Myeloperoxidase and serum amyloid A contribute to impaired in vivo reverse cholesterol transport during the acute phase response but not group IIA secretory phospholipase A2

Abstract

Atherosclerosis is linked to infl ammation. HDL protects against atherosclerotic cardiovascular disease, mainly by mediating cholesterol effl ux and reverse cholesterol transport (RCT). The present study aimed to test the impact of acute infl ammation as well as selected acute phase proteins on RCT with a macrophage-to-feces in vivo RCT assay using intraperitoneal administration of [3 H]cholesterol-labeled macrophage foam cells. In patients with acute sepsis, cholesterol effl ux toward plasma and HDL were signifi cantly decreased (P < 0.001). In mice, acute infl ammation (75 μg/mouse lipopolysaccharide) decreased [3 H] cholesterol appearance in plasma (P < 0.05) and tracer excretion into feces both within bile acids (-84%) and neutral sterols (-79%, each P < 0.001). In the absence of systemic infl ammation, overexpression of serum amyloid A (SAA, adenovirus) reduced overall RCT (P < 0.05), whereas secretory phospholipase A2 (sPLA2, transgenic mice) had no effect. Myeloperoxidase injection reduced tracer appearance in plasma (P < 0.05) as well as RCT (-36%, P < 0.05). Hepatic expression of bile acid synthesis genes (P < 0.01) and transporters mediating biliary sterol excretion (P < 0.01) was decreased by infl ammation. In conclusion, our data demonstrate that acute infl ammation impairs cholesterol effl ux in patients and macrophage-to-feces RCT in vivo in mice. Myeloperoxidase and SAA contribute to a certain extent to reduced RCT during infl ammation but not sPLA2. However, reduced bile acid formation and decreased biliary sterol excretion might represent major contributing factors to decreased RCT in infl ammation. Copyright © 2010 by the American Society for Biochemistry and Molecular Biology, Inc.