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Reduced lipoapoptosis, hedgehog pathway activation and fibrosis in caspase-2 deficient mice with non-alcoholic steatohepatitis
  1. M V Machado1,2,
  2. G A Michelotti1,
  3. T de Almeida Pereira1,
  4. J Boursier1,3,
  5. L Kruger1,
  6. M Swiderska-Syn1,
  7. G Karaca1,
  8. G Xie1,
  9. C D Guy3,
  10. B Bohnic1,
  11. K R Lindblom4,5,
  12. E Johnson4,5,
  13. S Kornbluth4,5,
  14. A M Diehl1
  1. 1Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
  2. 2Gastroenterology Department, Hospital de Santa Maria, CHLN, Lisbon, Portugal
  3. 3HIFIH Laboratory, UPRES 3859, SFR 4208, LUNAM University, Angers, France
  4. 4Division of Pathology, Duke University Medical Center, Durham, North Carolina, USA
  5. 5Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina, USA
  1. Correspondence to Professor Anna Mae Diehl, Division of Gastroenterology, Department of Medicine, Duke University Medical Center, 595 LaSalle Street, Snyderman Building, Suite 1073, Durham, NC 27710, USA; diehl004{at}mc.duke.edu

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.

Design 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.

  • APOPTOSIS
  • CELL DEATH
  • FATTY LIVER
  • MOLECULAR BIOLOGY
  • NONALCOHOLIC STEATOHEPATITIS

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