Cargando…

Orphan Nuclear Receptor RORγ Modulates the Genome-Wide Binding of the Cholesterol Metabolic Genes during Mycotoxin-Induced Liver Injury

Maintaining lipid homeostasis is crucial to liver function, the key organ that governs the whole-body energy metabolism. In contrast, lipid dysregulation has been implicated in mycotoxin-induced liver injury, by which the pathophysiological regulation and the molecular components involved remain elu...

Descripción completa

Detalles Bibliográficos
Autores principales: Li, Kaiqi, Li, Hao, Zhang, Kexin, Zhang, Jinying, Hu, Ping, Li, Yanwei, Gu, Haotian, Liu, Hao-Yu, Yang, Zhangping, Cai, Demin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397974/
https://www.ncbi.nlm.nih.gov/pubmed/34444698
http://dx.doi.org/10.3390/nu13082539
_version_ 1783744727777017856
author Li, Kaiqi
Li, Hao
Zhang, Kexin
Zhang, Jinying
Hu, Ping
Li, Yanwei
Gu, Haotian
Liu, Hao-Yu
Yang, Zhangping
Cai, Demin
author_facet Li, Kaiqi
Li, Hao
Zhang, Kexin
Zhang, Jinying
Hu, Ping
Li, Yanwei
Gu, Haotian
Liu, Hao-Yu
Yang, Zhangping
Cai, Demin
author_sort Li, Kaiqi
collection PubMed
description Maintaining lipid homeostasis is crucial to liver function, the key organ that governs the whole-body energy metabolism. In contrast, lipid dysregulation has been implicated in mycotoxin-induced liver injury, by which the pathophysiological regulation and the molecular components involved remain elusive. Here we focused on the potential roles of orphan nuclear receptor (NR) RORγ in lipid programming, and aimed to explore its action on cholesterol regulation in the liver of mycotoxin-exposed piglets. We found that liver tissues were damaged in the mycotoxin-exposed piglets compared to the healthy controls, revealed by histological analysis, elevated seral ALT, AST and ALP levels, and increased caspase 3/7 activities. Consistent with the transcriptomic finding of down-regulated cholesterol metabolism, we demonstrated that both cholesterol contents and cholesterol biosynthesis/transformation gene expressions in the mycotoxin-exposed livers were reduced, including HMGCS1, FDPS, SQLE, EBP, FDFT1 and VLDLR. Furthermore, we reported that RORγ binds to the cholesterol metabolic genes in porcine hepatocytes using a genome-wide ChIP-seq analysis, whereas mycotoxin decreased the RORγ binding occupancies genome-wide, especially at the cholesterol metabolic pathway. In addition, we revealed the enrichment of co-factors p300 and SRC, the histone marks H3K27ac and H3K4me2, together with RNA Polymerase II (Pol-II) at the locus of HMGCS1 in hepatocytes, which were reduced by mycotoxin-exposure. Our results provide a deep insight into the cholesterol metabolism regulation during mycotoxin-induced liver injury, and propose NRs as therapeutic targets for anti-mycotoxin treatments.
format Online
Article
Text
id pubmed-8397974
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-83979742021-08-29 Orphan Nuclear Receptor RORγ Modulates the Genome-Wide Binding of the Cholesterol Metabolic Genes during Mycotoxin-Induced Liver Injury Li, Kaiqi Li, Hao Zhang, Kexin Zhang, Jinying Hu, Ping Li, Yanwei Gu, Haotian Liu, Hao-Yu Yang, Zhangping Cai, Demin Nutrients Article Maintaining lipid homeostasis is crucial to liver function, the key organ that governs the whole-body energy metabolism. In contrast, lipid dysregulation has been implicated in mycotoxin-induced liver injury, by which the pathophysiological regulation and the molecular components involved remain elusive. Here we focused on the potential roles of orphan nuclear receptor (NR) RORγ in lipid programming, and aimed to explore its action on cholesterol regulation in the liver of mycotoxin-exposed piglets. We found that liver tissues were damaged in the mycotoxin-exposed piglets compared to the healthy controls, revealed