Orphan nuclear receptor ERRγ regulates hepatic TGF-β2 expression and fibrogenic response in CCl4-induced acute liver injury
Autor: | Steven Dooley, DK Kim, Yong-Hoon Kim, J Albin, Cho Sung Jin, Chul-Ho Lee, Hueng-Sik Choi, K Radhakrishnan, Yoon Seok Jung, J Kim, Inkyu Lee |
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Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
Health Toxicology and Mutagenesis Response element CCL4 010501 environmental sciences Toxicology 01 natural sciences 03 medical and health sciences Gene expression medicine Inverse agonist Secretion 0105 earth and related environmental sciences Acute liver injury business.industry Chemistry General Medicine Cell biology 030104 developmental biology medicine.anatomical_structure Nuclear receptor Hepatocyte Knockout mouse Cancer research business Transforming growth factor |
Zdroj: | Archives of Toxicology. 95:3071-3084 |
ISSN: | 1432-0738 0340-5761 |
Popis: | 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 CCl4 (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 CCl4-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 CCl4-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 CCl4-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 CC14-induced acute liver injury. |
Databáze: | OpenAIRE |
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