The pan‐caspase inhibitor Emricasan (IDN‐6556) decreases liver injury and fibrosis in a murine model of non‐alcoholic steatohepatitis

Abstract

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.

Lipotoxic lethal and sublethal stress signaling in hepatocytes: relevance to NASH pathogenesis

“…This information supports the use of free fatty acids to study lipotoxicity in vitro. We have learned that NASH is a very proapoptotic disease (44), and inhibition of apoptosis may well be therapeutic in this disease (137). Consistent with these observations, palmitate and stearate induce robust apoptosis in hepatocytes (75); saturated fatty acids are more toxic than unsaturated fatty acids, but even unsaturated fatty acids, such as oleate, sensitize hepatocytes to death receptor-mediated apoptosis (14,46).…”

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“…A study from Hepatitis C virus infected patients and in NASH using murine model showed the blockage of hepatocytes apoptosis through administration of Emricasan (IDN-6556), a pan-caspase inhibitor ameliorates liver injury and fibrosis [5,6]. Similar results were found with Cathepsin-B inhibitor R-3032, that attenuate lipotoxicity associated with cholestasis [7].…”

Hepatic neuregulin 4 signaling defines an endocrine checkpoint for steatosis-to-NASH progression

“…Mice with genetic deletion of caspase 8 in hepatocytes exhibited attenuated liver injury, inflammation, and fibrosis following methionine/cholinedeficient (MCD) diet feeding (14). Caspase inhibitors have been shown to be protective in animal models of NASH (15,16). Necroptosis is programmed necrosis that incorporates features of both apoptosis and necrosis (17,18).…”