Novel role of nuclear receptor rev-erbα in hepatic stellate cell activation

• Verfasst von: Li, Ting [VerfasserIn]
• Verfasst von: Eheim, Ashley [VerfasserIn]
• Verfasst von: Klein, Sabine [VerfasserIn]
• Verfasst von: Uschner, Frank E. [VerfasserIn]
• Verfasst von: Smith, Amber C. [VerfasserIn]
• Verfasst von: Brandon‐Warner, Elizabeth [VerfasserIn]
• Verfasst von: Ghosh, Sriparna [VerfasserIn]
• Verfasst von: Bonkovsky, Herbert L. [VerfasserIn]
• Verfasst von: Trebicka, Jonel [VerfasserIn]
• Verfasst von: Schrum, Laura W. [VerfasserIn]
• Titel: Novel role of nuclear receptor rev-erbα in hepatic stellate cell activation
• Titelzusatz: potential therapeutic target for liver injury
• Verf.angabe: 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
• E-Jahr: 2014
• Jahr: 4 February 2014
• Umfang: 14 S.
• Fussnoten: Gesehen am 17.08.2020
• Titel Quelle: Enthalten in: Hepatology
• Ort Quelle: New York [u.a.] : Wiley Interscience, 1981
• Jahr Quelle: 2014
• Band/Heft Quelle: 59(2014), 6, Seite 2383-2396
• ISSN Quelle: 1527-3350
• DOI: doi:10.1002/hep.27049
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1727143744

Abstract

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)