Orphan nuclear receptor ERRγ regulates hepatic TGF-β2 expression and fibrogenic response in CCl4-induced acute liver injury

Acute liver injury results from the complex interactions of various pathological processes. The TGF-β superfamily plays a crucial role in orchestrating fibrogenic response. In contrast to TGF-β1, a role of TGF-β2 in hepatic fibrogenic response has not been fully investigated. In this study, we showe...

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Published in:Archives of toxicology 2021-09, Vol.95 (9), p.3071-3084
Main Authors: Jung, Yoon Seok, Kim, Yong-Hoon, Radhakrishnan, Kamalakannan, Kim, Jina, Lee, In-Kyu, Cho, Sung Jin, Kim, Don-Kyu, Dooley, Steven, Lee, Chul-Ho, Choi, Hueng-Sik
Format: Article
Language:English
Subjects:
Acute toxicity
Biocompatibility
Biomedical and Life Sciences
Biomedicine
Carbon tetrachloride
Depletion
Environmental Health
Gene expression
Injuries
Interleukin 6
Inverse agonists
Liver
Molecular Toxicology
Occupational Medicine/Industrial Medicine
Overexpression
Pharmacology/Toxicology
Toxicity
Transcription
Transforming growth factor-b1
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Summary:Acute liver injury results from the complex interactions of various pathological processes. The TGF-β superfamily plays a crucial role in orchestrating fibrogenic response. In contrast to TGF-β1, a role of TGF-β2 in hepatic fibrogenic response has not been fully investigated. In this study, we showed that TGF-β2 gene expression and secretion are induced in the liver of CCl 4 (1 ml/kg)-treated WT mice. Studies with hepatocyte specific ERRγ knockout mice or treatment with an ERRγ-specific inverse agonist, GSK5182 (40 mg/kg), indicated that CCl 4 -induced hepatic TGF-β2 production is ERRγ dependent. Moreover, IL6 was found as upstream signal to induce hepatic ERRγ and TGF-β2 gene expression in CCl 4 -mediated acute toxicity model. Over-expression of ERRγ was sufficient to induce hepatic TGF-β2 expression, whereas ERRγ depletion markedly reduces IL6-induced TGF-β2 gene expression and secretion in vitro and in vivo. Promoter assays showed that ERRγ directly binds to an ERR response element in the TGF-β2 promoter to induce TGF-β2 transcription. Finally, GSK5182 diminished CCl 4 -induced fibrogenic response through inhibition of ERRγ-mediated TGF-β2 production. Taken together, these results firstly demonstrate that ERRγ can regulate the TGF-β2-mediated fibrogenic response in a mouse model of CC1 4 -induced acute liver injury.
ISSN:0340-5761
1432-0738
DOI:10.1007/s00204-021-03112-1