title: The pan-caspase inhibitor Emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitis.
abstract: OBJECTIVE
  Hepatocyte apoptosis, the hallmark of non-alcoholic steatohepatitis (NASH) contributes to liver injury and fibrosis. Although, both the intrinsic and extrinsic apoptotic pathways are involved in the pathogenesis of NASH, the final common step of apoptosis is executed by a family of cysteine-proteases termed caspases. Thus, our aim was to ascertain if administration of Emricasan, a pan-caspase inhibitor, ameliorates liver injury and fibrosis in a murine model of NASH.
  
  
  METHODS
  C57/BL6J-mice were fed regular chow or high fat diet (HFD) for 20 weeks. All mice were treated with vehicle or Emricasan.
  
  
  RESULTS
  Mice fed a HFD diet demonstrate a five-fold increase in hepatocyte apoptosis by the TUNEL assay and a 1.5-fold and 1.3-fold increase in caspase-3 and-8 activities respectively; this increase in apoptosis was substantially attenuated in mice fed a HFD treated with Emricasan (HFD-Em). Likewise, liver injury and inflammation were reduced in mice fed HFD-Em as compare to HFD by measuring serum aspartate aminotransferase and alanine aminotransferase levels, NAS histological score and IL 1-β, TNF-α, monocyte chemoattractant protein (MCP-1) and C-X-C chemokine ligand-2 (CXCL2) quantitative reverse-transcription polymerase chain reaction (qPCR). These differences could not be attributed to differences in hepatic steatosis as liver triglycerides content were similar in both HFD groups. Hepatic fibrosis was reduced by Emricasan in HFD animals by decreasing αSMA (a marker for hepatic stellate cell activation), fibrosis score, Sirius red staining, hydroxyproline liver content and profibrogenic cytokines by qPCR.
  
  
  CONCLUSIONS
  In conclusion, these data demonstrate that in a murine model of NASH, liver injury and fibrosis are suppressed by inhibiting hepatocytes apoptosis and suggests that Emricasan may be an attractive antifibrotic therapy in NASH.
authors.affiliation: Laboratory of Microbiology, Faculty of Chemical and Natural Sciences, National University of Misiones, CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas), Posadas, Argentina; Laboratory of Oxygen Metabolism, University Hospital, University of Buenos Aires, Buenos Aires, Argentina.
authors.forename: Fernando J
authors.initials: FJ
authors.lastname: Barreyro
authors.forename: Silvia
authors.initials: S
authors.lastname: Holod
authors.forename: Paola V
authors.initials: PV
authors.lastname: Finocchietto
authors.forename: Alejandra M
authors.initials: AM
authors.lastname: Camino
authors.forename: Jorge B
authors.initials: JB
authors.lastname: Aquino
authors.forename: Alejandra
authors.initials: A
authors.lastname: Avagnina
authors.forename: María C
authors.initials: MC
authors.lastname: Carreras
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Poderoso
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Gores
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005355:Fibrosis; D006505:Hepatitis / Q000517:prevention & control; D022781:Hepatocytes / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D010421:Pentanoic Acids / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C487112:3-(2-(2-tert-butylphenylaminooxalyl)aminopropionylamino)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid; D061945:Caspase Inhibitors; D010421:Pentanoic Acids
keywords: Emricasan; apoptosis; caspase inhibitor; fibrosis; non-alcoholic fatty liver disease