Department of Gastroenterology, Nara Medical University, Kashihara, Nara, Japan.
Department of Gastroenterology, Nara Medical University, Kashihara, Nara, Japan.
J Nutr Biochem. 2021 Mar;89:108573. doi: 10.1016/j.jnutbio.2020.108573. Epub 2020 Dec 31.
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/CCl). 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-β with downregulation of NADPH oxidase 1 (NOX1) and NOX4. In EtOH/CCl-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/CCl-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 ALD-related liver fibrosis.
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、活性氧和内源性脂多糖（LPS）在肝脏中的堆积。对于所有阶段的 ALD 患者，戒酒都是治疗的主要方法，而针对肝纤维化的药物治疗策略尚未建立。萝卜硫素是十字花科蔬菜中发现的一种植物化学物质，可激活核因子红细胞 2 相关因子 2（Nrf2），并具有抗癌、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，我们研究了萝卜硫素对 HepaRG 和 LX-2 细胞（人肝癌和肝星状细胞系）以及乙醇加四氯化碳（EtOH/CCl）诱导的酒精性肝纤维化小鼠模型中乙醛代谢和肝纤维化的影响。萝卜硫素处理可诱导 HepaRG 细胞中乙醛代谢的线粒体乙醛脱氢酶活性，并抑制 LX-2 细胞中乙醛诱导的增殖和纤维生成活性，同时上调 Nrf2 调节的抗氧化基因，包括 HMOX1、NQO1 和 GSTM3。此外，萝卜硫素可通过下调 NADPH 氧化酶 1（NOX1）和 NOX4 来减轻 LPS/Toll 样受体 4 介导的对转化生长因子-β的敏化作用。在 EtOH/CCl 处理的小鼠中，口服萝卜硫素给药可增强肝脏中乙醛的代谢。此外，萝卜硫素可显著抑制库普弗细胞浸润和纤维化，减少脂肪堆积和脂质过氧化，并诱导 EtOH/CCl 处理的小鼠中 Nrf2 调节的抗氧化反应基因。此外，萝卜硫素治疗可减轻肝脏对肠道来源的 LPS 的暴露，并抑制肝脏 Toll 样受体 4 信号通路。综上所述，这些结果表明萝卜硫素是治疗 ALD 相关肝纤维化的一种新的治疗策略。
