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Novel role of nuclear receptor Rev-erbalpha in hepatic stellate cell activation: potential therapeutic target for liver injury.

Authors: Li, T  Eheim, AL  Klein, S  Uschner, FE  Smith, AC  Brandon-Warner, E  Ghosh, S  Bonkovsky, HL  Trebicka, J  Schrum, LW 
Citation: Li T, etal., Hepatology. 2014 Jun;59(6):2383-96. doi: 10.1002/hep.27049. Epub 2014 Apr 29.
Pubmed: (View Article at PubMed) PMID:24497272
DOI: Full-text: DOI:10.1002/hep.27049

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-erbalpha, a transcriptional repressor involved in metabolic and circadian regulation known to promote adipogenesis in preadipocytes, in HSC transdifferentiation. We discovered that Rev-erbalpha 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-erbalpha, which demonstrated distributions similar to myosin, the major cellular motor protein. Cells overexpressing a cytoplasm-localized Rev-erbalpha exhibited enhanced contractility. Ectopically expressed Rev-erbalpha responded to both adipogenic ligand and fibrogenic transforming growth factor beta treatment. Rev-erb ligand SR6452 down-regulated cytoplasmic expression of Rev-erbalpha, decreased expression of fibrogenic markers and the activated phenotype in HSCs, and ameliorated fibrosis and PH in rodent models. CONCLUSIONS: Up-regulation of Rev-erbalpha is an intrinsic fibrogenic response characterized by cytoplasmic accumulation of the protein in activated HSCs. Cytoplasmic expression of Rev-erbalpha promotes a contractile phenotype. Rev-erbalpha 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-erbalpha. Our studies identify Rev-erbalpha as a novel regulator of HSC transdifferentiation and offers exciting new insights on the therapeutic potential of Rev-erb ligands.

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CRRD Object Information
CRRD ID: 10448995
Created: 2015-12-10
Species: All species
Last Modified: 2015-12-10
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.