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Mol Med. 2016 May 24;22. doi: 10.2119/molmed.2016.00033.

Activation of proteinase 3 contributes to Non-alcoholic Fatty Liver Disease (NAFLD) and insulin resistance.

Author information

1
Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
2
Nutrition, Metabolism and Genomics Group, Wageningen University and Research Centre, Wageningen, The Netherlands.
3
Department of Clinical Pathobiochemistry, University Clinic Carl-Gustav-Carus, Technische Universität Dresden, Dresden, Germany.
4
Synthon Research Laboratories, Nijmegen, The Netherlands.
5
Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO, USA.
6
Department of Medicine, University of Colorado Denver, Aurora, CO, USA.

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.

KEYWORDS:

diabetes; immunology; inflammation; liver disease; metabolism

PMID:
27261776
PMCID:
PMC5004724
DOI:
10.2119/molmed.2016.00033
[Indexed for MEDLINE]
Free PMC Article

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