title: Endoplasmic reticulum stress induces fibrogenic activity in hepatic stellate cells through autophagy.
abstract: OBJECTIVE
  Metabolic stress during liver injury enhances autophagy and provokes stellate cell activation, with secretion of scar matrix. Conditions that augment protein synthesis increase demands on the endoplasmic reticulum (ER) folding capacity and trigger the unfolded protein response (UPR) to cope with resulting ER stress. Generation of reactive oxygen species (ROS) is a common feature of hepatic fibrogenesis, and crosstalk between oxidant stress and ER stress has been proposed. The aim of our study was to determine the impact of oxidant and ER stress on stellate cell activation.
  
  
  METHODS
  Oxidant stress was induced in hepatic stellate cells using H2O2 in culture or by ethanol feeding in vivo, and the UPR was analyzed. Because the branch of the UPR mainly affected was IREα, we blocked this pathway in stellate cells and analyzed the fibrogenic response, together with autophagy and downstream MAPK signaling. The Nrf2 antioxidant response was also evaluated in stellate cells under oxidant stress conditions.
  
  
  RESULTS
  H2O2 treatment in culture or ethanol feeding in vivo increased the UPR based on splicing of XBP1 mRNA, which triggered autophagy. The Nrf2-mediated antioxidant response, as measured by qRT-PCR of its target genes was also induced under ER stress conditions. Conversely, blockade of the IRE1α pathway in stellate cells significantly decreased both their activation and autophagic activity in a p38 MAPK-dependent manner, leading to a reduced fibrogenic response.
  
  
  CONCLUSIONS
  These data implicate mechanisms underlying protein folding quality control in regulating the fibrogenic response in hepatic stellate cells.
authors.affiliation: Division of Liver Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Virginia
authors.initials: V
authors.lastname: Hernández-Gea
authors.forename: Moira
authors.initials: M
authors.lastname: Hilscher
authors.forename: Raphael
authors.initials: R
authors.lastname: Rozenfeld
authors.forename: Maribel P
authors.initials: MP
authors.lastname: Lim
authors.forename: Natalia
authors.initials: N
authors.lastname: Nieto
authors.forename: Sabine
authors.initials: S
authors.lastname: Werner
authors.forename: Lakshmi A
authors.initials: LA
authors.lastname: Devi
authors.forename: Scott L
authors.initials: SL
authors.lastname: Friedman
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001343:Autophagy / Q000502:physiology*; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D004722:Endoribonucleases / Q000378:metabolism; D055166:Hepatic Stellate Cells / Q000378:metabolism* / Q000473:pathology*; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D018384:Oxidative Stress; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D012326:RNA Splicing; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D056811:Unfolded Protein Response; D000071717:X-Box Binding Protein 1
chemical_list: D000975:Antioxidants; D004268:DNA-Binding Proteins; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases