Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, P.R. China.
Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Cell Death Dis. 2024 Oct 23;15(10):770. doi: 10.1038/s41419-024-07151-1.
Nonalcoholic steatohepatitis (NASH) is a prevalent chronic disease, yet its exact mechanisms and effective treatments remain elusive. Nuclear receptor subfamily 5 group A member 2 (NR5A2), a transcription factor closely associated with cholesterol metabolism in the liver, has been hindered from comprehensive investigation due to the lethality of NR5A2 loss in cell lines and animal models. To elucidate the role of NR5A2 in NASH, we generated hepatocyte-specific knockout mice for Nr5a2 (Nr5a2) and examined their liver morphology across different age groups under a regular diet. Furthermore, we established cell lines expressing haploid levels of NR5A2 and subsequently reintroduced various isoforms of NR5A2. In the liver of Nr5a2 mice, inflammation and fibrosis spontaneously emerged from an early age, independent of lipid accumulation. Pyroptosis occurred in NR5A2-deficient cell lines, and different isoforms of NR5A2 reversed this form of cell death. Our findings unveiled that inhibition of NR5A2 triggers pyroptosis, a proinflammatory mode of cell death primarily mediated by the activation of the NF-κB pathway induced by reactive oxygen species (ROS). As a transcriptionally regulated molecule of NR5A2, aldehyde dehydrogenase 1 family member B1 (ALDH1B1) participates in pyroptosis through modulation of ROS level. In conclusion, the diverse isoforms of NR5A2 exert hepatoprotective effects against NASH by maintaining a finely tuned balance of ROS, which is contingent upon the activity of ALDH1B1.
非酒精性脂肪性肝炎（NASH）是一种普遍存在的慢性疾病，但它的确切机制和有效治疗方法仍不明确。核受体亚家族 5 组 A 成员 2（NR5A2）是一种与肝脏胆固醇代谢密切相关的转录因子，由于 NR5A2 在细胞系和动物模型中的缺失具有致命性，因此其研究受到了阻碍。为了阐明 NR5A2 在 NASH 中的作用，我们生成了肝细胞特异性 Nr5a2 敲除小鼠（Nr5a2），并在常规饮食条件下检查了不同年龄组小鼠的肝脏形态。此外，我们还建立了表达单倍体水平 NR5A2 的细胞系，并随后重新引入了各种 NR5A2 同工型。在 Nr5a2 小鼠的肝脏中，炎症和纤维化在早期就自发出现，与脂质积累无关。在 NR5A2 缺失的细胞系中发生了细胞焦亡，而不同的 NR5A2 同工型逆转了这种细胞死亡形式。我们的研究结果揭示了抑制 NR5A2 会触发细胞焦亡，这是一种主要由活性氧（ROS）诱导的 NF-κB 途径激活介导的促炎细胞死亡形式。作为 NR5A2 的转录调控分子，醛脱氢酶 1 家族成员 B1（ALDH1B1）通过调节 ROS 水平参与细胞焦亡。总之，NR5A2 的多种同工型通过维持 ROS 的精细平衡发挥对 NASH 的肝保护作用，而这依赖于 ALDH1B1 的活性。
