Laboratory of Molecular Nutrition and Health, Fishery College, Huazhong Agricultural University, Wuhan Hubei Province, China.
Diabetes and Nutritional Sciences Division, School of Medicine, King's College London, London, UK.
J Nutr Biochem. 2022 Feb;100:108883. doi: 10.1016/j.jnutbio.2021.108883. Epub 2021 Oct 12.
Oxidative stress can induce occurrence of non-alcoholic fatty liver disease (NAFLD). Nrf2 is a central regulator of cellular oxidative stress and also participates in the control of lipid deposition and metabolism. Here, we hypothesize that oxidative stress-mediated Nrf2 activation participates in the regulation of the Cu-induced lipid deposition. We found that Cu excess activated oxidative stress and autophagy, up-regulated lipogenesis and lipid metabolism, suppressed Keap1 expression and activated Nrf2 signaling. Moreover, Cu induced lipid deposition via oxidative stress and the mitochondrial dysfunction. Oxidative stress mediated Cu-induced activation of Nrf2 and autophagy. The activation of autophagy helps to alleviate Cu-induced lipid deposition and accordingly provided a protective role against Cu-induced NAFLD. Meantime, Cu-induced oxidative stress promoted Nrf2 recruitment to the PPARγ promoter, inducing target gene transcription, and subsequent lipogenesis. Our findings, for the first time, provide direct evidences for Nrf2 function in the modulation of lipogenic metabolism via the transcriptional activation of PPARγ, and elucidate the mechanisms by which Nrf2 functions as the central regulator of lipogenic genes and highlights the significance of Nrf2 as potential therapeutic targets for oxidative stress-associated obesity and NAFLD for fish and human beings.
氧化应激可诱导非酒精性脂肪性肝病（NAFLD）的发生。Nrf2 是细胞氧化应激的核心调节因子，也参与脂质沉积和代谢的控制。在这里，我们假设氧化应激介导的 Nrf2 激活参与了 Cu 诱导的脂质沉积的调节。我们发现 Cu 过量激活了氧化应激和自噬，上调了脂肪生成和脂质代谢，抑制了 Keap1 表达并激活了 Nrf2 信号通路。此外，Cu 通过氧化应激和线粒体功能障碍诱导脂质沉积。氧化应激介导 Cu 诱导的 Nrf2 和自噬的激活。自噬的激活有助于减轻 Cu 诱导的脂质沉积，从而对 Cu 诱导的 NAFLD 提供保护作用。同时，Cu 诱导的氧化应激促进了 Nrf2 向 PPARγ 启动子的募集，诱导靶基因转录，随后发生脂肪生成。我们的研究结果首次提供了 Nrf2 通过转录激活 PPARγ 调节脂肪生成代谢功能的直接证据，并阐明了 Nrf2 作为脂肪生成基因的核心调节因子的作用机制，并强调了 Nrf2 作为与氧化应激相关的肥胖和 NAFLD 的潜在治疗靶点对鱼类和人类的重要意义。
