Formononetin alleviates hepatic steatosis by facilitating TFEB-mediated lysosome biogenesis and lipophagy
Formononetin alleviates hepatic steatosis by facilitating TFEB-mediated lysosome biogenesis and lipophagy
复制标题
芒柄花素通过促进 TFEB 介导的溶酶体生物发生和脂肪吞噬来减轻肝脏脂肪变性
DOI：
10.1016/j.jnutbio.2019.07.005
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发表时间：
2019-11-01
影响因子：
5.6
通讯作者：
Li, Ping
中科院分区：
文献类型：
--
作者：
Wang, Yan;Zhao, Hailing;Li, Ping
据报道，刺芒柄花素可以改善高脂血症和肥胖，但其在抗非酒精性脂肪性肝病（NAFLD）中的作用和机制尚不清楚。脂噬是脂肪变性发展过程中的重要保护机制，通过自噬导致脂滴分解，防止细胞脂质积累。本研究旨在探讨刺芒柄花素治疗NAFLD的有益作用，并探讨脂噬作用在刺芒柄花素抗肝脂肪变性作用中的作用机制。刺芒柄花素治疗可显著改善HFD小鼠的肝脏脂肪变性。与此一致的是，刺芒柄花素也减少了ffas刺激的HepG2细胞和小鼠原代肝细胞的脂质积累。进一步的分析显示，脂肪变性增加了LC3B-II，这是自噬的标志，但由于缺乏溶酶体而导致自噬通量的阻断。刺芒柄花素促进了溶酶体的生物生成和自噬体与溶酶体的融合，缓解了自噬通量的阻塞，进一步诱导了脂噬。从机制上说，刺芒柄花素激活了单磷酸腺苷活化蛋白激酶（AMPK），并促进了随后的转录因子EB （TFEB）的核易位，而转录因子EB是溶酶体生物发生的关键调节因子。TFEB抑制显著消除了刺芒花素诱导的溶酶体生物生成、自噬体-溶酶体融合和脂质吞噬，同时减轻了脂质积累。刺芒柄花素通过tfeb介导的溶酶体生物发生改善肝脏脂肪变性，这为刺芒柄花素抗nafld作用提供了新的证据。(C) 2019 Elsevier Inc.版权所有。
Formononetin has been reported to ameliorate hyperlipidemia and obesity, but its effect and mechanism of action in anti-non-alcoholic fatty liver disease (NAFLD) remain unclear. Lipophagy is a critical protective mechanism during steatosis development that results in the decomposition of lipid droplets through autophagy and the prevention of cellular lipid accumulation. This study aimed to investigate the beneficial role of formononetin in treating NAFLD and explore the mechanism of lipophagy in formononetin anti-hepatic steatosis effects. Formononetin treatment significantly ameliorated hepatic steatosis in HFD mice. Consistently, formononetin also reduced FFAs-stimulated lipid accumulation in HepG2 cells and primary mouse hepatocytes. Further analysis revealed that steatosis increased LC3B-II, a marker of autophagy, but caused blockade of autophagic flux associated with a lack of lysosomes. Treatment with formononetin promoted lysosome biogenesis and autophagosome-lysosome fusion, relieving the blockade in autophagic flux and further induced lipophagy. Mechanistically, formononetin activated adenosine monophosphate activated protein kinase (AMPK) and promoted subsequent nuclear translocation of transcription factor EB (TFEB), a key regulator of lysosome biogenesis. TFEB inhibition markedly abolished formononetin-induced lysosome biogenesis, autophagosome-lysosome fusion and lipophagy and concomitantly alleviated lipid accumulation. Formononetin improved hepatic steatosis via TFEB-mediated lysosome biogenesis, which provides new evidence regarding formononetin's anti-NAFLD effects. (C) 2019 Elsevier Inc. All rights reserved.