The pan‐caspase inhibitor Emricasan (IDN‐6556) decreases liver injury and fibrosis in a murine model of non‐alcoholic steatohepatitis
Open Access
- 6 June 2014
- journal article
- Published by Wiley in Liver International
- Vol. 35 (3), 953-966
- https://doi.org/10.1111/liv.12570
Abstract
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. C57/BL6J-mice were fed regular chow or high fat diet (HFD) for 20 weeks. All mice were treated with vehicle or Emricasan. 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. 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.Funding Information
- Agencia Nacional para la Promoción Científica y Tecnológica (PICT-O UNAM-2011)
This publication has 69 references indexed in Scilit:
- PUMA-mediated apoptosis drives chemical hepatocarcinogenesis in miceJournal of Hepatology, 2011
- A position statement on NAFLD/NASH based on the EASL 2009 special conferenceJournal of Hepatology, 2010
- High-fructose, medium chain trans fat diet induces liver fibrosis and elevates plasma coenzyme Q9 in a novel murine model of obesity and nonalcoholic steatohepatitisJournal of Hepatology, 2010
- CD95 promotes tumour growthNature, 2010
- Increased fructose consumption is associated with fibrosis severity in patients with nonalcoholic fatty liver diseaseJournal of Hepatology, 2010
- Hepatocyte-specific deletion of the antiapoptotic protein myeloid cell leukemia-1 triggers proliferation and hepatocarcinogenesis in miceJournal of Hepatology, 2009
- Mechanisms of Hepatic FibrogenesisGastroenterology, 2008
- TRAIL mediates liver injury by the innate immune system in the bile duct-ligated mouseJournal of Hepatology, 2008
- Palmitoylation of CD95 facilitates formation of SDS-stable receptor aggregates that initiate apoptosis signalingThe EMBO Journal, 2006
- Design and validation of a histological scoring system for nonalcoholic fatty liver diseaseJournal of Hepatology, 2005