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Glucocorticoids Have Opposing Effects on Liver Fibrosis in Hepatic Stellate and Immune Cells

Authors :
Kim, Kang Ho
Lee, Jae Man
Zhou, Ying
Harpavat, Sanjiv
Moore, David D.
Source :
Molecular Endocrinology; August 2016, Vol. 30 Issue: 8 p905-916, 12p
Publication Year :
2016

Abstract

Liver fibrosis is a reversible wound-healing process that is protective in the short term, but prolonged fibrotic responses lead to excessive accumulation of extracellular matrix components that suppresses hepatocyte regeneration, resulting in permanent liver damage. Upon liver damage, nonparenchymal cells including immune cells and hepatic stellate cells (HSCs) have crucial roles in the progression and regression of liver fibrosis. Here, we report differential roles of the glucocorticoid receptor (GR), acting in immune cells and HSCs, in liver fibrosis. In the carbon tetrachloride hepatotoxin-induced fibrosis model, both steroidal and nonsteroidal GR ligands suppressed expression of fibrotic genes and decreased extracellular matrix deposition but also inhibited immune cell infiltration and exacerbated liver injury. These counteracting effects of GR ligands were dissociated in mice with conditional GR knockout in immune cells (GRLysM) or HSC (GRhGFAP): the impacts of dexamethasone on immune cell infiltration and liver injury were totally blunted in GRLysMmice, whereas the suppression of fibrotic gene expression was diminished in GRhGFAPmice. The effect of GR activation in HSC was further confirmed in the LX-2 HSC cell line, in which antifibrotic effects were mediated by GR ligand inhibition of Sma and mad-related protein 3 (SMAD3) expression. We conclude that GR has differential roles in immune cells and HSCs to modulate liver injury and liver fibrosis. Specific activation of HSC-GR without alteration of GR activity in immune cells provides a potential therapeutic approach to treatment of hepatic fibrosis.

Details

Language :
English
ISSN :
08888809 and 19449917
Volume :
30
Issue :
8
Database :
Supplemental Index
Journal :
Molecular Endocrinology
Publication Type :
Periodical
Accession number :
ejs39752842
Full Text :
https://doi.org/10.1210/me.2016-1029