Activation of proteinase 3 contributes to nonalcoholic fatty liver disease and insulin resistance

Erik J.M. Toonen, Andreea Manuela Mirea, Cees J. Tack, Rinke Stienstra, Dov B. Ballak, Janna A. Van Diepen, Anneke Hijmans, Triantafyllos Chavakis, Wim H. Dokter, Christine Tn Pham, Mihai G. Netea, Charles A. Dinarello, Leo A.B. Joosten

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Abstract

Activation of inflammatory pathways is known to accompany development of obesity-induced nonalcoholic fatty liver disease (NAFLD), insulin resistance and type 2 diabetes. In addition to caspase-1, the neutrophil serine proteases proteinase 3, neutrophil elastase and cathepsin G are able to process the inactive proinflammatory mediators interleukin (IL)-1β and IL-18 to their bioactive forms, thereby regulating inflammatory responses. In this study, we investigated whether proteinase 3 is involved in obesity-induced development of insulin resistance and NAFLD. We investigated the development of NAFLD and insulin resistance in mice deficient for neutrophil elastase/proteinase 3 and neutrophil elastase/cathepsin G and in wild-type mice treated with the neutrophil serine proteinase inhibitor human α-1 antitrypsin. Expression profiling of metabolically relevant tissues obtained from insulin-resistant mice showed that expression of proteinase 3 was specifically upregulated in the liver, whereas neutrophil elastase, cathepsin G and caspase-1 were not. Neutrophil elastase/proteinase 3-deficient mice showed strongly reduced levels of lipids in the liver after being fed a high-fat diet. Moreover, these mice were resistant to high–fat–diet-induced weight gain, inflammation and insulin resistance. Injection of proteinase 3 exacerbated insulin resistance in caspase-1–/– mice, indicating that proteinase 3 acts independently of caspase-1. Treatment with α-1 antitrypsin during the last 10 d of a 16-wk high-fat diet reduced hepatic lipid content and decreased fasting glucose levels. We conclude that proteinase 3 is involved in NAFLD and insulin resistance and that inhibition of proteinase 3 may have therapeutic potential.

Original languageEnglish
Pages (from-to)202-214
Number of pages13
JournalMolecular Medicine
Volume22
DOIs
StatePublished - Jan 1 2016

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    Toonen, E. J. M., Mirea, A. M., Tack, C. J., Stienstra, R., Ballak, D. B., Van Diepen, J. A., Hijmans, A., Chavakis, T., Dokter, W. H., Pham, C. T., Netea, M. G., Dinarello, C. A., & Joosten, L. A. B. (2016). Activation of proteinase 3 contributes to nonalcoholic fatty liver disease and insulin resistance. Molecular Medicine, 22, 202-214. https://doi.org/10.2119/molmed.2016.00033