Human secretory phospholipase A2 mediates decreased plasma levels of HDL cholesterol and ApoA-I in response to inflammation in human ApoA-I transgenic mice

Objective-Plasma levels of high density lipoprotein (HDL) cholesterol and apolipoprotein (apo)A-I are decreased in inflammatory states. Secretory phospholipase A(2) (sPLA(2)), an acute-phase protein, may play a key role in the pathophysiology of this phenomenon. Methods and Results-To investigate the effects of sPLA(2) on human-like HDL particles in vivo, we generated transgenic mice overexpressing human apoA-I and human sPLA(2) (apoA-I/sPLA(2) mice). Compared with apoA-I mice, apoA-I/sPLA(2) mice had significantly lower plasma levels of phospholipids, HDL cholesterol, and apoA-I (each P<0.01). HDL from apoA-I/sPLA(2) mice was significantly depleted in phospholipids and cholesteryl esters (each P<0.001) but was enriched in protein and triglycerides (each P<0.001). As assessed by gel filtration and nondenaturing gel electrophoresis, sPLA(2) overexpression in apoA-I mice resulted in a dramatic shift of the HDL particle size toward smaller particles. Furthermore, virtually all plasma sPLA(2) in apoA-I/sPLA(2) mice was found in association with the HDL fraction. The acute-phase response was induced in apoA-I/sPLA(2) double-transgenic and apoA-I single-transgenic mice by intraperitoneal lipopolysaccharide (LPS) injection. Plasma sPLA(2) was significantly increased after LPS injection in apoA-I/sPLA(2) mice. Twelve hours after LPS administration, plasma total cholesterol, HDL cholesterol, apoA-I, and phospholipids were unchanged in apoA-I transgenic control mice but had decreased significantly in the apoA-I/sPLA(2), mice (-57%, -62%, and -54%, -61%, respectively; each P<0.001). Both groups of mice had increased plasma levels of serum amyloid A (SAA) in response to LPS. To test the hypothesis that SAA may be an in vivo activator of sPLA(2), we specifically overexpressed SAA in apoA-I/sPLA(2) mice by means of liver-directed gene transfer. Despite high plasma levels of SAA, plasma lipid and lipoprotein profiles were not different than those in control mice. Conclusions-These results in a mouse model of human-like HDL indicate that sPLA(2) expression significantly influences HDL particle size and composition and demonstrate that an induction of sPLA(2) is required for the decrease in plasma HDL cholesterol in response to inflammatory stimuli in mice and that this effect is independent of SAA.