by histological analysis, elevated seral ALT, AST and ALP levels, and increased caspase 3/7 activities. Consistent with the transcriptomic finding of down-regulated cholesterol metabolism, we demonstrated that both cholesterol contents and cholesterol biosynthesis/transformation gene expressions in the mycotoxin-exposed livers were reduced, including HMGCS1, FDPS, SQLE, EBP, FDFT1 and VLDLR. Furthermore, we reported that RORγ binds to the cholesterol metabolic genes in porcine hepatocytes using a genome-wide ChIP-seq analysis, whereas mycotoxin decreased the RORγ binding occupancies genome-wide, especially at the cholesterol metabolic pathway. In addition, we revealed the enrichment of co-factors p300 and SRC, the histone marks H3K27ac and H3K4me2, together with RNA Polymerase II (Pol-II) at the locus of HMGCS1 in hepatocytes, which were reduced by mycotoxin-exposure. Our results provide a deep insight into the cholesterol metabolism regulation during mycotoxin-induced liver injury, and propose NRs as therapeutic targets for anti-mycotoxin treatments. MDPI 2021-07-25 /pmc/articles/PMC8397974/ /pubmed/34444698 http://dx.doi.org/10.3390/nu13082539 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Li, Kaiqi
Li, Hao
Zhang, Kexin
Zhang, Jinying
Hu, Ping
Li, Yanwei
Gu, Haotian
Liu, Hao-Yu
Yang, Zhangping
Cai, Demin
Orphan Nuclear Receptor RORγ Modulates the Genome-Wide Binding of the Cholesterol Metabolic Genes during Mycotoxin-Induced Liver Injury
title Orphan Nuclear Receptor RORγ Modulates the Genome-Wide Binding of the Cholesterol Metabolic Genes during Mycotoxin-Induced Liver Injury
title_full Orphan Nuclear Receptor RORγ Modulates the Genome-Wide Binding of the Cholesterol Metabolic Genes during Mycotoxin-Induced Liver Injury
title_fullStr Orphan Nuclear Receptor RORγ Modulates the Genome-Wide Binding of the Cholesterol Metabolic Genes during Mycotoxin-Induced Liver Injury
title_full_unstemmed Orphan Nuclear Receptor RORγ Modulates the Genome-Wide Binding of the Cholesterol Metabolic Genes during Mycotoxin-Induced Liver Injury
title_short Orphan Nuclear Receptor RORγ Modulates the Genome-Wide Binding of the Cholesterol Metabolic Genes during Mycotoxin-Induced Liver Injury
title_sort orphan nuclear receptor rorγ modulates the genome-wide binding of the cholesterol metabolic genes during mycotoxin-induced liver injury
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397974/
https://www.ncbi.nlm.nih.gov/pubmed/34444698
http://dx.doi.org/10.3390/nu13082539
work_keys_str_mv AT likaiqi orphannuclearreceptorrorgmodulatesthegenomewidebindingofthecholesterolmetabolicgenesduringmycotoxininducedliverinjury
AT lihao orphannuclearreceptorrorgmodulatesthegenomewidebindingofthecholesterolmetabolicgenesduringmycotoxininducedliverinjury
AT zhangkexin orphannuclearreceptorrorgmodulatesthegenomewidebindingofthecholesterolmetabolicgenesduringmycotoxininducedliverinjury
AT zhangjinying orphannuclearreceptorrorgmodulatesthegenomewidebindingofthecholesterolmetabolicgenesduringmycotoxininducedliverinjury
AT huping orphannuclearreceptorrorgmodulatesthegenomewidebindingofthecholesterolmetabolicgenesduringmycotoxininducedliverinjury
AT liyanwei orphannuclearreceptorrorgmodulatesthegenomewidebindingofthecholesterolmetabolicgenesduringmycotoxininducedliverinjury
AT guhaotian orphannuclearreceptorrorgmodulatesthegenomewidebindingofthecholesterolmetabolicgenesduringmycotoxininducedliverinjury
AT liuhaoyu orphannuclearreceptorrorgmodulatesthegenomewidebindingofthecholesterolmetabolicgenesduringmycotoxininducedliverinjury
AT yangzhangping orphannuclearreceptorrorgmodulatesthegenomewidebindingofthecholesterolmetabolicgenesduringmycotoxininducedliverinjury
AT caidemin orphannuclearreceptorrorgmodulatesthegenomewidebindingofthecholesterolmetabolicgenesduringmycotoxininducedliverinjury