Acute phase protein α1-Antitrypsin – a novel regulator of angiopoietin-like protein 4 transcription and secretion

The angiopoietin-like protein 4 (angptl4, also known as peroxisome proliferator-activated receptor (PPAR) gamma induced angiopoietin-related protein) is a multifunctional protein associated with acute phase response. The mechanisms accounting for the increase in angptl4 expression are largely unknown. This study is the first to show that human α1-antitrypsin (A1AT) up-regulates expression and release of angplt4 in human blood adherent mononuclear cells and in primary human lung microvascular endothelial cells in a concentration- and time-dependent manner. Mononuclear cells treated for 1h with A1AT (from 0.1 to 4 mg/ml) increased mRNA of angptl4 from 2 to 174-fold, respectively, relative to controls. In endothelial cells the maximal effect on angptl4 expression was achieved at 8h with 2 mg/ml of A1AT (11-fold induction versus controls). In ten emphysema patients receiving A1AT therapy (Prolastin) plasma angptl4 levels were higher relative to patients without therapy [ng/ml, mean (95% confidence interval) 127.1 (99.5 – 154.6) versus 76.8 (54.8 – 98.8), respectively, p = 0.045] and correlated with A1AT levels. The effect of A1AT on angptl4 expression was significantly diminished in cells pre-treated with a specific inhibitor of ERK1/2 activation (UO126), irreversible and selective PPARγ antagonist (GW9662), or genistein, a ligand for PPARγ. GW9662 did not alter the ability of A1AT to induce ERK1/2 phosphorylation, suggesting that PPARγ is a critical mediator in the A1AT-driven angptl4 expression. In contrast, the forced accumulation of hypoxia inducible factor 1-α, an up-regulator of angptl4 expression, enhanced the effect of A1AT. Thus, acute phase protein A1AT is a physiological regulator of angptl4, another acute phase protein.