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...

The long-chain (n-3) polyunsaturated fatty acids (PUFA) have been reported to exhibit health benefits and healing properties for the gastrointestinal tract. The aim of this study was to investigate the effects of dietary fish oil supplementation on the in vitro contractility of gut tissue. Rats (9 wk old) were fed synthetic diets supplemented with 170 g/kg Sunola oil (SO; 850 g/kg as oleic acid [18:1(n-9)]) or with 100 g/kg of the SO replaced by saturated animal fat (SF) or fish oil (FO) for 4 wk. In the colon, there was no difference in the sensitivity (50% effective concentration) or the maximal contraction among the three dietary groups induced by acetylcholine or 8-iso-prostaglandin (PG)E(2) with the rat colon being relatively insensitive to the thromboxane mimetic U-46619. However, in the ileum, the FO group had greater maximal contractions induced by acetylcholine and 8-iso-PGE(2) compared with the SO and SF groups (P < 0.05), and greater maximal contractions induced by PGE(2), PGF(2alpha) and U-46619 compared with the SF group (P < 0.05). FO feeding increased the incorporation of (n-3) PUFA (eicosapentaenoic [20:5(n-3)], docosapentaenoic [22:5(n-3)] and docosahexaenoic acids [22:6(n-3) primarily at the expense of (n-6) PUFA (linoleic [18:2(n-6)] and arachidonic acids [20:4(n-6)]) in the ileum and colon phospholipid fatty acids (P < 0.05). The FO group had a lower cecal digesta pH (P < 0.001) and a greater butyrate concentration than the SF group (P < 0.05). These results suggest that dietary (n-3) PUFA may modulate the contractility of the small intestine.

Context:In mice, scavenger receptor class B, type I (SR-BI) receptor protein deficiency is associated with elevated high-density lipoprotein (HDL)-cholesterol (HDL-C) levels.Objective: Our objective was to determine the relationship between SR-BI protein and HDL-C levels in humans.Design: This was a prospective study of adults with hyperalphalipoproteinemia. Fasting blood was obtained for lipid and lipoprotein measurement, genomic DNA, and monocyte-derived macrophages. SR-BI protein levels were measured by Western blots, and SR-BI activity was measured by cholesteryl ester (CE) uptake of each donor's radiolabeled HDL with their monocyte-derived macrophages, or by degradation and specific cell association of dual-labeled HDL in vitro. Setting:The study was performed in a tertiary university teaching hospital. Results:The mean age was 57.2 Ϯ 10.9 yr (n ϭ 65). SR-BI protein levels were inversely associated with HDL-C levels (P Ͻ 0.002), HDL particle size (P Ͻ 0.05), and positively associated with CE uptake (P Ͻ 0.004); there was no association with plasma apolipoprotein levels. SR-BI protein levels (P ϭ 0.01) were independent predictors of HDL-C levels. Subjects who were carriers of the A allele for the rs4238001 (glycine to serine at position 2) polymorphism [single nucleotide polymorphism (SNP)] had lower SR-BI protein levels (P ϭ 0.01), whereas carriers of the C allele for the rs2278986 SNP also had lower SR-BI protein levels (P ϭ 0.02). Body mass index (P ϭ 0.05), rs4238001 (P ϭ 0.01), and rs2278986 (P ϭ 0.01) SNPs were independent predictors of SR-BI protein levels. In vitro studies of murine macrophages stably expressing the glycine to serine at position 2 SNP showed less degradation (P Ͻ 0.0004) and specific cell association (P Ͻ 0.0004) of [ 125 I, 3 H]-CE-labeled HDL.Conclusions: SR-BI protein has an independent effect on HDL-C levels in women with hyperalphalipoproteinemia. Two SNPs were significantly associated with lower SR-BI protein levels. (J Clin Endocrinol

Purpose of review Inflammation and the concomitant acute phase response induce marked changes in the lipoprotein profile, particularly the HDL fraction. This review describes the transfer proteins and lipases that remodel HDL and regulate its plasma levels, discusses the changes occurring in their activities during inflammation, and the influence of this altered remodeling on HDL function. The review will also discuss the contribution of the ABC transporters to the protective actions of HDL. Recent findings Studies using different models showed that remodeling of AP HDL in vitro generates pre-beta migrating particles capable of cholesterol efflux. Induction of the APR in humans resulted in a reduction of HDL phospholipids without a change in HDL-cholesterol. However, the capacity of HDL to promote cholesterol efflux ex vivo was impaired. Studies with ABCA1 and ABCG1 knock-out mice demonstrated anti-inflammatory roles for these transporters by virtue of reducing cell membrane free cholesterol and lipid raft content, thus attenuating pro-inflammatory signaling pathways. Summary It is well known that HDL has anti-inflammatory properties which are diminished during inflammation. AP HDL contains SAA which can be liberated during remodeling by CETP and sPLA2, or other inflammatory factors. The ability of SAA and apoA-I to promote cholesterol efflux may confer protective effects during the APR.