Chan Benjamin K Y, Elmasry Mohamed, Forootan Shiva S, Russomanno Giusy, Bunday Tobias M, Zhang Fang, Brillant Nathalie, Starkey Lewis Philip J, Aird Rhona, Ricci Emanuele, Andrews Timothy D, Sison-Young Rowena L, Schofield Amy L, Fang Yongxiang, Lister Adam, Sharkey Jack W, Poptani Harish, Kitteringham Neil R, Forbes Stuart J, Malik Hassan Z, Fenwick Stephen W, Park B Kevin, Goldring Christopher E, Copple Ian M
Medical Research Council Centre for Drug Safety ScienceDepartment of Pharmacology & TherapeuticsInstitute of SystemsMolecular & Integrative BiologyUniversity of LiverpoolLiverpoolUnited Kingdom.
Department of Hepatobiliary SurgeryAintree University HospitalLiverpool University Hospitals NHS Foundation TrustLiverpoolUnited Kingdom.
Hepatology. 2021 Aug;74(2):973-986. doi: 10.1002/hep.31859. Epub 2021 Jul 13.
The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) regulates an array of cytoprotective genes, yet studies in transgenic mice have led to conflicting reports on its role in liver regeneration. We aimed to test the hypothesis that pharmacological activation of Nrf2 would enhance liver regeneration.
Wild-type and Nrf2 null mice were administered bardoxolone methyl (CDDO-Me), a potent activator of Nrf2 that has entered clinical development, and then subjected to two-thirds partial hepatectomy. Using translational noninvasive imaging techniques, CDDO-Me was shown to enhance the rate of restoration of liver volume (MRI) and improve liver function (multispectral optoacoustic imaging of indocyanine green clearance) in wild-type, but not Nrf2 null, mice following partial hepatectomy. Using immunofluorescence imaging and whole transcriptome analysis, these effects were found to be associated with an increase in hepatocyte hypertrophy and proliferation, the suppression of immune and inflammatory signals, and metabolic adaptation in the remnant liver tissue. Similar processes were modulated following exposure of primary human hepatocytes to CDDO-Me, highlighting the potential relevance of our findings to patients.
Our results indicate that pharmacological activation of Nrf2 is a promising strategy for enhancing functional liver regeneration. Such an approach could therefore aid the recovery of patients undergoing liver surgery and support the treatment of acute and chronic liver disease.
转录因子核因子红细胞2相关因子2（Nrf2）调控一系列细胞保护基因，但转基因小鼠研究对其在肝脏再生中的作用报道不一。我们旨在验证Nrf2的药物激活可增强肝脏再生这一假说。
给野生型和Nrf2基因敲除小鼠施用巴多昔芬甲酯（CDDO-Me），这是一种已进入临床开发阶段的强效Nrf2激活剂，然后进行三分之二部分肝切除术。利用转化型非侵入性成像技术，结果显示在部分肝切除术后，CDDO-Me可提高野生型小鼠肝脏体积的恢复速率（磁共振成像）并改善肝功能（吲哚菁绿清除的多光谱光声成像），但对Nrf2基因敲除小鼠无此作用。通过免疫荧光成像和全转录组分析发现，这些效应与肝细胞肥大和增殖增加、免疫和炎症信号抑制以及残余肝组织中的代谢适应有关。将原代人肝细胞暴露于CDDO-Me后也观察到类似过程受到调节，这突出了我们的研究结果对患者的潜在相关性。
我们的结果表明，Nrf2的药物激活是增强功能性肝脏再生的一种有前景的策略。因此，这种方法有助于接受肝脏手术患者的恢复，并支持急慢性肝病的治疗。
