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

Hepatology. 2014 Jun;59(6):2383-96. doi: 10.1002/hep.27049. Epub 2014 Apr 29.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Transdifferentiation*
  • Cytoplasm / metabolism
  • Hepatic Stellate Cells / metabolism*
  • Humans
  • Liver / injuries
  • Liver / metabolism
  • Liver Cirrhosis / etiology*
  • Liver Cirrhosis / metabolism
  • Male
  • Myosins / antagonists & inhibitors
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / agonists
  • Nuclear Receptor Subfamily 1, Group D, Member 1 / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Up-Regulation

Substances

  • Nuclear Receptor Subfamily 1, Group D, Member 1
  • Myosins