorated HFD-induced NAFLD and impaired glucose metabolism. Abnormal lipid metabolism and inflammation in HFD-fed mice were relieved when RCAN2 was downregulated. Besides, hepatocyte Huh-7 cells, treated with free fatty acids (oleic acid and palmitic acid), were used as NAFLD models in vitro. We found that knockdown of RCAN2 inhibited the accumulation of lipid droplets and inflammation induced by free fatty acids. RCAN2 interference increased the activity of calcineurin (CaN), which enhanced the nuclear translocation of Transcription factor EB (TFEB). Autophagosome and lysosome biogenesis was augmented, and autophagy-dependent lipid degradation (lipophagy) was promoted. Collectively, we demonstrate that RCAN2 insufficiency protects against NAFLD by promoting TFEB-mediated lipophagy.</div></div>\",\"PeriodicalId\":23174,\"journal\":{\"name\":\"Toxicology and applied pharmacology\",\"volume\":\"495 \",\"pages\":\"Article 117210\"},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2025-02-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Toxicology and applied pharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0041008X24004095\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Toxicology and applied pharmacology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0041008X24004095","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}

引用次数: 0

摘要

非酒精性脂肪性肝病（NAFLD）是慢性肝病的主要病因。本研究旨在探讨钙调神经磷酸酶2 （Calcineurin 2, RCAN2）调节因子在NAFLD中的作用及其相关机制。采用高脂饲料（HFD）建立小鼠NAFLD模型。在小鼠体内注射腺相关病毒干扰RCAN2。RCAN2敲低可改善hfd诱导的NAFLD和糖代谢受损。当RCAN2下调时，hfd喂养小鼠的脂质代谢异常和炎症得到缓解。此外，以游离脂肪酸（油酸和棕榈酸）处理的肝细胞Huh-7细胞作为体外NAFLD模型。我们发现RCAN2的下调抑制了脂滴的积累和游离脂肪酸引起的炎症。RCAN2干扰增加了钙调神经磷酸酶（calcalineurin, CaN）的活性，促进了转录因子EB （Transcription factor EB， TFEB）的核易位。自噬体和溶酶体的生物发生增强，自噬依赖性脂质降解（脂噬）被促进。总的来说，我们证明RCAN2不足通过促进tfeb介导的脂质吞噬来预防NAFLD。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Knockdown of regulator of Calcineurin 2 promotes transcription factor EB-mediated lipophagy to prevent non-alcoholic fatty liver disease

查看原文本刊更多论文

Knockdown of regulator of Calcineurin 2 promotes transcription factor EB-mediated lipophagy to prevent non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is a major cause of chronic liver disease. The present work aimed to explore the function of regulator of Calcineurin 2 (RCAN2) in NAFLD and its related mechanisms. Mice were fed with high-fat diet (HFD) to construct NAFLD model. Adeno-associated virus injection was performed to interference with RCAN2 in mice. RCAN2 knockdown meliorated HFD-induced NAFLD and impaired glucose metabolism. Abnormal lipid metabolism and inflammation in HFD-fed mice were relieved when RCAN2 was downregulated. Besides, hepatocyte Huh-7 cells, treated with free fatty acids (oleic acid and palmitic acid), were used as NAFLD models in vitro. We found that knockdown of RCAN2 inhibited the accumulation of lipid droplets and inflammation induced by free fatty acids. RCAN2 interference increased the activity of calcineurin (CaN), which enhanced the nuclear translocation of Transcription factor EB (TFEB). Autophagosome and lysosome biogenesis was augmented, and autophagy-dependent lipid degradation (lipophagy) was promoted. Collectively, we demonstrate that RCAN2 insufficiency protects against NAFLD by promoting TFEB-mediated lipophagy.

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

Toxicology and applied pharmacology 医学-毒理学

CiteScore

6.80

自引率

2.60%

发文量

309

审稿时长

32 days

期刊介绍： Toxicology and Applied Pharmacology publishes original scientific research of relevance to animals or humans pertaining to the action of chemicals, drugs, or chemically-defined natural products. Regular articles address mechanistic approaches to physiological, pharmacologic, biochemical, cellular, or molecular understanding of toxicologic/pathologic lesions and to methods used to describe these responses. Safety Science articles address outstanding state-of-the-art preclinical and human translational characterization of drug and chemical safety employing cutting-edge science. Highly significant Regulatory Safety Science articles will also be considered in this category. Papers concerned with alternatives to the use of experimental animals are encouraged. Short articles report on high impact studies of broad interest to readers of TAAP that would benefit from rapid publication. These articles should contain no more than a combined total of four figures and tables. Authors should include in their cover letter the justification for consideration of their manuscript as a short article.