Novel role of nuclear receptor rev-erbα in hepatic stellate cell activation: potential therapeutic target for liver injury
Hepatic stellate cell (HSC) transdifferentiation from a quiescent, adipocyte-like cell to a highly secretory and contractile myofibroblast-like phenotype contributes to negative pathological consequences, including fibrosis/cirrhosis with portal hypertension (PH). Antiadipogenic mechanisms have been...
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| Main Authors: | , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
4 February 2014
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| In: |
Hepatology
Year: 2014, Volume: 59, Issue: 6, Pages: 2383-2396 |
| ISSN: | 1527-3350 |
| DOI: | 10.1002/hep.27049 |
| Online Access: | Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1002/hep.27049 Verlag, lizenzpflichtig, Volltext: https://aasldpubs.onlinelibrary.wiley.com/doi/abs/10.1002/hep.27049 
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| Author Notes: | Ting Li, Ashley L. Eheim, Sabine Klein, Frank E. Uschner, Amber C. Smith, Elizabeth Brandon‐Warner, Sriparna Ghosh, Herbert L. Bonkovsky, Jonel Trebicka, and Laura W. Schrum |
| Summary: | Hepatic stellate cell (HSC) transdifferentiation from a quiescent, adipocyte-like cell to a highly secretory and contractile myofibroblast-like phenotype contributes to negative pathological consequences, including fibrosis/cirrhosis with portal hypertension (PH). Antiadipogenic mechanisms have been shown to underlie activation of HSCs. We examined the role of heme-sensing nuclear receptor Rev-erbα, a transcriptional repressor involved in metabolic and circadian regulation known to promote adipogenesis in preadipocytes, in HSC transdifferentiation. We discovered that Rev-erbα protein was up-regulated in activated HSCs and injured livers; however, transcriptional repressor activity was not affected by fibrogenic treatments. Surprisingly, increased protein expression was accompanied with increased cytoplasmic accumulation of Rev-erbα, which demonstrated distributions similar to myosin, the major cellular motor protein. Cells overexpressing a cytoplasm-localized Rev-erbα exhibited enhanced contractility. Ectopically expressed Rev-erbα responded to both adipogenic ligand and fibrogenic transforming growth factor beta treatment. Rev-erb ligand SR6452 down-regulated cytoplasmic expression of Rev-erbα, decreased expression of fibrogenic markers and the activated phenotype in HSCs, and ameliorated fibrosis and PH in rodent models. Conclusions: Up-regulation of Rev-erbα is an intrinsic fibrogenic response characterized by cytoplasmic accumulation of the protein in activated HSCs. Cytoplasmic expression of Rev-erbα promotes a contractile phenotype. Rev-erbα acts as a bifunctional regulator promoting either anti- or profibrogenic response, depending on milieu. Rev-erb ligand SR6452 functions by a previously undescribed mechanism, targeting both nuclear activity and cytoplasmic expression of Rev-erbα. Our studies identify Rev-erbα as a novel regulator of HSC transdifferentiation and offers exciting new insights on the therapeutic potential of Rev-erb ligands. (Hepatology 2014;59:2383-2396) |
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| Item Description: | Gesehen am 17.08.2020 |
| Physical Description: | Online Resource |
| ISSN: | 1527-3350 |
| DOI: | 10.1002/hep.27049 |