Chongqing Key Lab of Medicinal Chemistry & Molecular Pharmacology, Chongqing University of Technology, Chongqing, 400054, China.
College of Pharmacy and Bioengineering, Chongqing University of Technology, Chongqing, 400054, China.
Acta Pharmacol Sin. 2022 Mar;43(3):645-658. doi: 10.1038/s41401-021-00681-w. Epub 2021 May 14.
Accumulating evidence indicates that mitochondrial dysfunction and oxidative stress play a pivotal role in the initiation and progression of nonalcoholic fatty liver disease (NAFLD). In this study, we found that blueberry-derived exosomes-like nanoparticles (BELNs) could ameliorate oxidative stress in rotenone-induced HepG2 cells and high-fat diet (HFD)-fed C57BL/6 mice. Preincubation with BELNs decreased the level of reactive oxygen species (ROS), increased the mitochondrial membrane potential, and prevented cell apoptosis by inducing the expression of Bcl-2 and heme oxygenase-1 (HO-1) and decreasing the content of Bax in rotenone-treated HepG2 cells. We also found that preincubation with BELNs accelerated the translocation of Nrf2, an important transcription factor of antioxidative proteins, from the cytoplasm to the nucleus in rotenone-treated HepG2 cells. Moreover, administration of BELNs improved insulin resistance, ameliorated the dysfunction of hepatocytes, and regulated the expression of detoxifying/antioxidant genes by affecting the distribution of Nrf2 in the cytoplasm and nucleus of hepatocytes of HFD-fed mice. Furthermore, BELNs supplementation prevented the formation of vacuoles and attenuated the accumulation of lipid droplets by inhibiting the expression of fatty acid synthase (FAS) and acetyl-CoA carboxylase 1 (ACC1), the two key transcription factors for de novo lipogenesis in the liver of HFD-fed mice. These findings suggested that BELNs can be used for the treatment of NAFLD because of their antioxidative activity.
越来越多的证据表明，线粒体功能障碍和氧化应激在非酒精性脂肪性肝病（NAFLD）的发生和发展中起着关键作用。在这项研究中，我们发现蓝莓衍生的外体样纳米颗粒（BELNs）可以改善鱼藤酮诱导的 HepG2 细胞和高脂肪饮食（HFD）喂养的 C57BL/6 小鼠中的氧化应激。BELNs 预处理可降低活性氧（ROS）水平、增加线粒体膜电位，并通过诱导 Bcl-2 和血红素加氧酶-1（HO-1）的表达和降低 Bax 的含量来防止细胞凋亡，从而减轻鱼藤酮处理的 HepG2 细胞中的细胞凋亡。我们还发现，BELNs 预处理可加速抗氧化蛋白重要转录因子 Nrf2 从细胞质向细胞核的易位，从而减轻鱼藤酮处理的 HepG2 细胞中的氧化应激。此外，BELNs 的给药可改善胰岛素抵抗、改善肝细胞功能障碍，并通过影响 Nrf2 在 HFD 喂养小鼠肝细胞的细胞质和细胞核中的分布来调节解毒/抗氧化基因的表达。此外，BELNs 的补充可通过抑制脂肪酸合成酶（FAS）和乙酰辅酶 A 羧化酶 1（ACC1）的表达来防止空泡的形成和减轻脂滴的积累，这两种酶是肝脏中从头合成脂质的关键转录因子。这些发现表明，由于 BELNs 具有抗氧化活性，因此可将其用于治疗 NAFLD。
