title: Reduced lipoapoptosis, hedgehog pathway activation and fibrosis in caspase-2 deficient mice with non-alcoholic steatohepatitis.
abstract: OBJECTIVE
  Caspase-2 is an initiator caspase involved in multiple apoptotic pathways, particularly in response to specific intracellular stressors (eg, DNA damage, ER stress). We recently reported that caspase-2 was pivotal for the induction of cell death triggered by excessive intracellular accumulation of long-chain fatty acids, a response known as lipoapoptosis. The liver is particularly susceptible to lipid-induced damage, explaining the pandemic status of non-alcoholic fatty liver disease (NAFLD). Progression from NAFLD to non-alcoholic steatohepatitis (NASH) results, in part, from hepatocyte apoptosis and consequential paracrine-mediated fibrogenesis. We evaluated the hypothesis that caspase-2 promotes NASH-related cirrhosis.
  
  
  METHODS
  Caspase-2 was localised in liver biopsies from patients with NASH. Its expression was evaluated in different mouse models of NASH, and outcomes of diet-induced NASH were compared in wild-type (WT) and caspase-2-deficient mice. Lipotoxicity was modelled in vitro using hepatocytes derived from WT and caspase-2-deficient mice.
  
  
  RESULTS
  We showed that caspase-2 is integral to the pathogenesis of NASH-related cirrhosis. Caspase-2 is localised in injured hepatocytes and its expression was markedly upregulated in patients and animal models of NASH. During lipotoxic stress, caspase-2 deficiency reduced apoptosis, inhibited induction of profibrogenic hedgehog target genes in mice and blocked production of hedgehog ligands in cultured hepatocytes.
  
  
  CONCLUSIONS
  These data point to a critical role for caspase-2 in lipid-induced hepatocyte apoptosis in vivo for the production of apoptosis-associated fibrogenic factors and in the progression of lipid-induced liver fibrosis. This raises the intriguing possibility that caspase-2 may be a promising therapeutic target to prevent progression to NASH.
authors: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA Gastroenterology Department, Hospital de Santa Maria, CHLN, Lisbon, Portugal.
authors: M V
authors: MV
authors: Machado
authors: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors: G A
authors: GA
authors: Michelotti
authors: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors: T de Almeida
authors: Tde A
authors: Pereira
authors: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA HIFIH Laboratory, UPRES 3859, SFR 4208, LUNAM University, Angers, France.
authors: J
authors: J
authors: Boursier
authors: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors: L
authors: L
authors: Kruger
authors: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors: M
authors: M
authors: Swiderska-Syn
authors: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors: G
authors: G
authors: Karaca
authors: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors: G
authors: G
authors: Xie
authors: HIFIH Laboratory, UPRES 3859, SFR 4208, LUNAM University, Angers, France.
authors: C D
authors: CD
authors: Guy
authors: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors: B
authors: B
authors: Bohinc
authors: Division of Pathology, Duke University Medical Center, Durham, North Carolina, USA Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA.
authors: K R
authors: KR
authors: Lindblom
authors: Division of Pathology, Duke University Medical Center, Durham, North Carolina, USA Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA.
authors: E
authors: E
authors: Johnson
authors: Division of Pathology, Duke University Medical Center, Durham, North Carolina, USA Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA.
authors: S
authors: S
authors: Kornbluth
authors: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA.
authors: A M
authors: AM
authors: Diehl
mesh_terms: D000328:Adult; D000818:Animals; D017209:Apoptosis; D053143:Caspase 2 / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental; D004195:Disease Models, Animal; D018450:Disease Progression; D053823:Hedgehog Proteins / Q000502:physiology; D022781:Hepatocytes / Q000378:metabolism / Q000502:physiology; D006801:Humans; D008099:Liver / Q000378:metabolism; D008103:Liver Cirrhosis / Q000209:etiology / Q000503:physiopathology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications / Q000503:physiopathology* / Q000517:prevention & control; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D053823:Hedgehog Proteins; D053143:Caspase 2
keywords: APOPTOSIS; CELL DEATH; FATTY LIVER; MOLECULAR BIOLOGY; NONALCOHOLIC STEATOHEPATITIS