He Chufeng, Zhang Qile, Zhu Ruiwen, Tse Gary, Wong Wing Tak
School of Life Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China; State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong 999077, China.
School of Life Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China; State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong 999077, China.
Eur J Pharmacol. 2024 Nov 15;983:177003. doi: 10.1016/j.ejphar.2024.177003. Epub 2024 Sep 14.
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.
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.
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.
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.
营养过剩易引发代谢功能障碍相关脂肪性肝病（MAFLD）。然而，目前尚无针对MAFLD的特异性药物治疗方法。梓醇（ASP）是从杜仲叶中提取的一种环烯醚萜苷，可减轻肥胖和MAFLD。然而，ASP改善MAFLD的潜在机制和药理作用在很大程度上仍有待研究。本研究旨在利用高脂饮食诱导的MAFLD小鼠模型，探讨ASP改善MAFLD的作用及其潜在机制。
六周龄C57BL/6雄性小鼠喂食高脂饮食12周以诱导MAFLD，随后每日给予ASP治疗（经口灌胃50mg/kg）7周。使用HepG2细胞进行体外研究。采用核因子红细胞2相关因子2（Nrf2）抑制剂ML385来探究ASP的作用机制。
ASP刺激脂肪分解并抑制从头脂肪生成，有助于减轻肥胖小鼠肝脏和HepG2细胞中的脂质沉积。ASP恢复了ATP生成，并逆转了肥胖小鼠肝脏和HepG2细胞中线粒体能量代谢和生物发生的损伤。ASP减轻了肥胖小鼠肝脏和HepG2细胞中的氧化应激，显示出其抗氧化价值。令人印象深刻的是，ASP显著促进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，证明其作为肝脏Nrf2激活剂的潜力。Nrf2抑制消除了ASP对脂质沉积、氧化应激和线粒体功能障碍的保护作用，强调了ASP激活的肝脏Nrf2信号在改善MAFLD中的关键作用。
本研究提供了首个证据，证明ASP刺激的Nrf2激活在减轻MAFLD中起关键作用，强调了其作为靶向脂肪性肝病的肝脏Nrf2激活剂的潜力。这些发现为ASP在MAFLD中刺激线粒体代谢和脂肪分解提供了新证据，为将ASP开发为减轻MAFLD进展的治疗药物和膳食补充剂铺平了道路。
