Activation of Proteinase 3 Contributes to Nonalcoholic Fatty Liver Disease and Insulin Resistance View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2016-01

AUTHORS

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 T N Pham, Mihai G Netea, Charles A Dinarello, Leo A B Joosten

ABSTRACT

Activation of inflammatory pathways is known to accompany development of obesity-induced non-alcoholic 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 pro-inflammatory mediators IL-1β and IL-18 to their bioactive forms, thereby regulating inflammatory responses. In the present 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 alpha-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 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 alpha-1 antitrypsin during the last 10 days of a 16 week 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. More... »

PAGES

202-214

Identifiers

URI

http://scigraph.springernature.com/pub.10.2119/molmed.2016.00033

DOI

http://dx.doi.org/10.2119/molmed.2016.00033

DIMENSIONS

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PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/27261776


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