title: Caspase 3 inactivation protects against hepatic cell death and ameliorates fibrogenesis in a diet-induced NASH model.
abstract: OBJECTIVE
  Hepatocyte cell death is a key feature of nonalcoholic steatohepatitis (NASH). As the contribution of specific caspases remains unclear, our aim was to ascertain the effect of caspase 3 suppression on liver injury and fibrogenesis.
  
  
  METHODS
  C57BL/6 wild-type (WT) and caspase 3 knock out (Casp3 (-/-)) mice were placed on a methionine- and choline-deficient (MCD) diet for 6 weeks to induce steatohepatitis and liver fibrosis. Thereafter, liver injury, liver fibrosis and hepatocellular apoptosis were quantified in liver sections. Additionally, expression of proteins associated with liver inflammation and fibrogenesis was analyzed.
  
  
  RESULTS
  WT mice fed MCD diet showed marked activation of caspase 3 in hepatocytes, in conjunction with steatohepatitis and increased hepatic triglyceride levels, hepatocyte ballooning, inflammation and fibrosis. Casp3 (-/-) mice fed the MCD diet showed similar serum aminotransferase levels and NAFLD activity scores (NAS) compared with WT MCD-fed mice. However, Casp3 (-/-) mice on the MCD diet showed a marked reduction in expression of transcripts for profibrogenic genes, which translated into reduced hepatic collagen deposition. These changes were associated with decreased levels of apoptosis, and a significant reduction in the expression of cytokines involved in inflammatory signaling. Casp3 (-/-) mice on the MCD showed a reduction in expression of chemokine receptor 2 (CCR2) leading to ameliorated infiltration of inflammatory lymphocyte antigen 6 complex, locus C1 (Ly6c) positive monocytes.
  
  
  CONCLUSIONS
  These findings support a prominent role for hepatocyte caspase 3 activation in NASH-related apoptosis, fibrogenesis and fibrosis which in part is mediated via CCR2-dependent infiltration of Ly6c positive monocytes.
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
authors.forename: Samjhana
authors.initials: S
authors.lastname: Thapaliya
authors.forename: Alexander
authors.initials: A
authors.lastname: Wree
authors.forename: Davide
authors.initials: D
authors.lastname: Povero
authors.forename: Maria Eugenia
authors.initials: ME
authors.lastname: Inzaugarat
authors.forename: Michael
authors.initials: M
authors.lastname: Berk
authors.forename: Laura
authors.initials: L
authors.lastname: Dixon
authors.forename: Bettina G
authors.initials: BG
authors.lastname: Papouchado
authors.forename: Ariel E
authors.initials: AE
authors.lastname: Feldstein
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism*; D002794:Choline / Q000008:administration & dosage / Q000494:pharmacology; D003094:Collagen / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005234:Fatty Liver / Q000201:enzymology* / Q000473:pathology*; D005786:Gene Expression Regulation; D055166:Hepatic Stellate Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000201:enzymology*; D008103:Liver Cirrhosis / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008715:Methionine / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease; D054390:Receptors, CCR2 / Q000235:genetics / Q000378:metabolism
chemical_list: D000950:Antigens, Ly; C515335:Ccr2 protein, mouse; C494192:Ly-6C antigen, mouse; D054390:Receptors, CCR2; D003094:Collagen; D008715:Methionine; D053148:Caspase 3; D002794:Choline