Downregulation of RIP3 Improves the Protective Effect of ATF6 in an Acute Liver Injury Model

Background. Activating transcription factor 6 (ATF6) and receptor-interacting protein 3 (RIP3) are important signaling proteins in endoplasmic reticulum (ER) stress and necroptosis, respectively. However, their regulatory relationship and clinical significance are unknown. We investigate the impact...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Mei-Ying Huang, Dian-Wei Wan, Jie Deng, Wen-Jie Guo, Yue Huang, Huan Chen, De-Lin Xu, Zhi-Gang Jiang, Yuan Xue, Yi-Huai He
Formato:	article
Lenguaje:	EN
Publicado:	Hindawi Limited 2021
Materias:	Medicine R
Acceso en línea:	https://doaj.org/article/25b3e19dd72d40c5a7305e37c7df661a
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:25b3e19dd72d40c5a7305e37c7df661a
record_format	dspace
spelling	oai:doaj.org-article:25b3e19dd72d40c5a7305e37c7df661a2021-11-15T01:19:02ZDownregulation of RIP3 Improves the Protective Effect of ATF6 in an Acute Liver Injury Model2314-614110.1155/2021/8717565https://doaj.org/article/25b3e19dd72d40c5a7305e37c7df661a2021-01-01T00:00:00Zhttp://dx.doi.org/10.1155/2021/8717565https://doaj.org/toc/2314-6141Background. Activating transcription factor 6 (ATF6) and receptor-interacting protein 3 (RIP3) are important signaling proteins in endoplasmic reticulum (ER) stress and necroptosis, respectively. However, their regulatory relationship and clinical significance are unknown. We investigate the impact of ATF6 on RIP3 expression, and its role in hepatocyte necroptosis in an acute liver injury model. Methods. In vivo and in vitro experiments were carried out. LO2 cells were treated with thapsigargin (TG). In vivo, male BALB/c mice were treated with carbon tetrachloride (CCl4, 1 mL/kg) or tunicamycin (TM, 2 mg/kg). Then, the impact of ATF6 or RIP3 silencing on liver injury, hepatocyte necroptosis, and ER stress-related protein expression was examined. Results. TG induced ER stress and necroptosis and ATF6 and RIP3 expression in LO2 cells. The knockdown of ATF6 significantly decreased RIP3 expression (p<0.05) and increased ER stress and necroptosis. The downregulation of RIP3 significantly reduced necroptosis and ER stress (p<0.05). Similar results were observed in CCl4 or the TM-induced mouse model. The knockdown of ATF6 significantly decreased CCl4-induced RIP3 expression and increased liver injury, necroptosis, and ER stress in mice livers (p<0.05). In contrast, the downregulation of RIP3 significantly reduced liver injury, hepatocyte necroptosis, and ER stress. Conclusions. Hepatocyte ATF6 has multiple roles in acute liver injury. It reduces hepatocyte necroptosis via negative feedback regulation of ER stress. In addition, ATF6 can upregulate the expression of RIP3, which is not helpful to the recovery process. However, downregulating RIP3 reduces hepatocyte necroptosis by promoting the alleviation of ER stress. The findings suggest that RIP3 could be a plausible target for the treatment of liver injury.Mei-Ying HuangDian-Wei WanJie DengWen-Jie GuoYue HuangHuan ChenDe-Lin XuZhi-Gang JiangYuan XueYi-Huai HeHindawi LimitedarticleMedicineRENBioMed Research International, Vol 2021 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R
spellingShingle	Medicine R Mei-Ying Huang Dian-Wei Wan Jie Deng Wen-Jie Guo Yue Huang Huan Chen De-Lin Xu Zhi-Gang Jiang Yuan Xue Yi-Huai He Downregulation of RIP3 Improves the Protective Effect of ATF6 in an Acute Liver Injury Model
