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 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)