肝细胞特异性 NR5A2 缺乏症可通过下调 ALDH1B1 的表达诱导热变态反应并加剧非酒精性脂肪性肝炎。

IF 8.1 1区 生物学 Q1 CELL BIOLOGY Cell Death & Disease Pub Date : 2024-10-23 DOI:10.1038/s41419-024-07151-1
Rong Zhao, Zizhen Guo, Kaikai Lu, Qian Chen, Farooq Riaz, Yimeng Zhou, Luyun Yang, Xiaona Cheng, Litao Wu, Kexin Cheng, Lina Feng, Sitong Liu, Xiaodan Wu, Minghua Zheng, Chunyan Yin, Dongmin Li
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引用次数: 0

摘要

非酒精性脂肪性肝炎(NASH)是一种普遍存在的慢性疾病,但其确切的发病机制和有效的治疗方法却仍然难以捉摸。核受体 5 亚家族 A 组成员 2(NR5A2)是一种与肝脏胆固醇代谢密切相关的转录因子,但由于 NR5A2 在细胞系和动物模型中缺失会导致死亡,因此一直未能对其进行全面研究。为了阐明 NR5A2 在 NASH 中的作用,我们产生了 Nr5a2 的肝细胞特异性基因敲除小鼠(Nr5a2HKO),并在常规饮食条件下对其不同年龄组的肝脏形态进行了检测。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 NR5A2 的各种异构体。在 Nr5a2HKO 小鼠的肝脏中,炎症和纤维化从幼年开始自发出现,与脂质积累无关。NR5A2缺陷细胞系发生了猝死,而不同异构体的NR5A2能逆转这种细胞死亡形式。我们的研究结果揭示了抑制 NR5A2 会引发热凋亡,这是一种促炎性细胞死亡模式,主要由活性氧(ROS)诱导的 NF-κB 通路激活介导。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 水平参与热凋亡。总之,NR5A2 的不同异构体通过维持 ROS 的微调平衡对 NASH 发挥保肝作用,而这取决于 ALDH1B1 的活性。
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Hepatocyte-specific NR5A2 deficiency induces pyroptosis and exacerbates non-alcoholic steatohepatitis by downregulating ALDH1B1 expression.

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 (Nr5a2HKO) 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 Nr5a2HKO 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.

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来源期刊
Cell Death & Disease
Cell Death & Disease CELL BIOLOGY-
CiteScore
15.10
自引率
2.20%
发文量
935
审稿时长
2 months
期刊介绍: Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism. Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following: Experimental medicine Cancer Immunity Internal medicine Neuroscience Cancer metabolism
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