Activation of proteinase 3 contributes to Non-alcoholic Fatty Liver Disease (NAFLD) and insulin resistance.
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.
Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
Erik J M
EJ
Toonen
Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
Andreea-Manuela
AM
Mirea
Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
Cees J
CJ
Tack
Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.|Nutrition, Metabolism and Genomics Group, Wageningen University and Research Centre, Wageningen, The Netherlands.
Rinke
R
Stienstra
Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
Dov B
DB
Ballak
Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
Janna A
JA
van Diepen
Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
Anneke
A
Hijmans
Department of Clinical Pathobiochemistry, University Clinic Carl-Gustav-Carus, Technische Universität Dresden, Dresden, Germany.
Triantafyllos
T
Chavakis
Synthon Research Laboratories, Nijmegen, The Netherlands.
Wim H
WH
Dokter
Department of Medicine, Division of Rheumatology, Washington University School of Medicine, St. Louis, MO, USA.
Christine T N
CT
Pham
Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
Mihai G
MG
Netea
Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.|Department of Medicine, University of Colorado Denver, Aurora, CO, USA.
Charles A
CA
Dinarello
Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands.
Leo A B
LA
Joosten
D000818:Animals; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D019272:Leukocyte Elastase / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D053146:Myeloblastin / Q000235:genetics* / Q000378:metabolism*; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics / Q000378:metabolism*; D009765:Obesity / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism*; D015854:Up-Regulation
C000622097:Prtn3 protein, mouse; D012697:Serine Endopeptidases; D019272:Leukocyte Elastase; D053146:Myeloblastin
diabetes; immunology; inflammation; liver disease; metabolism