title: Endoplasmic Reticulum stress induces hepatic stellate cell apoptosis and contributes to fibrosis resolution.
abstract: BACKGROUND
  Survival of hepatic stellate cells (HSCs) is a hallmark of liver fibrosis, while the induction of HSC apoptosis may induce recovery. Activated HSC are resistant to many pro-apoptotic stimuli. To this issue, the role of Endoplasmic Reticulum (ER) stress in promoting apoptosis of HSCs and consequently fibrosis resolution is still debated.
  
  
  OBJECTIVE
  To evaluate the potential ER stress-mediated apoptosis of HSCs and fibrosis resolution
  
  
  METHODS
  HSCs were incubated with the ER stress agonists, tunicamycin or thapsigargin. In vivo, HSC were isolated from normal, bile duct-ligated (BDL) and bile duct-diverted (BDD) rats.
  
  
  RESULTS
  In activated HSC, the specific inhibitor of ER stress-induced apoptosis, calpastatin, is significantly increased vs. quiescent HSCs. Calpain is conversely reduced in activated HSCs. This pattern of protein expression provides HSCs resistance to the ER stress signals of apoptosis (apoptosis-resistant phenotype). However, both tunicamycin and thapsigargin are able to induce apoptosis in HSCs in vitro, completely reversing the calpain/calpastatin pattern expression. Furthermore, in vivo, the fibrosis resolution observed in rat livers subjected to bile duct ligation (BDL) and subsequent bile duct diversion (BDD), leads to fibrosis resolution through a mechanism of HSCs apoptosis, potentially associated with ER stress: in fact, BDD rat liver shows an increased number of apoptotic HSCs associated with reduced calapstatin and increased calpain protein expression, leading to an apoptosis-sensible phenotype.
  
  
  CONCLUSIONS
  ER stress sensitizes HSC to apoptosis both in vitro and in vivo. Thus, ER stress represents a key target to trigger cell death in activated HSC and promotes fibrosis resolution.
authors.affiliation: Department of Gastroenterology, Polytechnic University of Marche,  Ancona, Italy.
authors.forename: Samuele
authors.initials: S
authors.lastname: De Minicis
authors.forename: Cinzia
authors.initials: C
authors.lastname: Candelaresi
authors.forename: Laura
authors.initials: L
authors.lastname: Agostinelli
authors.forename: Silvia
authors.initials: S
authors.lastname: Taffetani
authors.forename: Stefania
authors.initials: S
authors.lastname: Saccomanno
authors.forename: Chiara
authors.initials: C
authors.lastname: Rychlicki
authors.forename: Luciano
authors.initials: L
authors.lastname: Trozzi
authors.forename: Marco
authors.initials: M
authors.lastname: Marzioni
authors.forename: Antonio
authors.initials: A
authors.lastname: Benedetti
authors.forename: Gianluca
authors.initials: G
authors.lastname: Svegliati-Baroni
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001652:Bile Ducts / Q000601:surgery; D015153:Blotting, Western; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005355:Fibrosis / Q000503:physiopathology*; D055166:Hepatic Stellate Cells / Q000502:physiology*; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008026:Ligation; D008099:Liver / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D019284:Thapsigargin / Q000494:pharmacology; D014415:Tunicamycin / Q000494:pharmacology
chemical_list: D002135:Calcium-Binding Proteins; D034741:RNA, Small Interfering; D014415:Tunicamycin; D019284:Thapsigargin; C033668:calpastatin; D002154:Calpain; D053181:Caspase 8