Potential conflict of interest: Dr. Bonkovsky consults for and advises AI. He consults for Lundbeck and Novartis. He received grants from Vertex and Clinuvel.
Novel role of nuclear receptor rev-erbα in hepatic stellate cell activation: Potential therapeutic target for liver injury
Article first published online: 29 APR 2014
© 2014 by the American Association for the Study of Liver Diseases
Volume 59, Issue 6, pages 2383–2396, June 2014
How to Cite
Li, T., Eheim, A. L., Klein, S., Uschner, F. E., Smith, A. C., Brandon-Warner, E., Ghosh, S., Bonkovsky, H. L., Trebicka, J. and Schrum, L. W. (2014), Novel role of nuclear receptor rev-erbα in hepatic stellate cell activation: Potential therapeutic target for liver injury. Hepatology, 59: 2383–2396. doi: 10.1002/hep.27049
This work was supported by funding from the Carolinas HealthCare System and Deutsche Forschungsgemeinschaft (SFB TRR57 project 18).
- Issue published online: 28 MAY 2014
- Article first published online: 29 APR 2014
- Accepted manuscript online: 4 FEB 2014 07:37AM EST
- Manuscript Accepted: 30 JAN 2014
- Manuscript Received: 22 AUG 2013
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)