The lipid ties of α1-antitrypsin: Structural and functional aspects.

ABSTRACT

α1-antitrypsin (AAT) is an acute-phase protein that functions as an inhibitor of serine proteases, such as neutrophil elastase. A significant body of evidence shows that AAT has a pivotal role in protecting tissues from neutrophil-induced damage, preserving endothelial function, and improving outcomes of cardiovascular and cerebrovascular diseases, though the mechanism of its activity is not fully elucidated. In terms of several significant anti-inflammatory and immunomodulatory properties, AAT's capacity to inhibit elastase has been determined to be non-essential. With the discovery of a role for diverse binding partners in AAT biology, it is intriguing to learn that AAT attaches to cholesterol, fatty acids, lipid rafts, and lipoproteins and conformational changes in its hydrophobic binding site affect its activity. The complex formation of fatty acids or lipoproteins with native or modified AAT impacts its protease inhibitory action as well as its anti-inflammatory properties. As such, AAT-enriched HDL particles exhibit improved anti-inflammatory action. These findings contribute to our understanding of AAT's mechanism of action and may provide a fresh platform for investigating the therapeutic significance of AAT therapy in an informed manner outside of genetic AAT deficiency.