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

Fernando J. Barreyro, Silvia Holod, Paola V. Finocchietto, Alejandra M. Camino, Jorge B. Aquino, Alejandra Avagnina, María C. Carreras, Juan J. Poderoso, Gregory James Gores

Research output: Contribution to journalArticle

119 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)953-966
Number of pages14
JournalLiver International
Volume35
Issue number3
DOIs
StatePublished - Mar 1 2015

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Caspase Inhibitors
High Fat Diet
Fatty Liver
Liver Cirrhosis
Wounds and Injuries
Apoptosis
Hepatocytes
Liver
Reverse Transcription
Fibrosis
CXC Chemokines
Hepatic Stellate Cells
Polymerase Chain Reaction
Cysteine Proteases
3-(2-(2-tert-butylphenylaminooxalyl)aminopropionylamino)-4-oxo-5-(2,3,5,6-tetrafluorophenoxy)pentanoic acid
Caspase 8
Chemokine CCL2
Hydroxyproline
In Situ Nick-End Labeling
Caspases

Keywords

  • Apoptosis
  • Caspase inhibitor
  • Emricasan
  • Fibrosis
  • Non-alcoholic fatty liver disease

ASJC Scopus subject areas

  • Hepatology

Cite this

The pan-caspase inhibitor Emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitis. / Barreyro, Fernando J.; Holod, Silvia; Finocchietto, Paola V.; Camino, Alejandra M.; Aquino, Jorge B.; Avagnina, Alejandra; Carreras, María C.; Poderoso, Juan J.; Gores, Gregory James.

In: Liver International, Vol. 35, No. 3, 01.03.2015, p. 953-966.

Research output: Contribution to journalArticle

Barreyro, FJ, Holod, S, Finocchietto, PV, Camino, AM, Aquino, JB, Avagnina, A, Carreras, MC, Poderoso, JJ & Gores, GJ 2015, 'The pan-caspase inhibitor Emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitis', Liver International, vol. 35, no. 3, pp. 953-966. https://doi.org/10.1111/liv.12570
Barreyro, Fernando J. ; Holod, Silvia ; Finocchietto, Paola V. ; Camino, Alejandra M. ; Aquino, Jorge B. ; Avagnina, Alejandra ; Carreras, María C. ; Poderoso, Juan J. ; Gores, Gregory James. / The pan-caspase inhibitor Emricasan (IDN-6556) decreases liver injury and fibrosis in a murine model of non-alcoholic steatohepatitis. In: Liver International. 2015 ; Vol. 35, No. 3. pp. 953-966.
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abstract = "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.",
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AU - Holod, Silvia

AU - Finocchietto, Paola V.

AU - Camino, Alejandra M.

AU - Aquino, Jorge B.

AU - Avagnina, Alejandra

AU - Carreras, María C.

AU - Poderoso, Juan J.

AU - Gores, Gregory James

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