Alpha-1-antitrypsin as candidate for treating NAFLD

Summary of Mirea, A et al; IL-1 Family Cytokine Pathways Underlying NAFLD: Towards New Treatment Strategies. Trends in Molecular Medicine 2018; Volume 24, Issue 5, Pages 458-471 . For the full article, click here.
Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Eventhough underlying mechanisms are not fully understood, pahways responsible for the activation of inflammatory cytokines like TNF and members of the IL-1 cytokine family are key in the development of NAFLD. Recent studies reported that not only the inflammasome-caspase-1 pathway is responsible for the activation of proinflammatory cytokines: neutrophil serine proteases (NSPs) are as well. This opinion article describes new insights about the NSPs as potent cytokine activators that contribute to liver disease progression.

Why Alpha-1-antitrypsin?

Alpha-1-antitrypsin (AAT) is a natural occuring serine peptidase inhibitor produced by the liver of both inflammasome-dependent and independent cytokine activation pathways. It is the most abundant circulating protease inhibitor known. It mainly targets enzymes released by neutrophils, especially neutrophil elastase (NE) but also proteinase 3 (PR3) and Cathepsin G (CG). These NSPs are stored in the azurophilic granules of neutrophils. When neutrophils are activated, NSPs will be released and can activate for example proinflammatory cytokines. In the extracellular matrix AAT can inhibit NSPs and this leads to the inhibition of cytokine activation. A deficit of AAT is responsible for insufficient inhibition of NSPs and thus for inflammation-induced liver diseases. In patients, AAT has already been shown to be a succesful therapy in COPD and cystic fybrosis: Administration of AAT in patients with COPD or cystic fybrosis has proven efficient in inhibiting neutrophil elastase activity in the lung function.
Since AAT is a potent inducer of IL-1Ra it is a reason to consider that this protein is a good candidate for treating IL-1-mediated diseases.