The Pan-Caspase Inhibitor Emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitis
| Autor: | Gregory J. Gores, Silvia Holod, Jorge B. Aquino, Alejandra M. Camino, Fernando Barreyro, Juan José Poderoso, Paola Finocchietto, Alejandra Avagnina, Maria Cecilia Carreras |
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| Jazyk: | angličtina |
| Rok vydání: | 2015 |
| Předmět: |
Male
Pathology medicine.medical_specialty CIENCIAS MÉDICAS Y DE LA SALUD Caspase inhibitor Drug Evaluation Preclinical Apoptosis Biology Diet High-Fat Hepatitis Fibrosis Non-alcoholic Fatty Liver Disease medicine Animals Pentanoic Acids Liver injury Caspase inhibitors Hepatology Emricasan Non alcoholic purl.org/becyt/ford/3.1 [https] Bioquímica y Biología Molecular medicine.disease Caspase Inhibitors Mice Inbred C57BL Medicina Básica Disease Models Animal Liver Murine model Hepatocytes purl.org/becyt/ford/3 [https] Steatohepatitis Non-alcoholic fatty liver disease |
| Zdroj: | CONICET Digital (CONICET) Consejo Nacional de Investigaciones Científicas y Técnicas instacron:CONICET |
| DOI: | 10.1111/liv.12570/abstract |
| Popis: | BACKGROUND & AIMS: Hepatocyte apoptosis, the hallmark of non-alcoholic steatohepatitis (NASH) contributes to liver injury and fibrosis. Although, both the intrinsic and extrinsic apoptotic pathways are involved in the pathogenesis of NASH, the final common step of apoptosis is executed by a family of cysteine-proteases termed caspases. Thus, our aim was to ascertain if administration of Emricasan, a pan-caspase inhibitor, ameliorates liver injury and fibrosis in a murine model of NASH. METHODS: C57/BL6J-mice were fed regular chow or high fat diet (HFD) for 20 weeks. All mice were treated with vehicle or Emricasan. RESULTS: Mice fed a HFD diet demonstrate a five-fold increase in hepatocyte apoptosis by the TUNEL assay and a 1.5-fold and 1.3-fold increase in caspase-3 and-8 activities respectively; this increase in apoptosis was substantially attenuated in mice fed a HFD treated with Emricasan (HFD-Em). Likewise, liver injury and inflammation were reduced in mice fed HFD-Em as compare to HFD by measuring serum aspartate aminotransferase and alanine aminotransferase levels, NAS histological score and IL 1-β, TNF-α, monocyte chemoattractant protein (MCP-1) and C-X-C chemokine ligand-2 (CXCL2) quantitative reverse-transcription polymerase chain reaction (qPCR). These differences could not be attributed to differences in hepatic steatosis as liver triglycerides content were similar in both HFD groups. Hepatic fibrosis was reduced by Emricasan in HFD animals by decreasing αSMA (a marker for hepatic stellate cell activation), fibrosis score, Sirius red staining, hydroxyproline liver content and profibrogenic cytokines by qPCR. CONCLUSION: In conclusion, these data demonstrate that in a murine model of NASH, liver injury and fibrosis are suppressed by inhibiting hepatocytes apoptosis and suggests that Emricasan may be an attractive antifibrotic therapy in NASH. Fil: Barreyro, Fernando Javier. Universidad Nacional de Misiones. Facultad de Ciencias Exactas, Químicas y Naturales. Departamento de Microbiología; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Metabolismo del Oxígeno; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Holod, Silvia. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Metabolismo del Oxígeno; Argentina Fil: Finocchietto, Paola Vanesa. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Metabolismo del Oxígeno; Argentina Fil: Camino, Alejandra M.. DIM Clínica Privada; Argentina Fil: Aquino, Jorge Benjamin. Universidad Austral; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Avagnina, Alejandra. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; Argentina Fil: Carreras, Maria Cecilia. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Metabolismo del Oxígeno; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Poderoso, Juan José. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín. Laboratorio de Metabolismo del Oxígeno; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Gores, Gregory J.. Mayo Clinic College of Medicine; Estados Unidos |
| Databáze: | OpenAIRE |
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