HDL Remodeling During the Acute Phase Response

Abstract

Objective-The purpose of this study was to examine the interactive action of serum amyloid A (SAA), group IIA secretory phospholipase A 2 (sPLA 2 -IIA), and cholesteryl ester transfer protein (CETP) on HDL remodeling and cholesterol efflux during the acute phase (AP) response elicited in humans after cardiac surgery. Methods and Results-Plasma was collected from patients before (pre-AP), 24 hours after (AP-1 d), and 5 days after cardiac surgery (AP-5 d). SAA levels were increased 16-fold in AP-1 d samples. Key Words: SAA Ⅲ HDL Ⅲ CETP Ⅲ apoA-I Ⅲ inflammation I nflammation induces major changes in HDL levels and composition. Mediators of inflammation such as tumor necrosis factor (TNF)-␣ and interleukin (IL)-6 induce expression of serum amyloid A 1 and group IIA secretory phospholipase A 2 (sPLA 2 -IIA), 2 which dramatically alter HDL apolipoprotein content and levels, respectively. Acute phase SAA in the plasma is associated with HDL, where it can comprise the major apolipoprotein. 3 The increase in sPLA 2 -IIA activity results in hydrolysis of HDL surface phospholipids and a decrease in HDL particle size. 4 The plasma cholesteryl ester transfer protein (CETP) is an integral component of reverse cholesterol transport and regulates HDL cholesterol concentrations. By promoting the transfer of cholesteryl esters (CE) from HDL to apoB-containing lipoprotein particles, HDL-derived CE is taken up via the LDL receptor and cleared by the liver. 5 An additional result of CETP action is the generation of lipid-poor apoA-I, 6 a key acceptor in ATP-binding cassette transporter AI (ABCA1)-mediated lipid efflux. 7 The presence of SAA on HDL holds the potential to impact both the CE transfer and the apoA-I liberating ability of CETP. sPLA 2 -IIA could also impact the latter action of CETP as apoA-I was shown to dissociate more readily from CETP-remodeled reconstituted HDL after hydrolysis by bee venom phospholipase A 2 . 8 Given the centrality of inflammation in atherogenesis, there is a paucity of information regarding CETP function when acute phase HDL is the "substrate." In the present study, we used plasma from patients undergoing cardiac surgery with cardiopulmonary bypass as a "standardized" insult where the oxygenator membrane activates macrophages to produce cytokines. 9 We characterized the SAAcontaining acute phase (AP) HDL during the acute phase to define the polydisperse HDL "substrate" that CETP would encounter. We further investigated CETP function in the acute phase, particularly as it relates to the presence of SAA and sPLA 2 on AP HDL, with respect to its CE transfer and apoA-I liberating functions.Teleologically, the dramatic changes in HDL composition and metabolism during inflammation must serve a short-term purpose to allow the organism to survive a noxious assault. Acute tissue injury results in cell death with large quantities of cell membranes rich in phospholipids and cholesterol generated. Macrophages are mobilized to such sites, ingest these fragments, and acquire considerable lipid load. 10 We thus e...

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

“…Aliquots (40 l) of the diluted samples were injected into a Superose 6 10/300 (GE Healthcare Life Sciences) chromatography (12,13). 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).…”

“…A number of HDL-modifying processes can potentially generate small lipid-free/lipid-poor apoA-I particles. These include HDL remodeling within plasma, for example, through the actions or combined actions of CETP, hepatic and endothelial lipase, and SR-BI (15,66,67). Like apoA-I, apoA-II is also cleared through the kidney and can be reabsorbed through cubilin/megalin receptors.…”

Dysfunctional HDL: From Structure-Function-Relationships to Biomarkers

“…It has been suggested that such remodeling may compromise the antiatherogenic functions of HDL (Jahangiri et al 2009). These observations have prompted explorative studies into HDL composition.…”

Acute Phase Proteins: Structure and Function Relationship

“…During an acute phase response, SAA becomes the main apolipoprotein on HDL, and the displaced Apo-AI then becomes available to extract cellular free cholesterol upon interacting with cell-surface (Tam et al, 2008). For this reason, and because SAA itself may also extract cholesterol from cells (Stonik et al, 2004), it is thought that SAA plays a role in cholesterol metabolism and atherosclerosis (Jahangiri et al, 2009). Whether SAA is pro-or anti-atherogenic is not yet clear, since putative beneficial effects on cholesterol metabolism may be mitigated by effects on inflammation-a known risk factor for atherosclerosis (Libby et al, 2002).…”