description	Background. Activating transcription factor 6 (ATF6) and receptor-interacting protein 3 (RIP3) are important signaling proteins in endoplasmic reticulum (ER) stress and necroptosis, respectively. However, their regulatory relationship and clinical significance are unknown. We investigate the impact of ATF6 on RIP3 expression, and its role in hepatocyte necroptosis in an acute liver injury model. Methods. In vivo and in vitro experiments were carried out. LO2 cells were treated with thapsigargin (TG). In vivo, male BALB/c mice were treated with carbon tetrachloride (CCl4, 1 mL/kg) or tunicamycin (TM, 2 mg/kg). Then, the impact of ATF6 or RIP3 silencing on liver injury, hepatocyte necroptosis, and ER stress-related protein expression was examined. Results. TG induced ER stress and necroptosis and ATF6 and RIP3 expression in LO2 cells. The knockdown of ATF6 significantly decreased RIP3 expression (p<0.05) and increased ER stress and necroptosis. The downregulation of RIP3 significantly reduced necroptosis and ER stress (p<0.05). Similar results were observed in CCl4 or the TM-induced mouse model. The knockdown of ATF6 significantly decreased CCl4-induced RIP3 expression and increased liver injury, necroptosis, and ER stress in mice livers (p<0.05). In contrast, the downregulation of RIP3 significantly reduced liver injury, hepatocyte necroptosis, and ER stress. Conclusions. Hepatocyte ATF6 has multiple roles in acute liver injury. It reduces hepatocyte necroptosis via negative feedback regulation of ER stress. In addition, ATF6 can upregulate the expression of RIP3, which is not helpful to the recovery process. However, downregulating RIP3 reduces hepatocyte necroptosis by promoting the alleviation of ER stress. The findings suggest that RIP3 could be a plausible target for the treatment of liver injury.
format	article
author	Mei-Ying Huang Dian-Wei Wan Jie Deng Wen-Jie Guo Yue Huang Huan Chen De-Lin Xu Zhi-Gang Jiang Yuan Xue Yi-Huai He
author_facet	Mei-Ying Huang Dian-Wei Wan Jie Deng Wen-Jie Guo Yue Huang Huan Chen De-Lin Xu Zhi-Gang Jiang Yuan Xue Yi-Huai He
author_sort	Mei-Ying Huang
title	Downregulation of RIP3 Improves the Protective Effect of ATF6 in an Acute Liver Injury Model
title_short	Downregulation of RIP3 Improves the Protective Effect of ATF6 in an Acute Liver Injury Model
title_full	Downregulation of RIP3 Improves the Protective Effect of ATF6 in an Acute Liver Injury Model
title_fullStr	Downregulation of RIP3 Improves the Protective Effect of ATF6 in an Acute Liver Injury Model
title_full_unstemmed	Downregulation of RIP3 Improves the Protective Effect of ATF6 in an Acute Liver Injury Model
title_sort	downregulation of rip3 improves the protective effect of atf6 in an acute liver injury model
publisher	Hindawi Limited
publishDate	2021
url	https://doaj.org/article/25b3e19dd72d40c5a7305e37c7df661a
work_keys_str_mv	AT meiyinghuang downregulationofrip3improvestheprotectiveeffectofatf6inanacuteliverinjurymodel AT dianweiwan downregulationofrip3improvestheprotectiveeffectofatf6inanacuteliverinjurymodel AT jiedeng downregulationofrip3improvestheprotectiveeffectofatf6inanacuteliverinjurymodel AT wenjieguo downregulationofrip3improvestheprotectiveeffectofatf6inanacuteliverinjurymodel AT yuehuang downregulationofrip3improvestheprotectiveeffectofatf6inanacuteliverinjurymodel AT huanchen downregulationofrip3improvestheprotectiveeffectofatf6inanacuteliverinjurymodel AT delinxu downregulationofrip3improvestheprotectiveeffectofatf6inanacuteliverinjurymodel AT zhigangjiang downregulationofrip3improvestheprotectiveeffectofatf6inanacuteliverinjurymodel AT yuanxue downregulationofrip3improvestheprotectiveeffectofatf6inanacuteliverinjurymodel AT yihuaihe downregulationofrip3improvestheprotectiveeffectofatf6inanacuteliverinjurymodel
_version_	1718428970372825088

Downregulation of RIP3 Improves the Protective Effect of ATF6 in an Acute Liver Injury Model

Ejemplares similares