Cargando…

Ufbp1, a Key Player of Ufm1 Conjugation System, Protects Against Ketosis-Induced Liver Injury via Suppressing Smad3 Activation

The dairy cattle suffer from severe liver dysfunction during the pathogenesis of ketosis. The Ufm1 conjugation system is crucial for liver development and homeostasis. Ufm1 binding protein (Ufbp1) is a putative Ufm1 target and an integral component, but its role in ketosis-induced liver injury is un...

Descripción completa

Detalles Bibliográficos
Autores principales: Chen, Fanghui, Sheng, Le, Xu, Chenjie, Li, Jun, Ali, Ilyas, Li, Honglin, Cai, Yafei
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297976/
https://www.ncbi.nlm.nih.gov/pubmed/34307359
http://dx.doi.org/10.3389/fcell.2021.676789
_version_ 1783725965206093824
author Chen, Fanghui
Sheng, Le
Xu, Chenjie
Li, Jun
Ali, Ilyas
Li, Honglin
Cai, Yafei
author_facet Chen, Fanghui
Sheng, Le
Xu, Chenjie
Li, Jun
Ali, Ilyas
Li, Honglin
Cai, Yafei
author_sort Chen, Fanghui
collection PubMed
description The dairy cattle suffer from severe liver dysfunction during the pathogenesis of ketosis. The Ufm1 conjugation system is crucial for liver development and homeostasis. Ufm1 binding protein (Ufbp1) is a putative Ufm1 target and an integral component, but its role in ketosis-induced liver injury is unclear so far. The purpose of this study is to explore the key role of Ufbp1 in liver fibrosis caused by ketosis in vivo and in vitro. Liver tissues were collected from ketotic cows and Ufbp1 conditional knockout (CKO) mice in vivo. However, Ufbp1(–/–) mouse embryonic fibroblast cells and Hela cells were used for in vitro validation. Subsequently, various assays were performed to reveal the underlying molecular mechanisms of the Ufbp1 protective effect. In this study, hepatic fibrosis, endoplasmic reticulum (ER) stress, and apoptosis were reported in the liver of ketotic cows, fibrotic markers (alpha-smooth muscle actin, Collagen1) and ER stress markers (glucose-regulated protein 78, CEBP homologous protein) were upregulated remarkably, and the apoptosis-related genes (Bcl2, Bax) were in line with expectations. Interestingly, Ufbp1 expression was almost disappeared, and Smad2/Smad3 protein was largely phosphorylated in the liver of ketotic cows, but Ufbp1 deletion caused Smad3 phosphorylation apparently, rather than Smad2, and elevated ER stress was observed in the CKO mice model. At the cellular level, Ufbp1 deficiency led to serious fibrotic and ER stress response, Smad3 was activated by phosphorylation significantly and then was translocated into the nucleus, whereas p-Smad2 was largely unaffected in embryonic fibroblast cells. Ufbp1 overexpression obviously suppressed Smad3 phosphorylation in Hela cells. Ufbp1 was found to be in full combination with Smad3 using endogenous immunoprecipitation. Taken together, our findings suggest that downregulation or ablation of Ufbp1 leads to Smad3 activation, elevated ER stress, and hepatocyte apoptosis, which in turn causes liver fibrosis. Ufbp1 plays a protective role in ketosis-induced liver injury.
format Online
Article
Text
id pubmed-8297976
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Frontiers Media S.A.
record_format MEDLINE/PubMed
spelling pubmed-82979762021-07-23 Ufbp1, a Key Player of Ufm1 Conjugation System, Protects Against Ketosis-Induced Liver Injury via Suppressing Smad3 Activation Chen, Fanghui Sheng, Le Xu, Chenjie Li, Jun Ali, Ilyas Li, Honglin Cai, Yafei Front Cell Dev Biol Cell and Developmental Biology The dairy cattle suffer from severe liver dysfunction during the pathogenesis of ketosis. The Ufm1 conjugation system is crucial for liver development and homeostasis. Ufm1 binding protein (Ufbp1) is a putative Ufm1 target and an integral component, but its role in ketosis-induced liver injury is unclear so far. The purpose of this study is to explore the key role of Ufbp1 in liver fibrosis caused by ketosis in vivo