Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, 85721, USA; National & Local Joint Engineering Research Center of Biodiagnosis and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China; International Joint Research Center on Cell Stress and Disease Diagnosis and Therapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China.
Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, AZ, 85721, USA.
Redox Biol. 2023 Feb;59:102570. doi: 10.1016/j.redox.2022.102570. Epub 2022 Dec 5.
Caloric excess and sedentary lifestyles have led to an epidemic of obesity, metabolic syndrome, and non-alcoholic fatty liver disease (NAFLD). The objective of this study was to investigate the mechanisms underlying high fat diet (HFD)-induced NAFLD, and to explore NRF2 activation as a strategy to alleviate NAFLD.
Herein, we demonstrated that high fat diet (HFD) induced lipid peroxidation and ferroptosis, both of which could be alleviated by NRF2 upregulation. Mechanistically, HFD suppressed autophagosome biogenesis through AMPK- and AKT-mediated mTOR activation and decreased ATG7, resulting in KEAP1 stabilization and decreased NRF2 levels in mouse liver. Furthermore, ATG7 is required for HFD-induced NRF2 downregulation, as ATG7 deletion in Cre-inducible ATG7 knockout mice decreased NRF2 levels and enhanced ferroptosis, which was not further exacerbated by HFD. This finding was recapitulated in mouse hepatocytes, which showed a similar phenotype upon treatment with saturated fatty acids (SFAs) but not monounsaturated fatty acids (MUFAs). Finally, NRF2 activation blocked fatty acid (FA)-mediated NRF2 downregulation, lipid peroxidation, and ferroptosis. Importantly, the HFD-induced alterations were also observed in human fatty liver tissue samples.
HFD-mediated autophagy inhibition, NRF2 suppression, and ferroptosis promotion are important molecular mechanisms of obesity-driven metabolic diseases. NRF2 activation counteracts HFD-mediated NRF2 suppression and ferroptotic cell death. In addition, SFA vs. MUFA regulation of NRF2 may underlie their harmful vs. beneficial effects. Our study reveals NRF2 as a key player in the development and progression of fatty liver disease and that NRF2 activation could serve as a potential therapeutic strategy.
热量过剩和久坐不动的生活方式导致肥胖症、代谢综合征和非酒精性脂肪性肝病（NAFLD）流行。本研究旨在探讨高脂肪饮食（HFD）诱导 NAFLD 的机制，并探索 NRF2 激活作为缓解 NAFLD 的策略。
本文证明高脂肪饮食（HFD）诱导脂质过氧化和铁死亡，这两者都可以通过 NRF2 的上调来缓解。在机制上，HFD 通过 AMPK 和 AKT 介导的 mTOR 激活抑制自噬体生物发生，并降低 ATG7，导致 KEAP1 稳定和小鼠肝中 NRF2 水平降低。此外，ATG7 是 HFD 诱导的 NRF2 下调所必需的，因为 Cre 诱导型 ATG7 敲除小鼠中的 ATG7 缺失降低了 NRF2 水平并增强了铁死亡，而 HFD 并没有进一步加重这种情况。这一发现在小鼠肝细胞中得到了重现，它们在用饱和脂肪酸（SFAs）而不是单不饱和脂肪酸（MUFAs）处理后表现出类似的表型。最后，NRF2 激活阻断脂肪酸（FA）介导的 NRF2 下调、脂质过氧化和铁死亡。重要的是，在人类脂肪肝组织样本中也观察到 HFD 诱导的改变。
HFD 介导的自噬抑制、NRF2 抑制和铁死亡促进是肥胖驱动的代谢性疾病的重要分子机制。NRF2 激活拮抗 HFD 介导的 NRF2 抑制和铁死亡细胞死亡。此外，SFA 与 MUFA 对 NRF2 的调节可能是它们有害与有益作用的基础。我们的研究揭示了 NRF2 是脂肪肝疾病发展和进展的关键因素，NRF2 激活可能是一种潜在的治疗策略。
