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

lesterol transport during the acute phase response but not group IIA secretory phospholipase A 2 . J. Lipid Res . 2010. 51: 743-754. Supplementary key words feces • infl ammation • sepsis • atherosclerosis • miceEpidemiological studies established a strong inverse association between plasma HDL cholesterol levels and the risk of atherosclerotic cardiovascular disease (CVD) ( 1, 2 ). A major anti-atherogenic activity of HDL is regarded to be reverse cholesterol transport (RCT), a process comprising removal of excess cholesterol from peripheral cells, most importantly macrophage foam cells in atherosclerotic lesions, and transport back to the liver for subsequent excretion into bile and feces ( 2, 3 ). Understanding the pathophysiological factors regulating RCT is therefore of prime importance.Infl ammation is strongly linked to atherosclerosis ( 4-6 ). The atherosclerotic plaque itself is increasingly considered a site of chronic infl ammation within the vessel wall ( 5, 7 ). In addition, markers of infl ammation are elevated in plasma of patients with established atherosclerotic CVD, and circulating levels of several acute phase proteins 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 A 2 (sPLA 2 , 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 sPLA 2 . However, reduced bile acid formation and decreased biliary sterol excretion might represent major contributing factors to decreased RCT in infl ammation. -Annema, W., N. Nijstad, M. Tölle, J. F. de Boer, R. V. C. Buijs, P. Heeringa, M. van der Giet, and U. J. F. Tietge. Myeloperoxidase and serum amyloid A contribute to impaired in vivo reverse cho-

Impact of individual acute phase serum amyloid A isoforms on HDL metabolism in mice

“…Native SAA has been shown to alter both the protein and lipid composition of AP-HDL (14) and also to influence HDL remodeling (15) and cholesterol efflux from cells (16). Although several studies have reported that inflammation impedes reverse cholesterol transport to the liver (17)(18)(19), we have recently shown that impairment of reverse cholesterol transport in mice during inflammation does not depend on SAA (20). An absence of SAA also did not affect atherosclerosis in an apoE-deficient mouse model (21).…”

Proteomic diversity of high density lipoproteins: our emerging understanding of its importance in lipid transport and beyond

“…SAA can increase in expression up to 1000-fold within 24 h of onset of APR in certain animal models ( 44 ). SAA appears to work toward preserving the cholesterol content of peripheral tissues by reducing HDL's ability to promote cholesterol effl ux ( 45 ) and whole-body transfer of macrophage cholesterol to the feces ( 46 ). This may enhance local repair processes.…”

“…This may enhance local repair processes. However, SAA increases both holoparticle uptake of HDL ( 46 ) and selective uptake of cholesteryl ester by the liver and adrenals via SR-BI ( 47 ). Because the adrenals rely heavily on HDLderived cholesterol for steroid hormone production, Fig.…”

High-Density Lipoproteins

“…161 By contrast, Malle's group found reduced cholesterol efflux capacity by both SAA-enriched HDLs and lipid-free SAA. 162, 163 Interestingly, adenovirus-mediated expression of SAA reduced the fecal excretion of macrophage-derived cholesterol in mice, 164 indicating that SAA interferes with macrophage reverse cholesterol transport, possibly by mechanisms other than cholesterol efflux. In addition, SAA was found to reduce the antioxidative capacity of HDLs by displacing PON1 and PAF-AH.…”

“…180 The observation of decreased macrophage cholesterol transport in mice after injection of MPO brought in vivo evidence for the pathophysiological relevance of the previous in vitro findings. 164 In addition to the loss of protective activities on cholesterol efflux and esterification as well as endothelial function and survival, MPO-modified HDL gains pro-inflammatory activities as it induces NF-κB activation and VCAM-1 expression in endo-Multifunctional but Vulnerable HDL of 27-hydroxycholesterol in HDLs beyond the concentration of cholesterol. 219 The phospholipid content and composition have a strong effect on the size, shape, fluidity, and surface charge of HDLs.…”