and in vitro. Liver tissues were collected from ketotic cows and Ufbp1 conditional knockout (CKO) mice in vivo. However, Ufbp1(–/–) mouse embryonic fibroblast cells and Hela cells were used for in vitro validation. Subsequently, various assays were performed to reveal the underlying molecular mechanisms of the Ufbp1 protective effect. In this study, hepatic fibrosis, endoplasmic reticulum (ER) stress, and apoptosis were reported in the liver of ketotic cows, fibrotic markers (alpha-smooth muscle actin, Collagen1) and ER stress markers (glucose-regulated protein 78, CEBP homologous protein) were upregulated remarkably, and the apoptosis-related genes (Bcl2, Bax) were in line with expectations. Interestingly, Ufbp1 expression was almost disappeared, and Smad2/Smad3 protein was largely phosphorylated in the liver of ketotic cows, but Ufbp1 deletion caused Smad3 phosphorylation apparently, rather than Smad2, and elevated ER stress was observed in the CKO mice model. At the cellular level, Ufbp1 deficiency led to serious fibrotic and ER stress response, Smad3 was activated by phosphorylation significantly and then was translocated into the nucleus, whereas p-Smad2 was largely unaffected in embryonic fibroblast cells. Ufbp1 overexpression obviously suppressed Smad3 phosphorylation in Hela cells. Ufbp1 was found to be in full combination with Smad3 using endogenous immunoprecipitation. Taken together, our findings suggest that downregulation or ablation of Ufbp1 leads to Smad3 activation, elevated ER stress, and hepatocyte apoptosis, which in turn causes liver fibrosis. Ufbp1 plays a protective role in ketosis-induced liver injury. Frontiers Media S.A. 2021-07-08 /pmc/articles/PMC8297976/ /pubmed/34307359 http://dx.doi.org/10.3389/fcell.2021.676789 Text en Copyright © 2021 Chen, Sheng, Xu, Li, Ali, Li and Cai. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Chen, Fanghui
Sheng, Le
Xu, Chenjie
Li, Jun
Ali, Ilyas
Li, Honglin
Cai, Yafei
Ufbp1, a Key Player of Ufm1 Conjugation System, Protects Against Ketosis-Induced Liver Injury via Suppressing Smad3 Activation
title Ufbp1, a Key Player of Ufm1 Conjugation System, Protects Against Ketosis-Induced Liver Injury via Suppressing Smad3 Activation
title_full Ufbp1, a Key Player of Ufm1 Conjugation System, Protects Against Ketosis-Induced Liver Injury via Suppressing Smad3 Activation
title_fullStr Ufbp1, a Key Player of Ufm1 Conjugation System, Protects Against Ketosis-Induced Liver Injury via Suppressing Smad3 Activation
title_full_unstemmed Ufbp1, a Key Player of Ufm1 Conjugation System, Protects Against Ketosis-Induced Liver Injury via Suppressing Smad3 Activation
title_short Ufbp1, a Key Player of Ufm1 Conjugation System, Protects Against Ketosis-Induced Liver Injury via Suppressing Smad3 Activation
title_sort ufbp1, a key player of ufm1 conjugation system, protects against ketosis-induced liver injury via suppressing smad3 activation
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297976/
https://www.ncbi.nlm.nih.gov/pubmed/34307359
http://dx.doi.org/10.3389/fcell.2021.676789
work_keys_str_mv AT chenfanghui ufbp1akeyplayerofufm1conjugationsystemprotectsagainstketosisinducedliverinjuryviasuppressingsmad3activation
AT shengle ufbp1akeyplayerofufm1conjugationsystemprotectsagainstketosisinducedliverinjuryviasuppressingsmad3activation
AT xuchenjie ufbp1akeyplayerofufm1conjugationsystemprotectsagainstketosisinducedliverinjuryviasuppressingsmad3activation
AT lijun ufbp1akeyplayerofufm1conjugationsystemprotectsagainstketosisinducedliverinjuryviasuppressingsmad3activation
AT aliilyas ufbp1akeyplayerofufm1conjugationsystemprotectsagainstketosisinducedliverinjuryviasuppressingsmad3activation
AT lihonglin ufbp1akeyplayerofufm1conjugationsystemprotectsagainstketosisinducedliverinjuryviasuppressingsmad3activation
AT caiyafei ufbp1akeyplayerofufm1conjugationsystemprotectsagainstketosisinducedliverinjuryviasuppressingsmad3activation