Derlin-1 promotes diet-induced non-alcoholic fatty liver disease via increasing RIPK3-mediated necroptosis

IF 7.1 2区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Ting Wang , Dehua Wang , Ge Kuang , Xia Gong , Li Zhang , Jingyuan Wan , Ke Li
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Abstract

Background & aims

Unrestricted endoplasmic reticulum (ER) stress and the continuous activation of ER associated protein degradation (ERAD) pathway might lead to the aggravation of non-alcoholic steatohepatitis (NASH). Derlin-1 has been considered to be an integral part of the ERAD pathway, which is involved in the regulation of the transport and excretion of protein degradation products within ER. However, the regulatory role and mechanism of Derlin-1 in NASH remains unclear.

Methods

The expression of Derlin-1 was firstly detected in the liver of normal and NASH animal model and patient. Then, western diet (WD)-induced NASH mice were administrated with the lentivirus-mediated Derlin-1 knockdown or overexpression. Finally, RIPK3 knockout mice were used to explore the mechanism. The liver injury, hepatic steatosis, inflammation, and fibrosis as well as ER stress signal pathway were evaluated.

Results

The levels of Derlin-1 were significantly elevated in the liver of WD-fed mice and NASH patients when compared to the control group. Furthermore, Derlin-1 knockdown attenuated WD-induced liver injury, lipid accumulation, inflammatory response, and fibrosis. Conversely, overexpression of Derlin-1 presented the completely opposite results. Mechanistically, Derlin-1 enhanced ER stress pathways and led to necroptosis, and RIPK3 knockout dramatically reduced Derlin-1 expression and reversed the progression of NASH aggravated by Derlin-1.

Conclusions

Notably, Derlin-1 is a critical modulator in NASH. It may accelerate the progression of NASH by regulating the activation of the ERAD pathway and further aggravating the ER stress, which might be involved in RIPK3-mediated necroptosis. Therefore, targeting Derlin-1 as a novel intervention point holds the potential to delay or even reverse NASH.

Abstract Image

Derlin-1通过增加RIPK3介导的坏死促进饮食诱导的非酒精性脂肪肝。
背景与目的:不受限制的内质网(ER)应激和ER相关蛋白降解(ERAD)途径的持续激活可能会导致非酒精性脂肪性肝炎(NASH)的恶化。Derlin-1一直被认为是ERAD通路中不可或缺的一部分,它参与调节ER内蛋白质降解产物的运输和排泄。然而,Derlin-1在NASH中的调控作用和机制仍不清楚:方法:首先检测正常和NASH动物模型及患者肝脏中Derlin-1的表达。方法:首先检测正常和NASH动物模型及患者肝脏中Derlin-1的表达,然后用慢病毒介导的Derlin-1基因敲除或过表达西方饮食(WD)诱导的NASH小鼠。最后,用RIPK3基因敲除小鼠来探讨其机制。结果发现,Derlin-1的水平明显高于RIPK3基因敲除的小鼠,而RIPK3基因敲除的小鼠则明显低于Derlin-1基因敲除的小鼠:结果:与对照组相比,WD喂养小鼠和NASH患者肝脏中的Derlin-1水平明显升高。此外,敲除 Derlin-1 可减轻 WD 引起的肝损伤、脂质积累、炎症反应和纤维化。相反,Derlin-1的过表达却产生了完全相反的结果。从机制上讲,Derlin-1增强了ER应激通路并导致坏死,而RIPK3敲除可显著减少Derlin-1的表达并逆转Derlin-1加重的NASH进展:结论:值得注意的是,Derlin-1 是 NASH 的一个关键调节因子。结论:值得注意的是,Derlin-1 是 NASH 中的一个关键调节因子,它可能通过调节 ERAD 通路的激活和进一步加剧 ER 应激而加速 NASH 的进展,而 ER 应激可能参与了 RIPK3 介导的坏死。因此,将 Derlin-1 作为一个新的干预点,有可能延缓甚至逆转 NASH。
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来源期刊
Free Radical Biology and Medicine
Free Radical Biology and Medicine 医学-内分泌学与代谢
CiteScore
14.00
自引率
4.10%
发文量
850
审稿时长
22 days
期刊介绍: Free Radical Biology and Medicine is a leading journal in the field of redox biology, which is the study of the role of reactive oxygen species (ROS) and other oxidizing agents in biological systems. The journal serves as a premier forum for publishing innovative and groundbreaking research that explores the redox biology of health and disease, covering a wide range of topics and disciplines. Free Radical Biology and Medicine also commissions Special Issues that highlight recent advances in both basic and clinical research, with a particular emphasis on the mechanisms underlying altered metabolism and redox signaling. These Special Issues aim to provide a focused platform for the latest research in the field, fostering collaboration and knowledge exchange among researchers and clinicians.
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