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Endoplasmic Reticulum stress induces hepatic stellate cell apoptosis and contributes to fibrosis resolution
Author(s) -
Minicis Samuele,
Candelaresi Cinzia,
Agostinelli Laura,
Taffetani Silvia,
Saccomanno Stefania,
Rychlicki Chiara,
Trozzi Luciano,
Marzioni Marco,
Benedetti Antonio,
SvegliatiBaroni Gianluca
Publication year - 2012
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/j.1478-3231.2012.02860.x
Subject(s) - unfolded protein response , thapsigargin , hepatic stellate cell , endoplasmic reticulum , apoptosis , microbiology and biotechnology , biology , tunicamycin , cancer research , endocrinology , biochemistry
Background Survival of hepatic stellate cells ( HSC s) 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 HSC s and consequently fibrosis resolution is still debated. Aim To evaluate the potential ER stress‐mediated apoptosis of HSCs and fibrosis resolution Methods HSC s 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 HSC s. Calpain is conversely reduced in activated HSC s. This pattern of protein expression provides HSC s resistance to the ER stress signals of apoptosis (apoptosis‐resistant phenotype). However, both tunicamycin and thapsigargin are able to induce apoptosis in HSC s 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 HSC s apoptosis, potentially associated with ER stress: in fact, BDD rat liver shows an increased number of apoptotic HSC s 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.