Abstract
IntroductionNon-alcoholic fatty liver disease (NAFLD) is becoming a major health problem worldwide. Inflammation plays an important role in disease pathogenesis and recent studies have shown a potential role for the neutrophil serine proteases (NSPs) proteinase-3 (PR3) and neutrophil elastase (NE) in NAFLD as well as an imbalance between NSPs and their natural inhibitor alpha-1 antitrypsin (AAT). The aim of this study was to investigate whether PR3 and NE plasma concentrations are associated with NAFLD and/or type 2 diabetes.MethodsTo explore this hypothesis we used several cohorts: a cohort of 271 obese individuals with liver steatosis, a cohort of 41 patients with biopsy-proven NAFLD, a cohort of 401 obese type 2 diabetes patients and a cohort of 205 lean healthy controls; and measured PR3 and NE plasma concentrations. In addition, we measured AAT plasma concentrations in order to investigate if the ratios between NSPs and their natural inhibitor were altered in NAFLD and type 2 diabetes when compared to healthy controls.ResultsOur data shows an increase in PR3 and NE concentrations and a decrease in AAT concentrations in obese patients when compared to controls. Moreover, PR3 plasma concentrations are increased in patients with liver steatosis. Furthermore, PR3 and NE concentrations in the liver are associated with the advanced stages of NAFLD characterized by NASH and/ or liver fibrosis. Additionally, PR3 and NE concentrations were up-regulated in patients with type 2 diabetes when compared to lean and obese controls.ConclusionWe conclude that circulating levels of NSPs associate with obesity-related metabolic disorders. Further research is needed to clearly establish the role of these proteases and investigate whether they could be used as non-invasive markers for NAFLD and/or type 2 diabetes.
Highlights
Non-alcoholic fatty liver disease (NAFLD) is becoming a major health problem worldwide
The disease can range from plain liver steatosis to a more severe form called non-alcoholic steatohepatitis (NASH) characterized by liver inflammation and hepatocyte ballooning, which can further progress into liver fibrosis, cirrhosis and even hepatocellular carcinoma (Machado and Cortez-Pinto 2014)
In order to see if the differences observed between these two groups were independent of the presence of type 2 diabetes we corrected for the presence of this disease when comparing them; p-values did not change after correction
Summary
Non-alcoholic fatty liver disease (NAFLD) is becoming a major health problem worldwide. Inflammation plays an important role in disease pathogenesis and recent studies have shown a potential role for the neutrophil serine proteases (NSPs) proteinase-3 (PR3) and neutrophil elastase (NE) in NAFLD as well as an imbalance between NSPs and their natural inhibitor alpha-1 antitrypsin (AAT). Non-alcoholic fatty liver disease (NAFLD) has a prevalence of approximately 25% among the global population (Younossi et al 2016), and is increasing rapidly, in parallel with the increasing prevalence of obesity. The well-known enzyme available for processing and activation of IL-1β is caspase-1, a cysteine protease activated by the NLRP3 inflammasome protein complex. The neutrophil serine proteases (NSPs) proteinase-3 (PR3) and neutrophil elastase (NE) are able to process IL-1 β to its bioactive form independently of caspase-1-NLRP3 inflammasome complex (Mirea et al 2018)
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