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Amelioration of hepatic inflammation in a mouse model of NASH using a dithiocarbamate derivative

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Abstract

Purpose

The process whereby liver inflammation develops in non-alcoholic steatohepatitis (NASH) is not fully understood. While modification of the inflammatory milieu is an attractive target to prevent the development of hepatocellular injury, most antiinflammatory agents have proven ineffective in this setting. Tetraethylthiuram disulfide (TDSF) is able to induce S-glutathionylation of NF-κB along with critical signaling proteins involved with inflammation, especially when complexed with a heavy metal. For this reason, we hypothesized that administration of TDSF would function to ameliorate necroinflammatory activity in a mouse model of NASH.

Methods

Mice were divided into five groups and received control chow versus a methionine-choline-deficient diet. After 6 weeks of TDSF versus sham gavage, animals were necropsied. Using conventional H&E staining, livers were examined using the Brunt scoring system by a hepatopathologist blinded to treatment groups. Validated mouse primer sets were used for quantitative real-time PCR to evaluate changes in mRNA expression.

Results

Livers treated with TDSF demonstrated a qualitative reduction in lobular inflammation, lipogranuloma formation, and Kupffer cell accumulation, but not steatosis. Significant reductions in inflammatory transcripts for α-1-collagen, TGF-β, Mmp2, MCP-1, and TNF-1α were also observed.

Conclusions

Animals treated with TDSF exhibit a reduction in lobular inflammation that is independent of lipid accumulation when administered MCD diet. Similar reductions are seen in several inflammatory transcripts associated with NASH. Additional work in this area may reveal a therapeutic role for TDSF or similar agents in curtailing inflammatory signaling within the liver.

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Authors and Affiliations

  1. Division of Transplantation, Department of Surgery, University of Texas, Southwestern, 5323 Harry Hines Blvd, Dallas, TX, USA

    Jason J. Schwartz

  2. Department of General Surgery, University of Utah, Salt Lake City, UT, USA

    Jason J. Schwartz, Elaine Hillas, Ann Phan, Heather Thiesset, Matthew Firpo & Jeffrey Sorensen

  3. Department of Pathology, University of Utah, Salt Lake City, UT, USA

    Lyska Emerson

  4. Georgia Health Sciences University, Section of Pulmonology, Augusta, GA, USA

    Thomas Kennedy

  5. Department of Gastroenterology and Hepatology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

    Mary Rinella

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  1. Jason J. Schwartz
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Correspondence to Jason J. Schwartz.

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Schwartz, J.J., Emerson, L., Hillas, E. et al. Amelioration of hepatic inflammation in a mouse model of NASH using a dithiocarbamate derivative. Hepatol Int 7, 600–609 (2013). https://doi.org/10.1007/s12072-013-9426-3

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  • DOI: https://doi.org/10.1007/s12072-013-9426-3

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