Review Article | Published:

Caspases in metabolic disease and their therapeutic potential

Cell Death & Differentiationvolume 25pages10101024 (2018) | Download Citation

Abstract

Caspases, a family of cysteine-dependent aspartate-specific proteases, are central to the maintenance of cellular and organismal homoeostasis by functioning as key mediators of the inflammatory response and/or apoptosis. Both metabolic inflammation and apoptosis play a central role in the pathogenesis of metabolic disease such as obesity and the progression of nonalcoholic steatohepatisis (NASH) to more severe liver disease. Obesity and nonalcoholic fatty liver disease (NAFLD) are the leading global health challenges associated with the development of numerous comorbidities including insulin resistance, type-2 diabetes and early mortality. Despite the high prevalence, current treatment strategies including lifestyle, dietary, pharmaceutical and surgical interventions, are often limited in their efficacy to manage or treat obesity, and there are currently no clinical therapies for NAFLD/NASH. As mediators of inflammation and cell death, caspases are attractive therapeutic targets for the treatment of these metabolic diseases. As such, pan-caspase inhibitors that act by blocking apoptosis have reached phase I/II clinical trials in severe liver disease. However, there is still a lack of knowledge of the specific and differential functions of individual caspases. In addition, cross-talk between alternate cell death pathways is a growing concern for long-term caspase inhibition. Evidence is emerging of the important cell-death-independent, non-apoptotic functions of caspases in metabolic homoeostasis that may be of therapeutic value. Here, we review the current evidence for roles of caspases in metabolic disease and discuss their potential targeting as a therapeutic strategy.

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Acknowledgements

The caspase work in our laboratory was supported by the National Health and Medical Research Council (NHMRC) of Australia project grants 1021456 and 1043057, a NHMRC Early Career Research Fellowship to CHW (1073771) and a NHMRC Senior Principal Research Fellowship to SK (1103006).

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Author notes

  1. Edited by G. Melino.

Affiliations

  1. Centre for Cancer Biology, University of South Australia & SA Pathology, Adelaide, SA, 5001, Australia

    • Claire H Wilson
    •  & Sharad Kumar

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Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding authors

Correspondence to Claire H Wilson or Sharad Kumar.

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DOI

https://doi.org/10.1038/s41418-018-0111-x