Sulforaphane ameliorates ethanol plus carbon tetrachloride-induced liver fibrosis in mice through the Nrf2-mediated antioxidant response and acetaldehyde metabolization with inhibition of the LPS/TLR4 signaling pathway
Sulforaphane ameliorates ethanol plus carbon tetrachloride-induced liver fibrosis in mice through the Nrf2-mediated antioxidant response and acetaldehyde metabolization with inhibition of the LPS/TLR4 signaling pathway
复制标题
DOI：
10.1016/j.jnutbio.2020.108573
复制
发表时间：
2021-01-12
影响因子：
5.6
通讯作者：
Yoshiji, Hitoshi
中科院分区：
文献类型：
--
作者：
Ishida, Koji;Kaji, Kosuke;Yoshiji, Hitoshi
酒精性肝病（ALD）相关的纤维化是由多种机制引起的，包括乙醛、活性氧的积累和内源性脂多糖（LPS）的肝超负荷。酒精戒断是ALD各阶段患者的主要治疗方法，而肝纤维化的药理学策略尚未建立。萝卜硫素是一种在十字花科蔬菜中发现的植物化学物质，可激活核因子红细胞2相关因子2（Nrf 2），并发挥抗癌，抗糖尿病和抗菌作用;然而，很少有研究调查其在ALD相关纤维化发展中的疗效。在此，我们研究了莱菔硫烷对乙醛代谢和肝纤维化的影响，在HepaRG和LX-2细胞，人肝癌和肝星状细胞系，分别，以及在酒精性肝纤维化的小鼠模型，乙醇加四氯化碳（EtOH/CCl 4）诱导。莱菔硫烷处理诱导HepaRG细胞中乙酰丙酮酸去代谢线粒体醛脱氢酶的活性，并通过上调Nrf 2调节的抗氧化基因（包括HMOX 1、NQO 1和GSTM 3）抑制LX-2细胞中乙酰丙酮酸诱导的增殖和促纤维化活性。此外，萝卜硫素减弱LPS/Toll样受体4介导的对转化生长因子-β的敏感性，下调NADPH氧化酶1（NOX 1）和NOX 4。在EtOH/CCl 4处理的小鼠中，口服莱菔硫烷增强了肝脏乙醛代谢。此外，莱菔硫烷显着抑制枯否细胞浸润和纤维化，减少脂肪积累和脂质过氧化，并诱导Nrf 2调节的抗氧化反应基因在乙醇/四氯化碳处理的小鼠。此外，萝卜硫素治疗钝化了肝脏暴露的肠源性LPS和抑制肝脏Toll样受体4信号通路。综上所述，这些结果表明萝卜硫素作为一种新的治疗策略，在ALD相关的肝纤维化。(c)2020爱思唯尔公司保留所有权利。提供上标/下标
Alcoholic liver disease (ALD)-related fibrosis results from a variety of mechanisms including the accumulation of acetaldehyde, reactive oxygen species, and hepatic overload of endogenous lipopolysaccharide (LPS). Alcohol cessation is the therapeutic mainstay for patients with all stages of ALD, whereas pharmacological strategies for liver fibrosis have not been established. Sulforaphane, a phytochemical found in cruciferous vegetables, activates nuclear factor erythroid 2-related factor 2 (Nrf2) and exerts anticancer, antidiabetic, and antimicrobial effects; however, few studies investigated its efficacy in the development of ALD-related fibrosis. Herein, we investigated the effect of sulforaphane on acetaldehyde metabolism and liver fibrosis in HepaRG and LX-2 cells, human hepatoma and hepatic stellate cell lines, respectively, as well as in a mouse model of alcoholic liver fibrosis induced by ethanol plus carbon tetrachloride (EtOH/CCl4). Sulforaphane treatment induced the activity of acetaldehyde-metabolizing mitochondrial aldehyde dehydrogenase in HepaRG cells and suppressed the acetaldehyde-induced proliferation and profibrogenic activity in LX-2 cells with upregulation of Nrf2-regulated antioxidant genes, including HMOX1, NQO1, and GSTM3. Moreover, sulforaphane attenuated the LPS/toll-like receptor 4-mediated sensitization to transforming growth factor-beta with downregulation of NADPH oxidase 1 (NOX1) and NOX4. In EtOH/CCl4-treated mice, oral sulforaphane administration augmented hepatic acetaldehyde metabolism. Additionally, sulforaphane significantly inhibited Kupffer cell infiltration and fibrosis, decreased fat accumulation and lipid peroxidation, and induced Nrf2-regulated antioxidant response genes in EtOH/CCl4-treated mice. Furthermore, sulforaphane treatment blunted hepatic exposure of gut-derived LPS and suppressed hepatic toll-like receptor 4 signaling pathway. Taken together, these results suggest sulforaphane as a novel therapeutic strategy in ALDrelated liver fibrosis. (c) 2020 Elsevier Inc. All rights reserved.Superscript/Subscript Available