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Reduced lipoapoptosis, hedgehog pathway activation and fibrosis in caspase-2 deficient mice with non-alcoholic steatohepatitis.

Publication ,  Journal Article
Machado, MV; Michelotti, GA; Pereira, TDA; Boursier, J; Kruger, L; Swiderska-Syn, M; Karaca, G; Xie, G; Guy, CD; Bohinc, B; Lindblom, KR ...
Published in: Gut
July 2015

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.

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Published In

Gut

DOI

EISSN

1468-3288

Publication Date

July 2015

Volume

64

Issue

7

Start / End Page

1148 / 1157

Location

England

Related Subject Headings

  • Real-Time Polymerase Chain Reaction
  • Non-alcoholic Fatty Liver Disease
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Male
  • Liver Cirrhosis
  • Liver
  • Humans
  • Hepatocytes
  • Hedgehog Proteins
 

Citation

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Chicago
ICMJE
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Machado, M. V., Michelotti, G. A., Pereira, T. D. A., Boursier, J., Kruger, L., Swiderska-Syn, M., … Diehl, A. M. (2015). Reduced lipoapoptosis, hedgehog pathway activation and fibrosis in caspase-2 deficient mice with non-alcoholic steatohepatitis. Gut, 64(7), 1148–1157. https://doi.org/10.1136/gutjnl-2014-307362
Machado, M. V., G. A. Michelotti, T de Almeida Pereira, J. Boursier, L. Kruger, M. Swiderska-Syn, G. Karaca, et al. “Reduced lipoapoptosis, hedgehog pathway activation and fibrosis in caspase-2 deficient mice with non-alcoholic steatohepatitis.Gut 64, no. 7 (July 2015): 1148–57. https://doi.org/10.1136/gutjnl-2014-307362.
Machado MV, Michelotti GA, Pereira TDA, Boursier J, Kruger L, Swiderska-Syn M, et al. Reduced lipoapoptosis, hedgehog pathway activation and fibrosis in caspase-2 deficient mice with non-alcoholic steatohepatitis. Gut. 2015 Jul;64(7):1148–57.
Machado, M. V., et al. “Reduced lipoapoptosis, hedgehog pathway activation and fibrosis in caspase-2 deficient mice with non-alcoholic steatohepatitis.Gut, vol. 64, no. 7, July 2015, pp. 1148–57. Pubmed, doi:10.1136/gutjnl-2014-307362.
Machado MV, Michelotti GA, Pereira TDA, Boursier J, Kruger L, Swiderska-Syn M, Karaca G, Xie G, Guy CD, Bohinc B, Lindblom KR, Johnson E, Kornbluth S, Diehl AM. Reduced lipoapoptosis, hedgehog pathway activation and fibrosis in caspase-2 deficient mice with non-alcoholic steatohepatitis. Gut. 2015 Jul;64(7):1148–1157.

Published In

Gut

DOI

EISSN

1468-3288

Publication Date

July 2015

Volume

64

Issue

7

Start / End Page

1148 / 1157

Location

England

Related Subject Headings

  • Real-Time Polymerase Chain Reaction
  • Non-alcoholic Fatty Liver Disease
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Male
  • Liver Cirrhosis
  • Liver
  • Humans
  • Hepatocytes
  • Hedgehog Proteins