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

作者全名：Wang, Ting; Wang, Dehua; Kuang, Ge; Gong, Xia; Zhang, Li; Wan, Jingyuan; Li, Ke

作者地址：[Wang, Ting] Chongqing Med Univ, Affiliated Hosp 2, Dept Orthoped, Chongqing, Peoples R China; [Wang, Dehua; Li, Ke] Chongqing Med Univ, Affiliated Hosp 1, Dept Orthoped, Chongqing, Peoples R China; [Kuang, Ge; Wan, Jingyuan] Chongqing Med Univ, Chongqing Key Lab Biochem & Mol Pharmacol, Chongqing, Peoples R China; [Kuang, Ge; Wan, Jingyuan] Chongqing Med Univ, Dept Pharmacol, Chongqing, Peoples R China; [Gong, Xia] Chongqing Med Univ, Dept Anat, Chongqing, Peoples R China; [Zhang, Li] Chongqing Med Univ, Affiliated Hosp 2, Dept Ophthalmol, Chongqing, Peoples R China

通信作者：Li, K (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Orthoped, Chongqing, Peoples R China.; Wan, JY (通讯作者)，Chongqing Med Univ, Chongqing Key Lab Biochem & Mol Pharmacol, Chongqing, Peoples R China.; Zhang, L (通讯作者)，Chongqing Med Univ, Affiliated Hosp 2, Dept Ophthalmol, Chongqing, Peoples R China.

来源：FREE RADICAL BIOLOGY AND MEDICINE

ESI学科分类：BIOLOGY & BIOCHEMISTRY

WOS号：WOS:001219425500001

JCR分区：Q1

影响因子：7.1

年份：2024

卷号：217

期号：　

开始页：29

结束页：47

文献类型：Article

关键词：　

摘要：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.

基金机构：Natural Science Foundation Project of Chongqing; Chongqing Science and Technology Commission [cstc2020jcyj-msxmX0806]; Science and Technology Research Program of Chongqing Municipal Education Commission [KJQN202300403]; National Natural Science Foundation of China [81902293]; China Postdoctoral Science Foundation [2022M702604]

基金资助正文：This study was funded by Natural Science Foundation Project of Chongqing, Chongqing Science and Technology Commission (No. cstc2020jcyj-msxmX0806) ; Science and Technology Research Program of Chongqing Municipal Education Commission (No.KJQN202300403) ; National Natural Science Foundation of China (No.81902293) ; China Postdoctoral Science Foundation (No.2022M702604) .