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

YS Jung; J Albin; YH Kim; K Radhakrishnan; J Kim; IK Lee; SJ Cho; DK Kim; S Dooley; Lee CH; HS Choi

doi:10.1055/s-0041-1733620

Zeitschrift für Gastroenterologie, Inhaltsverzeichnis

Z Gastroenterol 2021; 59(08): e210
DOI: 10.1055/s-0041-1733620

Grundlagenorientierte Hepatologie

Donnerstag, 16. September 2021, 09:00-10:20 Uhr, Saal 4

Leber und Galle

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

YS Jung

¹Chonnam National University, School of Biological Sciences and Technology, Gwangju, Korea, Republik

,

J Albin

²Medizinische Fakultät Mannheim, Universität Heidelberg, Molekulare Hepatologie, II. Medizinische Klinik, Mannheim, Deutschland

,

YH Kim

³Korea Research Institute of Bioscience and Biotechnology, Laboratory Animal Resource Center, Daejeon, Korea, Republik

,

K Radhakrishnan

¹Chonnam National University, School of Biological Sciences and Technology, Gwangju, Korea, Republik

,

J Kim

⁴Daegu-Gyeongbuk Medical Innovation Foundation, New Drug Development Center, Daegu, Korea, Republik

,

IK Lee

⁵School of Medicine, Kyungpook National University, Department of Internal Medicine, Daegu, Korea, Republik

⁶Kyungpook National University, Research Institute of Aging and Metabolism, Daegu, Korea, Republik

,

SJ Cho

⁴Daegu-Gyeongbuk Medical Innovation Foundation, New Drug Development Center, Daegu, Korea, Republik

⁶Kyungpook National University, Research Institute of Aging and Metabolism, Daegu, Korea, Republik

,

DK Kim

⁷Chonnam National University, Department of Integrative Food, Bioscience and Biotechnology, Gwangju, Korea, Republik

,

S Dooley

²Medizinische Fakultät Mannheim, Universität Heidelberg, Molekulare Hepatologie, II. Medizinische Klinik, Mannheim, Deutschland

,

Lee CH

³Korea Research Institute of Bioscience and Biotechnology, Laboratory Animal Resource Center, Daejeon, Korea, Republik

⁸KRIBB School of Bioscience, Korea University of Science and Technology, Department of Functional Genomics, Daejeon, Korea, Republik

,

HS Choi

¹Chonnam National University, School of Biological Sciences and Technology, Gwangju, Korea, Republik

› Institutsangaben

Abstract

Volltext

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-b2 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-b2 production is ERRg dependent. Moreover, IL6 was found as upstream signal to induce hepatic ERRg and TGF-b2 gene expression in CCl₄ mediated acute toxicity model. Over-expression of ERRg was sufficient to induce hepatic TGF-b2 expression, whereas ERRg depletion markedly reduces IL6-induced TGF-b2 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 ERRg-mediated TGF-b2 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.