Reduced lipoapoptosis, hedgehog pathway activation and fibrosis in caspase-2 deficient mice with non-alcoholic steatohepatitis
Contribuinte(s) |
Laboratoire HIFIH ; Université d'Angers (UA) |
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Data(s) |
2015
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Resumo |
International audience <p>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.</p><p>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.</p><p>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.</p><p>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.</p> |
Identificador |
hal-01392300 https://hal.archives-ouvertes.fr/hal-01392300 DOI : 10.1136/gutjnl-2014-307362 OKINA : ua12792 |
Idioma(s) |
en |
Publicador |
HAL CCSD |
Relação |
info:eu-repo/semantics/altIdentifier/doi/10.1136/gutjnl-2014-307362 |
Fonte |
ISSN: 1468-3288 Gut https://hal.archives-ouvertes.fr/hal-01392300 Gut, 2015, 64 (7), pp.1148-1157. <10.1136/gutjnl-2014-307362> |
Palavras-Chave | #[SDV] Life Sciences [q-bio] |
Tipo |
info:eu-repo/semantics/article Journal articles |