Novel Role of Nuclear Receptor Rev-erb alpha in Hepatic Stellate Cell Activation: Potential Therapeutic Target for Liver Injury

作者：Li Ting^*; Eheim Ashley L; Klein Sabine; Uschner Frank E; Smith Amber C; Brandon Warner Elizabeth; Ghosh Sriparna; Bonkovsky Herbert L; Trebicka Jonel; Schrum Laura W

来源：Hepatology, 2014, 59(6): 2383-2396.

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

• 出版日期2014-6